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Availability of data and materials {29} | It is planned to make anonymous trial data on which scientific publications are based and all anonymous primary data publicly available for re- and meta-analyses after completion of the trial in an appropriate repository. | PMC9890770 | ||
Declarations | PMC9890770 | |||
Ethics approval and consent to participate {24} | MAY, RECRUITMENT | According to § 15 of the Professional Code for Physicians in Germany (Berufsordnung für die in Deutschland tätigen Ärztinnen und Ärzte), the coordinating investigator has consulted the Ethics Committee (EC) of the University of Ulm before the start of the trial. Approval was granted on 23 May 2022 (Number 76/22). Also, all other participating sites will or have already consulted their responsible ethics committees, before recruitment is started at the respective site. Any changes have to be documented in a written amendment. They will be restricted to exceptional cases. Amendments then become part of the clinical trial protocol. The EC will be informed of all subsequent protocol amendments in order to determine whether formal approval must be sought and whether the informed consent document should also be revised. The EC will be informed of the end of the trial by the coordinating investigator. | PMC9890770 | |
Consent for publication {32} | A model consent form is provided on request. | PMC9890770 | ||
Competing interests {28} | The authors declare that they have no competing interests. | PMC9890770 | ||
References | PMC9890770 | |||
Background | congenital heart disease, CHD | Esketamine is commonly used as a premedication for its sedation effect. However, the proper dosage for intranasal use in children with congenital heart disease (CHD) has not been determined. This study aimed to estimate the median effective dose (ED | PMC10114298 | |
Methods | Anxiety | SEPARATION | Thirty-four children with CHD who needed premedication in March 2021 were enrolled. Intranasal esketamine was initiated at a dose of 1 mg/kg. Based on the outcome of sedation in the previous patient, the dose for the subsequent patient was either increased or reduced by 0.1 mg/kg, which was adjusted between each child. Successful sedation was defined as a Ramsay Sedation Scale score ≥ 3 and Parental Separation Anxiety Scale score ≤ 2. The required ED | PMC10114298 |
Results | The 34 children enrolled had a mean age of 22.5 ± 16.4 (4–54) months and a mean weight of 11.2 ± 3.6 (5.5–20.5) kg; American Society of Anesthesiologists classification I–III. The ED | PMC10114298 | ||
Conclusions | The ED | PMC10114298 | ||
Trial registration | : The trial was registered in the Chinese Clinical Trial Registry Network (ChiCTR2100044551) on 24/03/2021. | PMC10114298 | ||
Keywords | PMC10114298 | |||
Background | nausea, anxiety, hypoxia, intracardiac right-to-left shunting, allergy, vomiting, pain, cyanotic CHD | ADVERSE REACTIONS, SEPARATION, HYPOXIA, ALLERGY | Preoperative pediatric anxiety occurs in approximately 50–60% of children, especially those aged 1–5 years. This may have a negative psychological impact on children undergoing surgery [Preoperative sedation can alleviate perioperative anxiety of young children, thus creating a good condition for parental separation and anesthesia induction [Intranasal premedication is simple and minimally invasive compared with intramuscular or intravenous injections. Absorption is more complete, avoiding first-pass metabolism, and provides anesthesiologists with an alternative route for preoperative sedation. Midazolam, dexmedetomidine, and ketamine are sedatives for preoperative sedation in children, among which dexmedetomidine is more commonly used. However, dexmedetomidine will likely slow the heart rate [Esketamine is also effective for pain relief because of ease of use and minimal effect on respiration. In addition, it has the feature of sympathetic activity, can increase systemic vascular resistance, and reduce intracardiac right-to-left shunting in children with cyanotic CHD, thus relieving hypoxia.To the best of our knowledge, there is a lack of research on the median effective dose (EDOur pilot experiments suggested that a dose of 0.5–1.5 mg/kg could achieve an expected sedative effect in most children, and no evident inhibition of breathing and circulation was observed. Adverse reactions such as allergy, nausea, and vomiting have not been recorded. At present, the dosage of esketamine has not been clearly determined. To rationally apply esketamine to clinical practice, we designed this experiment to determine the ED | PMC10114298 |
Methods | PMC10114298 | |||
Participants | liver/kidney dysfunction, airway abnormality, allergy | ALLERGY, OBSTRUCTIVE SLEEP APNEA SYNDROME | This prospective, randomized, single-blind study was approved by the ethics committee of by the Medical Ethics Committee of Shanghai Children’s Medical Center (SCMCIRB-K2020058-2) and registered in the Chinese Clinical Trial Registry Network (ChiCTR2100044551) on 24/03/2021. Inclusion of children with CHD was decided by the randomized number generated by computer simulation without sex limitation. Before signing the informed consent form, the guardians were informed of the possible risks associated with sedation and the precautions for care and monitoring.Included in this prospective study were 34 children with CHD, aged from 4 to 54 months and weighing from 5.5 to 20.5 kg, who underwent elective surgery for CHD in March 2021. The exclusion criteria were: American Society of Anesthesiologists (ASA) classification ≥ IV; allergy to the drug to be tested; severe liver/kidney dysfunction; increased intracranial pressure; inability to separate from parents/guardians; history of intranasal surgery; front facial deformity; airway abnormality; and the presence of obstructive sleep apnea syndrome. According to the requirements for the research design of the sequential method, 6–8 crossover points were expected to be included [ | PMC10114298 |
Methods | Before surgery, the parents/guardians of the participants were advised to routinely fast their children for 6 h, avoid breastfeeding for 4 h and feed them with light food for 2 h. The patients and their guardians were escorted to the operating room 60 min before surgery. The patient’s preoperative status was assessed by the anesthesiologist in a single-blind manner, including ASA classification, heart rate monitoring, non-invasive blood pressure, saturation of peripheral oxygen (SpOWe confirmed that all methods were performed following the relevant guidelines and regulations. | PMC10114298 | ||
Research Parameters | The primary endpoint of the present study was the ED | PMC10114298 | ||
Statistical analysis | Anxiety | REGRESSION, SEPARATION | Statistical data were analyzed by SPSS 20.0 (IBM Corp., Armonk, NY, USA) and Excel Software (Microsoft Corporation, Redmond, WA, USA). The normality test of measurement data was performed using the Kolmogorov-Smirnov method, and data for normal distribution are expressed as the mean ± standard deviation. Under homogeneity of variance, a paired t-test was used for data analysis between groups. Measurement data for abnormal distribution or with uneven variance were tested using the Kruskal-Wallis method. P < 0.05 was considered statistically significant. Probit regression was used to calculate ED
Ramsay Sedation Scale
Parental Separation Anxiety Scale(PSAS) | PMC10114298 |
Results | Anxiety, Tetralogy of Fallot, ductus arteriosus, coronary right ventricular fistula, ventricular septal defect, TOF, PVS, CHD, aortic stenosis, atrial septal defect | REGRESSION, PULMONARY VALVE STENOSIS, OBSTRUCTIVE SLEEP APNEA SYNDROME, AORTIC STENOSIS, SEPARATION, SEPARATION | Thirty-four patients were included in the study,, ASAI–III,21 boys and 13 girls, with a mean age of 22.5 ± 16.4 (4–54) months and a mean weight of 11.2 ± 3.6 (5.5–20.5) kg. The mean weight for successful and failed sedation was 11.0 ± 4.0 kg and 11.5 ± 3.1 kg, respectively. The CHD of the patients included ventricular septal defect in 17, atrial septal defect in 9, pulmonary valve stenosis (PVS) in 2, Tetralogy of Fallot (TOF) in 2, and aortic stenosis in 1, patent ductus arteriosus in 1, and coronary right ventricular fistula in 1. The flow chart of the research process is indicated in Fig.
Participant flow chartNotes: Twenty-one patients were excluded from the study based on the exclusion criteria, 16 were excluded due to the inability to separate from parents/guardians, and 5 due to obstructive sleep apnea syndrome.Nineteen (55.9%) of the 34 patients who achieved successful sedation with intranasal esketamine were first included for analysis, in whom the effect onset time (min) was 20.5 ± 5.3 min, the quickest sedation onset time was 11.5 min, and the slowest was 28 min with a mean of 20.5 min. The other 15 patients who failed to achieve sedation were also included for analysis, including 9 cases of parental separation failure (4 children were unsuccessful in separating from their parents/guardians and sedation failure)and 6 cases of loss of sedation. After including the drug dose covariate and the dependent variable of response success, the optimal solution was obtained after 12 iterations. Using the probability regression method, the ED
The Actual response curves and drug doses for intranasal esketamineNotes: The Esketamine dose for each patient. A successful dose is denoted by a solid circle; a failed dose is denoted by an open circle. The horizontal arrows represent crossover midpoints (failure to success).Heart rate, SpO
Vital signs of the pediatric patientsHR, heart rate; MAP, mean arterial pressure; SpONote: The observational parameters were observed continuously. Analysis of the mean vital signs obtained at the designated time points indicated that the hemodynamics and other vital signs remained generally stable throughout the experimental period and showed no significant difference between successful and failed sedation.
Ramsay Sedation Scale scores at all designated time pointsNote: The Ramsay Sedation Scale scores in successful sedation cases were significantly higher than the mean values of the sedation scores in all included patients at all designated time points. The final Parental Separation Anxiety Scale at 30 min was 1.3 ± 0.5 in successful sedation cases, significantly lower than 1.8 ± 1.0 in the whole cohort. All the above results showed statistically significant differences. *, P < 0.05 | PMC10114298 |
Discussion | anxiety | DISEASE | We determined that the preoperative EDMidazolam, dexmedetomidine, and Ketamine are commonly used for preoperative sedation in children. An early in vitro animal experiment suggested that ketamine may be able to exert a potent diastolic effect on the intima of the pulmonary artery, thus reducing pulmonary circulation resistance [Unlike the previously reported studies, our study is one of the few studies that confirmed the EDEarlier studies on preoperative medication in children with CHD suggested that both intranasal administrations of 2 mg/kg ketamine and oral administration of 5 mg/kg ketamine were safe and effective for preoperative medication in children with TOF [Our study found that the EDMost researchers also define “cooperation without anxiety” as the criterion of successful sedation without considering the presence or absence of deep sleeping. Intranasal administration of 6 mg/kg ketamine created an appropriate depth of sedation in approximately 92% of cases, with a mean onset time of 5.79 ± 1.42 min. As the dose of ketamine is relatively large, some researchers recommended using the high-concentration of 100 mg/ml [Although many studies believe that most children cannot comply with intranasal drug administration, only 1 child in our study had obvious non-compliance and resistance to intranasal premedication and needed physical restraint with the help of the parents for drug administration. The volume of drug administration in this study was less than 0.15 ml, and no child exhibited significant symptoms of pharmacochemical stimulation, suggesting that esketamine has minimal intranasal stimulation and the intranasal route is appropriate for drug administration. The intranasal stimulation symptoms observed in 36.1% of patients administered midazolam differed in several ways from those observed in this study [This study has several limitations. Firstly, we failed to make precise discriminations of the pediatric patient personality characteristics before the initiation of the study, knowing that different personalities may affect the sedative outcome on the day of surgery. In addition, we could not stratify the disease type and age because of the relatively small number of included patients. Therefore, we could not include patients of the same age group and the same kind of CHD for analysis. Thirdly, we did not use the atomizer. While atomizers offer a convenient means of administering nasal medication, their use is limited by the financial constraints faced by many caregivers who may require assistance in procuring the relatively expensive nasal atomizers. Finally, we did not further observe the sedative or analgesic effects after the patients entered the operating room. | PMC10114298 |
Acknowledgements | We thank all colleagues in the Department of Anesthesiology, Fujian Children’s Hospital, Shanghai Children’s Medical Center for their support in analyzing and collecting data for the paper, and for correcting the language and grammatical structure of the manuscript. We would like to thank Editage ( | PMC10114298 | ||
Author Contributions | J.B. | H.B. G and J.J. H were the major contributors to the drafting of the manuscript. J.B. and D.Q. L were responsible for contacting the hospitals. D.Q. L analyzed and interpreted the data. The questionnaire was designed by H.B. G, J.J. H, J B, and D.Q. L. All authors read and approved the submitted version of the manuscript. | PMC10114298 | |
Funding | This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | PMC10114298 | ||
Data Availability | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10114298 | ||
Declarations | PMC10114298 | |||
Ethics approval and consent to participate | The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Shanghai Children’s Medical Center. Written informed consent to participate in this study was provided by the participant’s legal guardian/next of kin. All methods were carried out in accordance with relevant guidelines and regulations. | PMC10114298 | ||
Consent for publication | Not applicable. | PMC10114298 | ||
Competing interests | The authors declare no competing interests. | PMC10114298 | ||
Abbreviations | Anxiety | SEPARATION | American Society of Anesthesiologistscongenital heart diseaseconfidence intervaleffective doseParental Separation Anxiety Scalesaturation of peripheral oxygenTetralogy of Fallot | PMC10114298 |
References | PMC10114298 | |||
1. Introduction | SECONDARY, TYPE 2 DIABETES | Among all tree nuts, walnuts contain the highest total polyphenols by weight. This secondary data analysis examined the effect of daily walnut supplementation on the total dietary polyphenols and subclasses and the urinary excretion of total polyphenols in a free-living elderly population. In this 2-year prospective, randomized intervention trial (ID NCT01634841), the dietary polyphenol intake of participants who added walnuts daily to their diets at 15% of daily energy were compared to those in the control group that consumed a walnut-free diet. Dietary polyphenols and subclasses were estimated from 24 h dietary recalls. Phenolic estimates were derived from Phenol-Explorer database version 3.6. Participants in the walnut group compared to the control group had a higher intake of total polyphenols, flavonoids, flavanols, and phenolic acids in mg/d (IQR): 2480 (1955, 3145) vs. 1897 (1369, 2496); 56 (42,84) vs. 29 (15, 54); 174 (90, 298) vs. 140 (61, 277); and 368 (246, 569) vs. 242 (89, 398), respectively. There was a significant inverse association between dietary flavonoid intake and urine polyphenol excretion; less urinary excretion may imply that some of the polyphenols were eliminated via the gut. Nuts had a significant contribution to the total polyphenols in the diet, suggesting that a single food like walnuts added to habitual diet can increase the polyphenol intake in a Western population. It is well-recognized that walnuts have a favorable nutrient and fatty acid profile, and their consumption is effective in reducing blood lipids [Walnuts are composed of an outer green husk with a hard shell inside the husk containing a walnut kernel covered with a seed coat or pellicle, where most polyphenols reside [Several studies have recently explored dietary compositional changes produced by adding walnuts to the diet. In a randomized parallel design intervention, participants at risk for type 2 diabetes who added walnuts to their habitual diet increased their energy, protein, total fat, and magnesium intake [ | PMC10005107 | |
2. Materials and Methods | PMC10005107 | |||
2.1. Study Design and Participants | WAHA | The WAHA study was a 2-year parallel group, observer-blinded randomized controlled trial (RCT) examining the effect of the usual diet supplemented with walnuts at 15% (30–60 g/d) of energy compared to a walnut free habitual diet on the aging outcomes in elderly participants [Detailed information about the WAHA study has been published elsewhere [ | PMC10005107 | |
2.2. Sociodemographic, Anthropometric, and Biochemical Outcomes | Demographic data, anthropometric measurements, and dietary and lifestyle habits were collected from the participants at the baseline according to the study protocols [ | PMC10005107 | ||
2.3. Estimation of Dietary Nutrient and Polyphenol Intake | Collection of dietary recall data and nutrient analysis was performed using the Nutrition Data System for Research (software version 2018) developed by the Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN. The 24-h dietary recalls were obtained by telephone or face-to-face interviews using a multiple-pass approach to capture information about the food items, beverages, and dietary supplements consumed during the past 24 h and the nutrient estimates were acquired using the systems’ nutrient database. A total of five unannounced dietary recalls per participant were obtained at random times during the study, and these included at least one weekend day. The dietary intake data were collected by trained research dietitians and conducted at diverse intervals over the 2 year study duration to account for seasonal variations of food intake [The polyphenol content of foods and beverages reported in the 24-h recalls were generated from the Phenol-Explorer database (version 3.6) [The contribution of food items to the total polyphenols, flavonoids, flavanols, phenolic acids, and lignans were entered into the dietary database in milligrams per 100 g per day. Food items found in the 24-h dietary recalls (24-HDR) and food composition data were matched and the intake of total dietary polyphenols and phenol subclasses was estimated using the following equation: 24-HDRs = Σ Pn × Gn. Here, p is the mg of phenolic compound per 100 g food, and G is the reported portion size of food in grams. | PMC10005107 | ||
2.4. Urinary Total Polyphenols | Spot urine samples [ | PMC10005107 | ||
2.5. Statistical Analyses | REGRESSION | From the LLU cohort, a total of In the descriptive analysis of urinary polyphenols, the means (SD) by treatment and time were determined. To compare the morning spot urine polyphenol excretion between treatment groups, linear regression mixed models fitted for both variables (mg GAE/L, mg GAE/g Cr) included the treatment, time, treatment × time interaction, age, gender, and BMI as fixed-effects terms and the participants as a random-effects term. To examine the association between spot urine polyphenol excretion at year 2 and the dietary intake of polyphenols and subclasses, a linear regression model was fitted for each combination of urine polyphenol (dependent variable) and log dietary polyphenol (independent variable), while adjusting for age, gender, and BMI. All analyses were performed using R version 4.2.2 with a significance level at | PMC10005107 | |
4. Discussion | WAHA | In this sub-study of the WAHA trial, we showed that the daily ingestion of walnuts for 2 years significantly increased the total dietary polyphenols and the subclasses of flavonoids, flavanols and phenolic acids in healthy elderly participants. To our knowledge, this is the first study to show that the inclusion of a single food (i.e., walnuts), with no other changes made to the usual diet, could significantly increase the total polyphenol intake. As expected, those who ate walnuts daily also showed higher intakes of energy, fiber, total fat, and unsaturated fatty acids. The results of this trial also show that participants in the walnut group consumed significantly higher amounts of total polyphenols and flavonoids (flavones, flavonols, and anthocyanidins), flavanols, and phenolic acids from nuts compared to those in the control group. This finding demonstrates that a single food such as walnuts can increase the intakes of total polyphenols and the polyphenol subclasses except for lignans. The walnut group had a higher intake of total polyphenols from fruits, and the flavanols and lignans from vegetables. The median daily intake of the total polyphenols of the control and walnut groups at 1897 mg/d and 2480 mg/d, respectively, of this elderly cohort residing in California was higher compared to that reported in adults in the U.S. by the National Health and Nutrition Examination Survey (NHANES) at 884 mg per 1000 kcal per day [While the walnut group showed a higher daily intake of polyphenols, this was not reflected in the urinary excretion of polyphenols tested in the spot urine samples obtained at the baseline, and at the end of either year 1 or year 2. Increased polyphenol metabolites have been identified in urine following the consumption of plant-based foods, suggesting that selected urinary polyphenols could be useful biomarkers to assess the intakes of polyphenol-rich foods and diets [In relation to the total polyphenol concentrations in the spot urine samples, our analyses did not show associations either with the dietary total polyphenols or flavanols and phenolic acid subclasses, but disclosed an inverse association with an intake of the flavonoid (flavanones + flavones) category. Studies in which the total urine polyphenols were measured with the F–C assay have shown weak to moderate associations with dietary polyphenol intakes in the 24-h [The quality of phenolic compounds present in walnuts is diverse, ranging from simple phenolic acids and flavonoids to highly polymerized molecules such as tannins. Walnut phenolics are usually found at the highest concentration in the seed coat (also called the pellicle) surrounding the edible kernel and may be bound to other plant components such as carbohydrates and proteins. Consequently, some polyphenolic compounds might not be released in compositional testing studies. Walnuts are distinguished by the predominance of the hydrolysable gallotannins, glansrins (ellagitanins), and ellagic acid and the condensed tannins that are polymers of flavan-3-ol (flavanol) catechin and epicatechin subunits. The Polyphenol-Explorer 3.6 database reports an average amount of total polyphenol assayed by the F–C reagent as 1575 mg/100 g of kernel. Average amounts per 100 g of the total flavonoids, flavanols, and phenolic acids in walnuts are reported as 65 mg, 60 mg, and 449 mg, respectively [Aside from the wide diversity and complexity of the phenolic substances found in walnuts, a number of other factors complicate efforts to obtain the exact accounts of their polyphenol composition. The concentration of phenolic compounds from different genomic walnut species and cultivars have been found to vary widely, with mean coefficients of variation of 25% or greater [It is important to note that the concentration of polyphenol in urine is determined by factors beyond the walnut phenol content and its structural matrix, but is related to human physiology, mainly sex and age, along with factors such as digestive and metabolic efficiency and the gut microbiota [Our study has many strengths. The WAHA study has a significantly long duration of intervention (2 years). The study also includes a relatively large number of participants who demonstrated excellent compliance, with a retention rate of 90%. Moreover, the dietary intake data were extensive, having been acquired using multiple 24-h recalls (up to five recalls) obtained throughout the 2 year period and carefully matched with Phenol-Explorer values to obtain a profile of its polyphenol content. The main limitation was that the urine samples were obtained from fasting participants following the first morning void, and as such, may not have captured a large enough quantity and diversity of phenolic metabolites excreted in a 24-h urine or in a longer collection period. It is well-known that the half-life of most polyphenol metabolites is relatively short and typically appear in urine within 1 to 24 h following ingestion [ | PMC10005107 | |
5. Conclusions | age-related chronic diseases | CVD, DISEASE | A single food such as walnuts eaten daily can increase dietary polyphenol intake. This is important as we now know that polyphenols have significant health benefits, being powerful anti-inflammatory and antioxidant phytochemicals. To reduce the risk for age-related chronic diseases, it may be prudent to include nuts such as walnuts as part of the usual diet to not only benefit from the unsaturated fatty acids and other nutrients that have CVD and neuroprotective effects, but also increase the polyphenol intake, which can synergistically influence the disease risk in a favorable manner. | PMC10005107 |
Author Contributions | Conceptualization, R.I.A., S.R., J.S. and E.R.; Methodology, R.I.A. and R.S.; Validation, R.S.; Formal analysis, K.O.; Writing—original draft preparation, R.I.A.; Writing—review and editing, R.I.A. and E.H.H.; Supervision, I.N., S.R. and R.S.; Project administration, R.S., I.N., M.C. and J.S.; Funding acquisition, J.S. All authors have read and agreed to the published version of the manuscript. | PMC10005107 | ||
Institutional Review Board Statement | The study protocol was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the institutional review boards of all centers. | PMC10005107 | ||
Informed Consent Statement | Informed consent was previously obtained from all subjects involved in the study. | PMC10005107 | ||
Data Availability Statement | Detailed data relating to the study are available upon request from the corresponding author. | PMC10005107 | ||
Conflicts of Interest | Rajaram, Sabaté, and Ros received research funding through their institutions from the California Walnut Commission. Sabaté and Ros were nonpaid members of the Scientific Advisory Council of the CWC. Dr Ros was a paid member of the CWC Health Research Advisory Group and has received personal money from the CWC for presentations. All other authors declare no conflicts of interest. | PMC10005107 | ||
2. Materials and Methods | PMC10305125 | |||
2.1. Study Design and Patients | diabetes mellitus, bone disorders | SYSTEMIC DISEASE, HEMORRHAGIC DISORDERS, DIABETES MELLITUS, OSTEOPOROSIS, BONE DISORDERS | This study was a prospective, randomized, and controlled clinical trial. Patients were recruited from the outpatient department of the Department of Periodontology, Krishnadevaraya College of Dental Sciences, Bengaluru.Patients over the age of 18 exhibiting a keratinized tissue width greater than 1.5 mm, Siebert’s class I and II defects corresponding to Cologne’s classification h1e and h2e defects, and with a span of not more than 25 mm, were included in the study. Patients with poor oral hygiene, thin biotypes (<0.8 mm), systemic diseases such as uncontrolled diabetes mellitus or hemorrhagic disorders, bone disorders such as osteoporosis, and who are taking immunosuppressive drugs were excluded from the study.A total of 20 healthy adults aged between 21 and 60 years and exhibiting inadequate alveolar ridge dimensions in the maxillary and mandibular regions were randomized into test (The study was performed in compliance with the ethical guidelines outlined in the World Medical Association Declaration of Helsinki (version VI, 2002). Ethical approval was obtained from the Ethical Committee of Krishnadevaraya College of Dental Sciences (affiliated with Rajiv Gandhi University of Health Sciences). Furthermore, all participants were apprised of the nature of the study, as well as the potential benefits and risks of their participation. All participants provided informed written consent. | PMC10305125 |
2.2. Clinical Measurement, Radiological Assessment, and Pre-Surgical Procedures | postoperative pain | HAND SWELLING | A preoperative clinical examination was carried out before the procedure. Study casts were prepared with dental stones for all the treated cases to plan the surgical procedure and estimate the amount of augmentation required.The clinical ridge height and width were measured preoperatively using a University of North Carolina 15* (UNC-15) periodontal probe. Radiographic measurements (were performed using Cone-Beam Computed Tomography (CBCT) and Newtom CBCT 3D imaging software (NNT Viewer). The gingival thickness was measured with an endodontic file.During the procedure, patients were requested to rate their degree of discomfort, postoperative pain, and swelling using a visual analog scale ranging from none (0) to severe (10).All clinical measurements were recorded at baseline, three months, and six months after the procedure by a single, blinded, qualified investigator. Radiological measurements were performed by a blinded oral and maxillofacial radiologist preoperatively, as well as three months and six months postoperatively. Ridge width was measured at 10.5 mm above the inferior alveolar canal in the coronal plain, and bone density was measured in HU. Scaling and root planning were performed for all patients two weeks before the procedure. | PMC10305125 |
2.3. Surgical Procedure | INFILTRATION | The area was anesthetized with lidocaine 2%, via a nerve block or infiltration. Disinfection with povidone-iodine was done followed by isolation of the area. | PMC10305125 | |
2.3.1. Minimalistic Alveolar Ridge Augmentation Technique | A vertical incision of approximately 10 mm was performed mesial to the defect, away from the marginal gingiva and towards the MGJ using Bard-Parker #15 blade (The blood flowing out of the pouch was collected with a 5 mL syringe in order to manipulate the graft material to prepare the osseous coagulum. The graft material (G GraftAfter the defect was adequately filled with the graft material ( | PMC10305125 | ||
2.3.2. LLLT Test Sites | At the test sites, LLLT was performed prior to bone graft deposition. A diode laser was employed to deliver LLLT on the exposed bone surface inside the pouch (The length of the edentulous ridge was taken into consideration in order to determine the amount of laser radiation to be delivered. The parameters used were 100 Mw, with a maximum energy distribution of 6 J/cm | PMC10305125 | ||
2.4. Statistical Analysis | The clinical and radiological measurements were transferred into Microsoft Excel datasheets, and statistical analyses were carried out. All statistical tests were conducted using Statistical Package for Social Sciences (SPSS) version 20.0 (SPSS Inc., Chicago, IL, USA) software. The data’s normality was assessed using the Shapiro–Wilk test. If the | PMC10305125 | ||
3. Results | Of the 20 patients (Data was analyzed, and statistical analyses were performed. The majority of the patients treated were males ( | PMC10305125 | ||
3.1. Clinical Observation | swelling | The surgical procedure took less than one hour in both of the groups. At three months follow-up, all of the sites had healed completely, with graft bulk palpable in the treated area. At six months follow-up, all the sites manifested good visible alveolar ridge width and aesthetic harmony. A total of 70% of the subjects in the test group and 80% of the subjects in the control group reported no discomfort or swelling during the procedure and postoperative time period. A total of 20% of the cases treated under the test category and 10% in the control group reported mild discomfort. Moderate discomfort was indicated by 10% of the subjects in both groups ( | PMC10305125 | |
3.2. Radiological Findings | ± | Radiographic assessment with CBCT at six months post-surgery showed an increase in MRW for all the cases treated (The MBD for the test group and control group, at baseline and six months, was 1040.70 ± 490 to 904.30 ± 402.55 and 1138.20 ± 342.50 to 1093.9 ± 380.36, respectively. MBD was found to decrease at six months in the grafted sites; however, there was no statistical difference noted between the groups (1040.70 ± 490 reduced to 904.30 ± 402.55, and 1138.20 ± 342.50 reduced to 1093.9 ± 380.36 in the test and control groups at baseline and six months, respectively). CBD was compared for both groups using the Mann–Whitney U test. The mean CBD for the test group was 136.40 and for the control group, it was 44.30, which was not statistically significant. | PMC10305125 | |
4. Discussion | postoperative pain, swelling, fibrous, tooth, ultra-conservative | SEQUELA, PERIOSTEUM, WOUND DEHISCENCE, HAND SWELLING, HYDROXYAPATITE, COMPLICATIONS | Most dental surgeries, such as guided bone regeneration and implant surgeries, require extensive soft and hard tissue manipulation, resulting in subsequent loss of the tissue volume. Over the years, surgical methods have been refined in order to take advantage of ultra-conservative approaches which cause the least possible sacrifice of the tissues, contributing to superior healing of the surgical sites.The rapid ridge resorption which follows tooth extraction is an inevitable sequela, making it more challenging to reclaim the lost alveolar bone. Increased complexity and lack of predictability are the main challenges for all ridge augmentation procedures.Block bone grafting—onlay grafting, ridge expansion, guided bone regeneration with titanium mesh, and distraction osteogenesis—are some of the invasive procedures presenting dubious outcomes, more often than not. The common complications encountered with such procedures are severe postoperative pain and swelling, membrane exposure, wound dehiscence, loss of graft material, and occurring most frequently, the need for additional membrane to secure the bone graft into position.Minimally invasive surgical procedures have been revolutionizing surgical periodontology. Its entry into ridge augmentation procedures is relatively recent, with the introduction of laparoscopic procedures [The mean ridge width (MRW) at the baseline in the test group was 5.05 ± 1.43 mm, and for the control group, it was 5.03 ± 0.82 mm. At 6 months, the MRW was 6.51 ± 1.57 mm and 7.17 ± 1.98 mm for the test and control groups, respectively. Thus, the gain in ridge width was 1.40 ± 0.95 mm and 2.14 ± 1.65 mm for the test and control groups, respectively, which showed the effectiveness of the MRA technique for ridge augmentation. The control group did show a marginally higher gain compared to the test group. However, this gain did not reach a statistically significant level. This could be explained by confounding factors, such as the age of the patients and individual healing characteristics.The horizontal ridge gain achieved in this study was similar to that obtained in a study by Kfir et al. in 2007 (Gain = 1.3–3.9 mm) and Block and Degan in 2004 [Unlike the results of the current study, a study by Lee et al. [Mean bone density is an important parameter for assessing the quality of regenerated bone. The test site showed an MBD of 1040 ± 490 HU at baseline, which reduced to 904 ± 402.55 HU at 6 months. At the control site, it was 1138.20 ± 342.50 HU, which reduced to 1093.9 ± 380.36 HU from baseline to 6 months. The change in bone density (CBD) was −136.40 HU in the test and −44.30 HU in the control group.The reduction in bone density (BD) at both sites could be attributed to the ongoing bone remodeling process. There were no comparative studies for the assessment of bone density in minimally invasive surgical procedures; however, in a study by Lorenz et al. [The bone substitute employed in the study was G Graft (combination of HA and collagen). G graft showed better results when used for socket preservation in molar extraction sockets compared with G Bone (a combination of BTCP and HA) in a study by Panday V et al. in 2015 [HA has been used as a graft substitute in regenerative periodontics for decades. A study by Lindgren et al. in 2010 [Comparison between the test and the control groups concerning the gain in ridge width, as well as bone density, did not reveal any statistically significant difference (The intragroup comparison of bone density (BD) did not show a significant change in the test or control groups. The control group’s mean bone density (MBD) decreased from 1138.20 342.50 HU to 1093.90 380.36 HU, while the test group’s MBD decreased from 1040.70 490.74 HU to 904.30 402.35 HU at baseline and six months. There seems to be no peripheral effect of biostimulation on bone healing in terms of regeneration. There have been a handful of studies regarding the impact of laser biostimulation on bone regeneration in human subjects. A study by Garcia et al. in 2015 [On the other hand, a study by Mandic in 2015 [The variations in the results observed for LLLT could be explained by the role of individual laser parameters, namely the active medium, wavelength, energy, exposure time, and frequency of exposure.The mean surgical time required for the test group was 0.45 ± 0.35 h, and for the control group, it was 0.61 ± 0.37 h. (We found the present technique to be simple, with reduced patient morbidity and a relatively reduced risk of loss of augmentation volume. Patient-reported outcomes are an integral part of the quality of treatment. In both the test and control groups, specific outcomes regarding any discomfort or swelling intraoperatively and postoperatively were recorded. A total of 70% of the subjects in the test group and 80% of the subjects in the control group reported no discomfort or swelling during the procedure and postoperative time period, while 10% of the subjects reported moderate discomfort, and the remaining fraction of the patients reported only mild discomfort. The difference in patient outcomes between the two groups was not statistically significant (Early in the1980s, Kent et al. proposed minimally invasive horizontal ridge augmentation (MIHRA) utilizing a subperiosteal tunneling technique in which a small vertical incision was made in the alveolar ridge, and hydroxyapatite particles were administered underneath the periosteum. Initially, the graft was successful, but studies conducted in the late 1980s revealed that injected hydroxyapatite particles were unstable, and fibrous encapsulation was observed, resulting in partial bone formation [Our study effectively employed a similar technique for maxilla and mandible ridge reconstruction. Based on the literature, this is the first study to investigate the bone quality (in Hounsfield units) regenerated by CBCT for minimally invasive ridge augmentation. The technique not only yielded significant ridge gain, but also showed better patient acceptance and simplicity of execution. This clinical study is unique in that it also explores the adjunctive utilization of LLLT for bone regeneration in human subjects.This study has several limitations. First, the sample size was small; thus, a larger sample size and a longer follow-up duration after implant placement could shed more light on the overall outcome of the study. Secondly, laser irradiation could have been performed for more than one day, which may have improved the outcomes in the test group. Additionally, other growth-promoting materials, in combination with bone grafts, could have been employed that may have altered the outcomes. | PMC10305125 |
Author Contributions | A.M.L. | Conceptualization, K.P.A. and R.P.; methodology, K.P.A., R.P., M.L.V.P. and S.K.B.; software, K.P.A.; validation, R.P., M.L.V.P., S.K.B., R.T. and H.A.; formal analysis, K.P.A. and R.P.; investigation, K.P.A. and S.K.B.; resources, R.T., H.A., A.M.L., K.P.S. and G.K.B.; data curation, K.P.A.; writing—original draft preparation, K.P.A., R.P. and S.K.B.; writing—review and editing, R.P., S.K.B., R.T. and H.A.; visualization, R.P., M.L.V.P. and S.K.B.; supervision, R.P. and M.L.V.P.; project administration, R.P., M.L.V.P. and S.K.B.; funding acquisition, S.K.B., K.P.A., N.T.S., R.T., A.M.L., K.P.S., H.A. and G.K.B. All authors have read and agreed to the published version of the manuscript. | PMC10305125 | |
Institutional Review Board Statement | This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Krishnadevaraya College of Dental Sciences for studies involving humans. (KCDS/110/PG 2017-18, 10/11/2017). | PMC10305125 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10305125 | ||
Data Availability Statement | The dataset used in the current study is available upon reasonable request. | PMC10305125 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10305125 | ||
References | Consort flow diagram showing the randomization, follow-up, and analysis involved in the study.Surgical technique: (CBCT analysis of the ridge width and bone density. (Description of patients and graft sites.Patient reported outcomes for both the control and test groups.Radiographic measurements.* Significant according to the unpaired | PMC10305125 | ||
Study design | DILATION, REACTIVE HYPEREMIA | The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. Flow-mediated dilation (FMD) and post-occlusive reactive hyperemia (PORH) was measured at baseline and after 18 months of treatment in 39 patients and compared with healthy controls. Other outcome measures were symptom severity and various physical function measures. | PMC9894436 | |
Results | ME/CFS patients had markedly reduced FMD compared to healthy controls at baseline (5.1% vs. 8.2%, p< 0.0001, adjusted for arterial diameter and sex), and significantly lower microvascular regulation measured by PORH than healthy controls (1354 PU vs. 2208 PU, p = 0.002). There were no differences between the treatment and placebo groups in symptom changes or vascular measures. As a group, the ME/CSF patients experienced a slight, but significant improvement in clinical symptoms after 18 months. PORH, but not FMD, was similarly improved (1360 to 1834 PU, p = 0.028). There was no significant correlation between FMD and PORH. There were non-significant tendencies towards associations between symptom severity/physical function measures and lower FMD and PORH, and a significant correlation between PORH and steps per 24 hours at baseline. | PMC9894436 | ||
Conclusions | DISEASE | ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease. | PMC9894436 | |
Data Availability | All relevant data are within the paper and its | PMC9894436 | ||
Introduction | ME/CFS disease, orthostatic intolerance, post-exertional malaise | REACTIVE HYPEREMIA, DISEASE, SYNDROME, DILATION, ENDOTHELIAL DYSFUNCTION | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with a massive negative impact on quality of life for affected patients [In previous studies, results indicated that a subgroup of ME/CFS patients experienced improvement of symptoms after therapeutic B-lymphocyte depletion using the monoclonal anti-CD20 antibody Rituximab [In order to explore this hypothesis further in a larger study, we conducted a randomized, double-blind placebo-controlled study (RituxME trial) [The clinical presentation of ME/CFS, with major symptoms arising from several organ systems, indicates disturbance of a biological system with widespread functions. Some of the most common and distressing symptoms of ME/CFS, i.e. orthostatic intolerance and post-exertional malaise [One previous study by Newton et al., investigating flow-mediated dilation (FMD) for large vessel endothelial function and post-occlusive reactive hyperemia (PORH) for microvascular function in ME/CFS patients, concluded that ME/CFS patients have both large and small vessel endothelial dysfunction as compared to age- and sex-matched controls [Our hypotheses for the present substudy were 1) FMD and PORH would be reduced in ME/CFS patients, compared to the healthy controls, and 2) There could be a correlation between ME/CFS disease severity and FMD/PORH levels, and lastly 3) If the treatment group showed symptom alleviation, this could be accompanied by an improvement of endothelial function. | PMC9894436 |
Materials and methods | PMC9894436 | |||
Study design | The present study was a substudy of the RituxME trial [ | PMC9894436 | ||
Variables | DISEASE | The main outcomes were measures of endothelial function (FMD and PORH) at baseline and after 18 months. Measures of disease severity at baseline and symptom change/clinical response at 18 months were other important variables. | PMC9894436 | |
Measures of symptoms and disease severity | The severity of ME/CFS was categorized into five groups (mild, mild-moderate, moderate, moderate/severe, severe). The categorization into different severity groups was based on thorough clinical assessment by the physician at the time of inclusion, and supported by patient-reported function level and questionnaires. Self-reported questionnaires at baseline included the Short-Form-36 Health Survey (SF-36) (version 1.2) [ | PMC9894436 | ||
Statistical analyses | SPSS versions 25 and 27 were used for statistical analyses. Chi square tests were used to compare groups for categorical variables and t-tests (equal variances not assumed) for comparing means of continuous variables. Normality was tested using the Shapiro-Wilk´s test. FMD in ME/CFS patients and in healthy controls were normally distributed, and differences in mean between groups at baseline were compared by analyses of covariance (ANCOVA) in order to adjust for sex and baseline arterial diameter. For PORH, data from the ME/CFS group showed normal distribution, while data were not normally distributed in the healthy control group, and Mann-Whitney test was used to assess difference between groups. FMD and PORH by ME/CFS severity groups were tested by ANOVA and Kruskal-Wallis tests, respectively.The variables that describe patient function (SF-36-PF, FSS, self-reported function level and mean steps per 26h) were not normally distributed, therefore, Wilcoxon signed rank tests for related samples were used to compare means at baseline and 18 months. Three patients, for whom we only had baseline vascular values, were excluded from these analyses. General Linear Models (GLM) for repeated measures were used to assess differences in changes of the outcomes measures (FMD or PORH), from baseline to 18 months, between the randomization groups (rituximab and placebo). The analysis syntax for GLM repeated measures for FMD and PORH, with treatment group (rituximab or placebo) as between-subjects factor, is included as a supporting file ( | PMC9894436 | ||
Results | PMC9894436 | |||
Baseline characteristics | Baseline characteristics of the participants are reported in | PMC9894436 | ||
Vascular measures—baseline | mean flow-mediated dilation | DILATION | Among ME/CFS patients, mean diameter pre-occlusion was 3.00 mm (SD 0.50 mm); mean post-occlusion diameter at maximum dilation was 3.15 mm (SD 0.51 mm). For healthy women, mean diameter pre-occlusion was 2.94 mm (SD 0.42 mm); mean post-occlusion diameter at maximum dilation was 3.19 mm (SD 0.44 mm). Compared by unpaired t-test (equal variances not assumed), mean flow-mediated dilation (FMD) in ME/CFS patients at baseline was 4.9% (SD 3.6), significantly lower than in healthy women (mean 4,9% vs 8.3%, p< 0.0001). This is also illustrated in | PMC9894436 |
Flow-mediated dilation and post-occlusive reactive hyperemia in ME/CFS patients and healthy controls. | DILATION | After administration of glyceryl nitrate sublingually, mean diameter was 3.69 mm (SD 0.59) in ME/CFS patients, and mean dilation in per cent was 23.3%, similar to healthy women (mean diameter 3.60 mm (SD 0.47) and mean dilation 22.6%). Adjusted for sex and baseline arterial diameter in ANCOVA, the results were similar and not significantly different between the two groups (p = 0.79) (In ME/CFS patients, mean PORH at baseline was 1354 PU (SD 754 PU). This was significantly lower than the control group (2208 PU, SD 1363 PU, p = 0.004 analyzed by Mann-Whitney test ( | PMC9894436 | |
Associations between vascular measures and disease severity | DISEASE | Correlation analyses between vascular measures and measures of disease severity and function levels are illustrated in | PMC9894436 | |
Associations between vascular measures and disease severity. | PMC9894436 | |||
18 months follow-up, changes in clinical status and vascular measures | The Bergen cohort of the RituxME trial with rituximab and placebo groups pooled, experienced a slight clinical improvement after 18 months ( | PMC9894436 | ||
Vascular measures at baseline and 18 months. | PMC9894436 | |||
Discussion | vascular dysfunction, preload failure, cardiovascular disease, endothelial dysfunction | CARDIOVASCULAR DISEASE, ENDOTHELIAL DYSFUNCTION, DISEASE, VASCULAR DILATION, SECONDARY, ENDOTHELIAL DYSFUNCTION | The present study is one of the first studies to investigate vascular function in ME/CFS patients, and was a substudy of a multi-center, national, randomized and placebo-controlled trial that investigated the effect of B-cell depletion using the monoclonal antibody rituximab in this poorly understood disease. We found significantly lower endothelial function measured with FMD, and lower microvascular regulation measured with PORH, in patients with ME/CFS compared to healthy control groups. The vascular dilation after administration of glyceryl nitrate in ME/CFS patients was similar to healthy controls, showing that the intrinsic ability to dilate adequately was present. We found no significant correlation between FMD and PORH. There were tendencies towards lower FMD and PORH in patients with moderate to severe ME/CFS symptoms. However, there were no significant correlations between measures of vascular function and disease severity or physical function measures except for a significant correlation between PORH and steps per 24 hours at baseline. Overall, the patients experienced a slight clinical improvement during follow-up in the trial. There was no corresponding improvement in endothelial function measured by FMD, but a significant improvement in PORH from baseline to repeated measurement at 18 months. There was no difference in changes of endothelial function (FMD or PORH) during follow-up between the rituximab and placebo groups.Our findings support our first hypothesis of reduced vascular function in ME/CFS patients, and confirm previous findings [Nevertheless, it is a significant and important finding that our group of ME/CFS patients had such markedly reduced vascular function compared to healthy individuals. The observed endothelial dysfunction argues for a pathomechanistic effect of the vascular system in ME/CFS.The mechanisms for vascular dysfunction in ME/CFS patients are unclear. Endothelial dysfunction, in both large and small vessels, is a well-known risk factor for cardiovascular disease later in life [We recently summarized our hypotheses on possible pathomechanisms in ME/CFS [However, the endothelial dysfunction could also be a secondary phenomenon and therefore not directly associated with disease severity or improvement in patients experiencing symptom fluctuations during follow-up. Another possible mechanism for reduced vascular function could be inactivity. A meta-analysis of the effects of exercise on FMD concluded that exercise training contributed to an increase in FMD [In the present study, there was no clear relation between endothelial dysfunction and severity of disease symptoms, although we observed a tendency towards higher FMD and PORH values in patients with milder symptoms.There was no correlation between microvascular function measured by PORH, and endothelial function of the brachial artery measured by FMD. These methods both measure endothelial-dependent vascular function, but large and small vessels are regulated by somewhat different mechanisms, and studies of both measures have often found a poor or lacking correlation between FMD and PORH [Strengths of the present study: The RituxME study was a high quality study, with a double-blind randomized design, and selection of patients according to well-established and stringent criteria. The patients followed a strict and thorough follow-up regime. Endothelial function was measured using two different and complementary methods, both well documented. Vascular measures in the healthy control groups were similar to other studies of healthy individuals in comparable age groups [Weaknesses of the present study: Our patient sample was limited (39 patients). However, such patient numbers are not uncommon in FMD studies, and are often sufficient to show significant differences between groups [Clinical implications of this study: We think our findings of reduced endothelial function, both micro- and macrovascular, are of clinical importance. FMD and PORH measurements are not regarded as useful diagnostic tools for any patients groups, but are used to evaluate risk on a group level. Our study supports growing evidence that ME/CFS patients have a markedly reduced endothelial function compared to the normal population. This is an important discovery in a field with a scarcity of objective and measurable abnormalities. Our study does not answer the question of why these patients have reduced endothelial function. Reduced endothelial function might be an associated symptom rather than a central mechanism of the disease. However, we suspect that in ME/CFS the endothelial dysfunction is related to an abnormal immune response, and may be a factor in the pathomechanism. Together with reduced venous tone (“preload failure”), and arteriovenous anastomoses [ | PMC9894436 |
Conclusions | DISEASE | ME/CFS patients in this study had reduced endothelial function, indicating that vascular homeostasis is affected in at least some of these patients and may play a role in the clinical presentation of this disease. There is a pressing need for more studies to investigate this important issue, in order to better understand causes and disease mechanisms. | PMC9894436 | |
Supporting information | PMC9894436 | |||
Study protocol. | (PDF)Click here for additional data file. | PMC9894436 | ||
GLM syntax. | (PDF)Click here for additional data file. | PMC9894436 | ||
Study file. | Patients and PORH controls.(XLSX)Click here for additional data file. | PMC9894436 | ||
Study file. | Patients and FMD controls.(XLSX)Click here for additional data file. | PMC9894436 | ||
Methods and finding | ADVERSE EVENTS | A literature search was performed in PubMed, EMBASE, Cochrane Library, Web of Science, and Open Grey databases from inception to October 28, 2022. Three randomized controlled trials (RCTs) and one non-randomized controlled trial (non-RCTs), including 358 patients met our inclusion criteria and were included in qualitative synthesis; only RCTs were eligible for quantitative synthesis (meta-analysis). Meta-analysis of adverse events (AE) in RCTs showed no significant differences in the incidence of AE in the MSCs group compared to the control group (Risk ratio: 2.35; 95% CI, 0.58 to 9.58; I | PMC10374120 | |
Conclusion | RA | EVENTS | This Systematic review and meta-analysis showed a favorable safety profile, without life-threatening events in subjects with RA, and a trend toward clinical efficacy that must be confirmed through high-quality RCTs, considerable sample size, and extended follow-up in subjects with RA. | PMC10374120 |
Data Availability | All relevant data are within the manuscript and its | PMC10374120 | ||
Introduction | rheumatic diseases, synovitis, rheumatic, RA disease, arthropathy, Rheumatoid arthritis, RA, autoimmune disease | RHEUMATIC DISEASES, SYNOVITIS, PROLIFERATION, AUTOIMMUNE DISEASES, ARTHROPATHY, RHEUMATOID ARTHRITIS, DISEASES, AUTOIMMUNE DISEASE, COMPLICATIONS | Rheumatoid arthritis (RA) is a chronic, inflammatory, and progressive autoimmune disease characterized by synovitis, destructive arthropathy, and systemic complications [According to the evidence, the prevalence of rheumatic diseases such as RA has increased in the last decades, with a global prevalence of 460 per 100.000 population between 1980 and 2019 [RA patients require long-term treatment, and according to the evidence, currently available drugs have limited efficacy [Mesenchymal stem cells (MSCs) are multipotent progenitor cells derived from bone marrow, adipose tissue, placenta, umbilical cord, and others. MSCs are characterized by their regenerative and differentiation properties in multiple tissues, such as cartilage, muscle, tendon/ligament, and bone. Furthermore, MSCs have anti-inflammatory and immunomodulatory effects that can contribute to the therapeutic impact on several diseases, as they inhibit the proliferation and modulate immune cell responses such as T cells, B cells, dendritic cells, and natural killer cells [The immunomodulatory effect of MSCs could restore immunotolerance in RA patients, allowing complete discontinuation of immunosuppressive therapy [In recent years, clinical studies have demonstrated the benefits of MSCs for many autoimmune diseases, including rheumatic conditions such as RA disease [ | PMC10374120 |
Materials and methods | The review protocol was registered on PROSPERO 2022 [CRD42022372228], available from: | PMC10374120 | ||
Search strategy | rheumatoid, arthritis rheumatoid | RHEUMATOID ARTHRITIS | We searched PubMed, EMBASE, Cochrane Library, Web of Science databases, and the system for information on grey literature—Open Grey. The following parameters were used in the included medical electronic databases, these parameters and restrictions applied were the same in all databases: ((arthritis rheumatoid [title/abstract]) OR (rheumatoid arthritis [title/abstract]) OR (anti-citrullinated protein antibodies [title/abstract]) OR (ACPAs [title/abstract]) OR (rheumatoid factor [title/abstract])) AND ((stem cell transplantation [title/abstract]) OR (stem cells [title/abstract]) OR (stem cell research [title/abstract]) OR (cell therapy [title/abstract]) OR (cell based therapy [title/abstract]) OR (cell-based therapy [title/abstract]) OR (stem cell transplantation [title/abstract]) OR (multipotent stem cells [title/abstract]) OR (multipotent stromal cells [title/abstract]) OR (mesenchymal stem cells [title/abstract]) OR (mesenchymal stromal cells [title/abstract]) OR (mesenchymal progenitor cells [title/abstract]) OR (wharton jelly cells [title/abstract]) OR (wharton’s jelly cells [title/abstract]) OR (umbilical cord cell* [title/abstract]) OR (MSC [title/abstract]) OR (MSCs [title/abstract]) OR (ADMSC [title/abstract]) OR (ADMSCs [title/abstract]) OR (BM-MSC [title/abstract]) OR (BM-MSCs [title/abstract]) OR (BMD-MSC [title/abstract]) OR (BMD-MSCs [title/abstract]) OR (BMDMSC [title/abstract]) OR (BMDMSCs [title/abstract]) NOT (hematopoietic stem cells [title/abstract]) NOT (mononuclear [title/abstract])) AND ((clinical [title/abstract] AND trial [title/abstract]) OR (clinical trials as topic [title/abstract]) OR (clinical trial [title/abstract]) OR (random* [title/abstract]) OR (random allocation [title/abstract]) OR (placebo [title/abstract]) OR (therapeutic use [title/abstract])) AND ((humans [title/abstract]) OR (patients [title/abstract])). These records were recovered from the creation of these databases until October 28, 2022, and were limited to human studies and the English language. The search strategy for each database consulted is included as supporting information files ( | PMC10374120 |
Article selection | First, duplicate records were removed before the screening. Two reviewers initially screened all articles by title and abstract to exclude articles unrelated to the main objective of this study. Then, two reviewers read the full manuscripts and selected the eligible ones; a third reviewer resolved any discrepancies that arose. | PMC10374120 | ||
Inclusion and exclusion criteria | rheumatoid arthritis, RA | RHEUMATOID ARTHRITIS, RHEUMATISM | We selected all randomized controlled trials (RCTs) or non-randomized controlled trials (non-RCTs) that met the following criteria: (i) patients > 18 years with a diagnosis of rheumatoid arthritis (RA) according to the classification criteria ACR (American College of Rheumatology) or EULAR (European League Against Rheumatism). (ii) patients with naive RA or refractory to first- or second-line treatment. (iii) studies involving mesenchymal stem cells therapy (MSCs), autologous or allogeneic, from any source (derived from BM-MSCs bone marrow; AD-MSCs adipose tissue; UC-MSCs umbilical cord; gingival, placenta, menstrual tissue) systemic or local administration. (iv) studies that include comparison groups with cell therapy (from different sources of origin or dosage), placebo, or standard therapy. (v) randomized controlled trials evaluating the efficacy and safety of mesenchymal stem cell therapy (MSC). (vi) studies conducted in the human population and published in English. Exclusion criteria were: (i) observational (analytical or descriptive) studies. (ii) studies without a control group or placebo. (iii) studies conducted on animals, children, or pregnant patients. (iv) studies without definitive results, unavailable full text, abstract of conferences, and editorial letters. | PMC10374120 |
Data extraction and quality/risk of bias assessment tools | Two independent reviewers extracted the data from all the articles according to the following information: The first author, published year, location, trial registration number, study type, study phase, study population, age, sex, sample size, infusion route, intervention, control, follow-up, efficacy outcomes, safety outcomes; all data were extracted on a predefined form and supervised by the primary author. After data extraction, we assessed the methodological quality or risk of bias in RCTs through version 2 of the Cochrane risk-of-bias tool (RoB 2), where judgment can be "Low" or "High" risk of bias or can express "Some concerns." Moreover, we judge the risk of bias in non-RCTs through the ROBINS-I tool. | PMC10374120 | ||
Outcomes | PMC10374120 | |||
1. Primary outcomes | DISEASE | Primary outcomes were an assessment of clinical activity through DAS-28 (disease activity score 28), HAQ (health assessment questionnaire), a measure of response: measured by the ACR scale 20, 50, 70 (American College of Rheumatology 20/50/70 criteria), and serology such as anti-CCP (anti-citrullinated protein antibodies), ESR (erythrocyte sedimentation rate), CRP (C-reactive protein). | PMC10374120 | |
2. Secondary outcomes | ADVERSE EVENTS | Secondary outcomes were the safety of treatment with MSCs: adverse events (AE), serious adverse events (SAE), and non-serious adverse events. | PMC10374120 | |
Statistical analysis | A meta-analysis of the data from 3 included studies was performed by Stata 17—multivariate meta-analysis software (StataCorp, Texas, USA). Risk ratio with their corresponding 95% confidence intervals (CIs) was used for dichotomous outcome pooling. We chose a random effects model in the analysis using the DerSimonian-Laird method with the correction of zero-count cells if I | PMC10374120 | ||
Results | PMC10374120 |
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