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Conclusion | PROM, depression, fatigue | SECONDARY | This secondary analysis of a randomized clinical trial found that the PROM monitoring and alert intervention, compared with the standard of care, led to small improvements in HRQOL and fatigue among patients with hip replacement and patients with knee replacement and in depression symptoms among patients with hip replacement. Whether the intervention is also cost-effective needs to be evaluated. Further research on the ideal time intervals, the timeframe, and effects of the different intervention steps, especially the potential caring effect of the monitoring and PROM-based telephone call follow-up conversations, is needed. | PMC10474554 |
Purpose | cHCC-CC | CHCC-CC, RECURRENCE, COMBINED HEPATOCELLULAR-CHOLANGIOCARCINOMA | To establish and validate a multiparameter prediction model for early recurrence after radical resection in patients diagnosed with combined hepatocellular-cholangiocarcinoma (cHCC-CC). | PMC10700214 |
Materials and methods | cHCC-CC | CHCC-CC | This study reviewed the clinical characteristics and preoperative CT images of 143 cHCC-CC patients who underwent radical resection from three institutions. A total of 110 patients from institution 1 were randomly divided into training set ( | PMC10700214 |
Results | tumor | TUMOR, RECURRENCE | The combined model demonstrated superior predictive performance compared to the clinical model, the CT model, the pathological model and the clinic-CT model in predicting the early postoperative recurrence. The nomogram based on the combined model included AST, ALP, tumor size, tumor margin, arterial phase peritumoral enhancement, and MVI (Microvascular invasion). The model had AUCs of 0.89 (95% CI 0.81–0.96), 0.85 (95% CI 0.70–0.99), and 0.86 (95% CI 0.72–1.00) in the training, testing, and validation sets, respectively, indicating high predictive power. DCA showed that the combined model had good clinical value and correction effect. | PMC10700214 |
Conclusion | cHCC-CC | CHCC-CC, RECURRENCE | A nomogram incorporating clinical characteristics and preoperative CT features can be utilized to effectively predict the early postoperative recurrence in patients with cHCC-CC. | PMC10700214 |
Keywords | PMC10700214 | |||
Introduction | cHCC-CC, HCC, intrahepatic cholangiocarcinoma | PRIMARY LIVER CARCINOMA, RECURRENCE, COMBINED HEPATOCELLULAR-CHOLANGIOCARCINOMA, HEPATOCELLULAR CARCINOMA, INTRAHEPATIC CHOLANGIOCARCINOMA, CHCC-CC | Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver carcinoma primarily consisting of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) [In the past, numerous models for predicting postoperative recurrence of HCC have been developed based on clinical, pathological, and radiomics characteristics [Given the rarity and poor prognosis of cHCC-CC, identifying the risk factors that influence the prognosis of cHCC-CC and predict its recurrence is crucial. This study aims to analyze the relationship between clinical, computed tomography (CT), and pathological features of cHCC-CC and early recurrence by collecting multicenter data from three institutions. In addition, the study aims to establish and validate a scoring model for early recurrence after cHCC-CC surgery to accurately predict individualized early recurrence and guide clinical decision-making. | PMC10700214 |
Materials and methods | PMC10700214 | |||
Patients | cHCC-CC, intrahepatic lesion, Cancer | METASTASIS, CHCC-CC, PATHOLOGY, DISEASES, CANCER | This is a retrospective study in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board (Approve Number: 2023-E423-01) of our hospital that waived the requirement of an informed consent. From January 1, 2012, to December 31, 2020, a retrospective analysis was conducted on 213 cHCC-CC patients confirmed by surgical pathology in three institutions (The 1st affiliated hospital of Guangxi medical University, People’s Hospital of Guangxi Zhuang Autonomous Region and Guangxi Medical University Affiliated Cancer Hospital). The inclusion criteria for patient selection were as follows: (1) presence of a single intrahepatic lesion; (2) confirmation of cHCC-CC through surgical pathology; (3) negative marginal state of resection after radical operation as confirmed under the microscope (R0); (4) high-quality enhanced CT images were obtained within 1 month; and (5) regular follow-up imaging examinations (such as ultrasound, CT, and MRI.) and laboratory examinations within 1 year after operation. The exclusion criteria included: (1) previous treatment for cHCC-CC before operation; (2) adjuvant therapy and extra-hepatic metastasis after operation; (3) loss to follow-up or died of other diseases during the follow-up; and (4) incomplete CT imaging data. (Fig. The flowchart of the inclusion process. Numbers in parentheses are numbers of patients. After applying inclusion and exclusion criteria, a total of 143 patients were included in the study. Therein, 110 patients from institution 1 (The 1st affiliated hospital of Guangxi medical University) were randomly divided into training set ( | PMC10700214 |
Follow-up | cHCC-CC, tumor, liver lesions | CHCC-CC, TUMOR, RECURRENCE | Early recurrence was defined as the occurrence of a new tumor within a year after radical resection of cHCC-CC. The starting point was the day of the operation, while the endpoint was the detection of intra- and extra-hepatic recurrence within a year post-surgery. All cHCC-CC patients were regularly monitored for 12 months after operation. Within the first six months post-surgery, monthly re-examinations were conducted. Afterward, re-examinations were scheduled every three to 6 months. The routine follow-up protocols include imaging examinations such as CT and MRI and US, and tumor markers such as serum AFP, abnormal prothrombin, AFP-L3, and other tumor markers. If new liver lesions were detected through imaging examinations like ultrasound, CT, MRI or confirmed through puncture or surgical pathological examination, the follow-up ended. The deadline of follow-up was January 31, 2023. | PMC10700214 |
Clinical, pathological data | The clinical data consist of several factors such as age, gender, hepatitis B surface antigen (HBsAg), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), glutamyl transpeptidase (GGT), Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB), total protein (TP), prealbumin (PA), total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL). The pathological data were also collected, including MVI, hepatocyte, glypican-3, CD34, CK19, and Ki67. | PMC10700214 | ||
CT examination | The CT scanners were the GE64 VCT and Siemens Dual Source CT in Institution 1; Siemens Sensation 64CT and Philips iCT256 in Institution 2; and Siemens Sensation 64CT and GE Discovery CT750 in Institution 3. After a plain CT scan, an enhanced scan was performed. A high-pressure syringe was used to inject 1.5 ml/kg of non-ionic contrast agent (300 mgI/ml) at a rate of 3 ml/s through the antecubital vein. The scanning process included the arterial phase (25–30 s), venous phase (55–60 s), and equilibrium period (120 s). The slice thickness was 2 mm, the tube voltage was 120 kV, the tube current was 280 mA, and the rotation speed was 0.5 s per rotation. | PMC10700214 | ||
Image analysis | tumor, cancer lesions, necrosis | LYMPH NODE ENLARGEMENT, DILATION, TUMOR, NECROSIS | The CT images were review independently by two radiologists with ten years of experience, and any discrepancies were resolved through consultation between the two or with a senior doctor who has twenty years of work experience. CT features include: (1) the measurement of the tumor size in the portal phase. (2) Assessing whether the tumor margin was smooth (smooth border) or non-smooth (lobulated or irregularly protruding) as it intrudes into the surrounding normal liver parenchyma. (3) Evaluating whether the tumor has a enhancing capsule, and whether the enhancing capsule was complete (none, complete, or incomplete). The enhancing capsule was defined as uniform and smooth enhancement around the tumor and was evaluated at its evident stage (in the venous phase or equilibrium phase). A complete capsule was defined as continuous coverage of more than 80% of the tumor. (4) The peritumoral enhancement in arterial phase was also determined (none or yes), which was defined as the presence of obvious enhancement in the peritumoral liver parenchyma in the arterial phase and isodensity in the portal venous phase and equilibrium phase. (5) Intratumoral necrosis was identified (none, < 25%, 25%-50%, 51%-75%, > 75%), defined as a low-density area within the tumor without enhancement on enhanced scan. (6) The presence of peritumoral satellite lesions (absent or present) was also recorded, which were defined as cancer lesions that were less than 2 cm from the tumor margin and less than 2 cm in diameter. (7) The dilation of bile duct (none or yes) was examined, defined as low-density conduits accompanying the blood vessels in portal venous phase. (8) Large vein invasion (none or yes) was evaluated, defined as portal vein or hepatic vein filling defect in the venous phase of enhanced scanning. (9) Hepatic porta and para-aortic lymph node enlargement (absent or present) were also noted, defined as lymph node short diameter of 1 cm or more. (10) Finally, the enhancement mode (wash in and wash out, inhomogeneous enhancement, or persistence enhancement) was identified [ | PMC10700214 |
Statistical analysis | The data were analyzed using SPSS 25.0 and R software (Version 41.0 | PMC10700214 | ||
Result | PMC10700214 | |||
Nomogram establishment | RECURRENCE | The risk prediction model using the nomogram was based on the combined model (Fig. Construct a nomogram based on the combined model and add the points of each variable to obtain the total points. The total points correspond to the risk probability of early postoperative recurrence (Risk), which can be visualized Readout of the nomogram predicts a patient’s risk probability of recurrence within one year after surgeryNomogram risk prediction model calibration curve. | PMC10700214 | |
Acknowledgements | Cancer | CANCER | We thank those who participated in the study, as well as the radiographers, nurses in the Radiology and Surgery department at the first affiliated hospital Guangxi medical University, People’s Hospital of Guangxi Zhuang Autonomous Region and Guangxi Medical University Affiliated Cancer Hospital in Nanning, China, for their work, support, and enthusiasm for the study. We also express our deep gratitude to Dr Lina Chen, from the CT collaboration of Siemens Healthcare Ltd in Shanghai, China, for her help of the data statistical analysis and the article grammar modification. | PMC10700214 |
Author contributions | HL | All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by CZ, XG, XH, YW, LC, NL, HL, JL. The first draft of the manuscript was written by CZ and XG, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. | PMC10700214 | |
Funding | This work was supported by Guangxi Natural Science Foundation Project, Guangxi, China, 2023GXNSFAA026053. National Natural Science Foundation of China, NSFC81360220, 81260214. | PMC10700214 | ||
Declarations | PMC10700214 | |||
Conflict of interest | The authors have not disclosed any competing interests. | PMC10700214 | ||
Ethical standard Research involves human participants | All data were from routine clinical test, and there was no clinical intervention for the participants in the study. | PMC10700214 | ||
Informed consent | All informed consents for the routine clinical tests were obtained from participants. While for the retrospective nature of this study, informed consents for participating in this study were waived by the Institutional Review Board. | PMC10700214 | ||
References | PMC10700214 | |||
Abstract | PMC10566543 | |||
Objective | demineralized lesions, orthodontic | To evaluate the effect of high-fluoride mouth rinse and high-fluoride toothpaste on the development of demineralized lesions (DLs) during orthodontic treatment. | PMC10566543 | |
Trial design | Three-armed parallel-group randomized controlled trial. | PMC10566543 | ||
Methods | incisors, caries, orthodontic, teeth or teeth, FMR, lateral incisors | CARIES | The trial was performed with 270 adolescent orthodontic patients. Randomization was performed in blocks of 30, enrolling the patients into one of the following groups: the fluoride mouth rinse (FMR) group receiving 0.2% sodium fluoride (NaF) mouth rinse plus 1450 ppm fluoride (F) toothpaste; high-fluoride toothpaste (HFT) group receiving 5000 ppm F toothpaste; and the Control (CTR) group receiving 1450 ppm F toothpaste. Inclusion criteria were patients scheduled for treatment in both arches with fixed appliances and age between 12 and 20 years. The primary outcome variable was the proportion of participants with at least one new demineralized lesion as assessed on digital photos taken before and after treatment, analysed by a blinded clinician. The analysis included all teeth or teeth in the aesthetic zone, i.e. all central incisors, lateral incisors, and canines. A random sample of 30 participants was assessed to check intra- and inter-reliability. For pairwise comparison between groups, Fisher’s non-parametric permutation test was used for continuous variables. Blinding was employed during the caries registration and data analysis. | PMC10566543 |
Recruitment | October 2010 to December 2012 | PMC10566543 | ||
Results | incisors, orthodontic | In total, 270 patients were randomized, of which 22 were excluded during treatment. Therefore, 248 participants were included in the study. The number of patients with an increase of ≥1 DL, including only central- and lateral incisors and canines, during orthodontic treatment, was significantly lower in the HFT group, 51/85 60%, compared to the CTR group, 64/82 78%, RR 0.77 (CI 0.62; 0.95), | PMC10566543 | |
Conclusions | To prevent demineralized lesions in the aesthetic zone, high-fluoride mouth rinse and high-fluoride toothpaste may be recommended. | PMC10566543 | ||
Limitations | The protocol was not registered, and the present study did not use a double-blinded design. | PMC10566543 | ||
Introduction | demineralized lesions, caries, orthodontic | DEMINERALIZATION, CARIES, SIDE EFFECT | Early demineralized lesions (DLs), also called white spot lesions (WSLs), are a common and undesirable side effect of orthodontic treatment with fixed appliances [There is good scientific support that fluoride complicates demineralization and facilitates remineralization [High-fluoride mouth rinse (0.2% NaF) is commonly recommended to patients with an increased caries risk. To the author’s knowledge, no large RCTs with sufficient power have compared the effect of high-fluoride toothpaste (5000 ppm F) and high-fluoride mouth rinse (0.2% NaF) on the development of DL during orthodontics. The aim of the present study is to evaluate the effect of high-fluoride toothpaste and high-fluoride mouth rinse for preventing DL during orthodontic treatment. The null hypothesis was that there is no difference between the fluoride methods in preventing DL during orthodontic treatment. | PMC10566543 |
Subjects and methods | PMC10566543 | |||
Trial design | The single study employed a prospective randomized controlled clinical trial with three arms parallel group with 1:1:1 allocation ratio. The study design was approved by the Research Ethical Board in Gothenburg, Sweden (Reg. no. 321-09). The study protocol was not registered. No changes were made to the methods after trial commencement. | PMC10566543 | ||
Participants, eligibility criteria, and settings | DISEASE, RECRUITMENT | Recruitment for the study started in October 2010 and continued to December 2012. In total, 300 participants who were referred to the Specialist Clinic for Orthodontic Dentistry, Public Dental Service (Mölndal, Sweden) were invited to participate in the study. The study population for the study was patients’ residents to one of nine different Public Dental Service Clinics. Five experienced orthodontists were involved in the orthodontic treatment. Inclusion criteria of the study were age between 12 and 20 years and scheduled for orthodontic treatment of both the upper and lower arches with fixed appliances (MBTTM (McLaughlin, Bennett, Trevisi), pre-adjusted with 0.022-inch slots; 3M Unitek Orthodontic Products, Monrovia, CA, USA) for an expected treatment duration of at least 1 year. The exclusion criteria were treatment with a removable appliance or a lingual fixed appliance and patients with severe disease. Severe disease was defined as patients who, due to their health, were not suitable for general dental care. The patients received information both verbally and in writing regarding the study. After agreeing to participate, each patient signed an informed consent form (or the caregiver signed if the patient was <18 years of age). All the participants lived in communities with a natural fluoride level of < 0.1 mg/L in tap water. | PMC10566543 | |
Interventions | Patients were randomly allocated to one of the following groups with associated fluoride protocols: | PMC10566543 | ||
Fluoride mouth rinse (FMR) group. | Caries, tooth | CARIES | Rinsing with a fluoride mouth rinse (0.2% NaF, corresponding to 900 ppm F, Flux; Actavis, Stockholm, Sweden) twice daily and tooth brushing twice a day; using standard toothpaste (1450 ppm F, Colgate Caries Control; Colgate-Palmolive, Lyngby, Denmark). The patients were instructed to use the provided fluoride mouth rinse after brushing their teeth. | PMC10566543 |
High-concentration fluoride toothpaste (HFT) group. | Tooth | Tooth brushing twice daily using a high-concentration fluoride toothpaste (5000 ppm F, Duraphat; Colgate-Palmolive). | PMC10566543 | |
Fluoride toothpaste (FT) control group. | tooth brushing and mouth, Caries, Tooth, FMR | CARIES | Tooth brushing twice daily using standard toothpaste (1450 ppm F, Colgate Caries Control; Colgate-Palmolive).The participants were given verbal and written information regarding product use. The patients were instructed to apply 2 cm (approximately 1 g) of toothpaste to the brush, in accordance with the manufacturer’s instructions. The recommended tooth brushing time was 2 min, performed after breakfast and before going to bed. The FMR group was instructed to rinse for 2 min with 10 ml of the fluoride mouth rinse. Patients were instructed not to use water during or after brushing and rinsing and to avoid intake of food and drink for at least 1 h after tooth brushing and mouth rinsing. The patients were also supplied with a toothbrush (Lactona, Bergen op Zoom, Netherlands) every third month, to be used throughout the treatment period. The fluoride products were provided free of charge to the patients, and the patient’s compliance to the products was evaluated in a questionnaire. | PMC10566543 |
Outcomes | SECONDARY | The predictor variables in this study were the use of different fluoride products. The primary outcome variable was the DL incidence; the proportion of participants with at least one new demineralized lesion, as assessed on digital photos taken before and after orthodontic treatment on the buccal surfaces of permanent teeth. Aesthetic impact (degree of injury from 1 to 4) was assessed as secondary outcomes. No changes were made to the trial outcomes after trial commencement. Before and after treatment, standard intraoral close-up photographs (one frontal photograph and two side photographs) were taken with a digital camera (Canon Powershot G7X; Canon, Inc., Tokyo, Japan) and stored in the patient’s digital journal (Edward). The photographs were taken before bonding, at the same visit as the bonding took place. The buccal surfaces of both of the maxillary and mandibular incisors, canines, premolars, and first molar were included in the DL registration. The photographs were taken ‘edge-to-edge’. The DL was assessed according to a Gorelick At baseline, the teeth were polished with a rubber cup and pumice paste and gently dried before photographs were taken. At the time of debonding, the composite material on the teeth surfaces was carefully removed with a slowly rotating carbide bur, followed by polishing with a rubber cup. After gently air drying, a new series of frontal and lateral digital photos were taken. The photographs were projected on a screen (Elite Display E222; Hewlett Packard, Palo Alto, CA, USA) in a dark room while one of the authors (HE) assessed DL. If in doubt when scoring, the lower score was chosen. Missing or poor photos were excluded from the analysis.In order to establish compliance regarding fluoride intake during treatment (at 1 year after installation of the fixed appliance), all the participants were asked to respond in writing to a questionnaire. The following questions were included in the questionnaire: | PMC10566543 | |
Sample size calculation | The sample size estimation was determined with a power calculation assessing superiority, with the significance level set at 0.05 and 80% power. With the α and β values set at 0.05 and 0.2, respectively, 66 patients per group were needed to disclose a difference of 25% between the groups in the proportion of patients with an increase of ≥1 DL during orthodontic treatment. With an expected attrition rate of 15%, a total number of 76 in each group was considered to be sufficient. | PMC10566543 | ||
Interim analyses and stopping guidelines | Not applicable. | PMC10566543 | ||
Randomization and blinding | In this single-blind trial, a randomization sequence was generated in blocks of 30 to ensure that equal numbers of patients were allocated to each group. Thirty paper sheets (10 FMR, 10 HFT, and 10 CTR) were folded and placed in a basket (AW). Before treatment commenced, each patient selected a paper sheet from the basket for randomization. Until the moment of assignment, the allocation sequence was concealed from those assigning participants to the intervention groups. The orthodontists and the orthodontic assistants enrolled participants to their intervention group. The author assessing DL was not involved in the clinical data collection or in the treatment of the patients and was blinded to the patient’s group allocation. The patient’s group affiliation was revealed after the statistical analysis. | PMC10566543 | ||
Statistical analysis | Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS® version 20.0 for Windows, SPSS, Inc., Chicago, IL, USA) and SAS 9.4 (SAS 9.4 by SAS Institute, Inc., Cary, NC, USA). For continuous variables, mean (SD)/median (min; max)/number are presented. For categorical variables, | PMC10566543 | ||
Results | PMC10566543 | |||
Participants and baseline data | In total, 270 participants were included in the study, of which 95 were males and 175 were females. The dropout rate was 8.1% (22 patients), including seven patients who were lost to follow-up due to several reasons (Flowchart for participants and dropouts in the trial. Adapted from CONSORT.At baseline, the gender distribution for the 248 patients was 84 (33.9%) males and 164 (66.1%) females. A similar distribution was also seen between the three intervention groups (Distribution of sex, age, and health conditions between the groups at baseline. | PMC10566543 | ||
DL on the patient level | teeth | At baseline, 17 patients (21.0%) in the FMR group showed 0 DL, while 22 patients (25.9%) in the HFT group and 15 (18.3%) patients in the control group showed 0 DL. There was no statistically significant difference between the groups regarding baseline DL status on patient level (Relative risks (risk ratios) for increase in ≥1, ≥2, and ≥3 demineralized lesion (DL) in all teeth and in the aesthetic zone, pairwise comparisons with 95% CI. Unadjusted values.The table presents demineralized lesions (DLs) on patient level, Aesthetic zone includes teeth 3-3 in the maxillary and mandibular arches. | PMC10566543 | |
DL based on surface level and lesion severity | canins, lateral incisors | In total, 5465 buccal tooth surfaces were scored before and after baseline. At baseline, the first molar was most frequently affected by DL, 163 (65.7%) patients showed DL on one, two, three or all first molars. During treatment, the central incisor, lateral incisors, and canins in the upper arch demonstrated the highest frequency of DL. During treatment, 94 patients (37.9%) showed DL on the right central incisor and 107 (43.1%) on the left central incisor, the corresponding figures for the lateral incisor and canines were 99 (39.9%), 94 (37.9%), and 38 (15.3%) and 35 (14.1%) (The distribution ( | PMC10566543 | |
Intra- and inter-examiner reliability levels | Cohen’s κ and weighted κ values were calculated to determine intra- (reassessment of the collection after 1 month) and inter-examiner reliability (two examiners assessed photographs from 30 patients) for DL measurements. The intra-examiner κ value was 0.81 (very good), and the inter-examiner κ value was 0.78 (good). Intra-rater weighted κ showed 0.81 (95% CI 0.78–0.84), and inter-rater weighted κ showed 0.78 (95% CI 0.75–0.81). | PMC10566543 | ||
Compliance | Compliance was evaluated 1 year after the initiation of treatment. Of the participants, 236 (95.2%) of the 248 participants stated that they brushed their teeth at least twice a day during the treatment. All patients stated that they used a fluoride toothpaste for brushing. In addition, 76 patients (93.8%) in the FMR group and 79 patients (92.4%) in the HFT group answered that they used additional high-fluoride products. | PMC10566543 | ||
Harms | allergy | ADVERSE EVENTS, ALLERGY | No patient reported any adverse events, such as allergy or other harms, in relation to using the fluoride products. | PMC10566543 |
Discussion | incisors, lateral incisors | The number of patients with an increase of ≥1 DL during orthodontic treatment was significantly higher in the CTR group compared to the HFT group and the FMR group when only central incisors, lateral incisors, and canines were included in the analysis. Therefore, in the aesthetic zone, patients benefitted from using fluoride mouth rinse and high-fluoride toothpaste compared to ordinary fluoride toothpaste. The positive effect of high-fluoride toothpaste and fluoride rinse on the development of DL are in line with the findings of previous clinical studies [DLs can persist and create aesthetic concerns for the patient even 12 years after treatment [This study showed a higher baseline prevalence of DL (proportion of patients with at least one white spot lesion) compared to studies with a similar study design [A weakness of the present study is that the randomization was performed manually with sealed envelopes. It would have been preferable to randomize the patients using computer-generated sequence numbers. Another study limitation is that the present study did not use a double-blinded design. The protocol was not published before trial commencement, which must be seen as a weakness. The study was planned 15 years ago, and at that time, trial registration was not a requirement as it is today. Furthermore, patients could have been prescribed additional fluoride products from their general dentist at their home clinics, which could have affected the patient’s DL status during treatment. However, there are several strengths of the study. The study had a randomized controlled trial design ensuring high scientific value. Furthermore, the assessor of the DL score was blinded to the patient’s group affiliation and not involved in the clinical procedure, which minimized the risk for bias. The large material size, sufficient power, and the fact that all the patients were provided with the same toothbrush and fluoride products are strengths of the present study. Furthermore, the good intra- and inter-rater agreement also strengthened the findings of this study. | PMC10566543 | |
Generalizability | The study findings can be generalized for patient groups with similar baseline DL status, mean age, inclusion/exclusion criteria, and treatment protocols. However, single centre reduces generalizability, albeit with multiple operators. | PMC10566543 | ||
Conclusions | incisors, orthodontic, lateral incisors | A positive effect of high fluoride toothpaste and fluoride mouth rinse in preventing DL on central incisors, lateral incisors, and canines during orthodontic treatment. DLs are still a problem during orthodontic treatment. Therefore, future randomized controlled clinical trials are needed to assess evidence-based guidelines for preventing DL during orthodontic treatment. | PMC10566543 | |
Supplementary Material | Click here for additional data file.Click here for additional data file. | PMC10566543 | ||
Funding | The Swedish Patent Revenue Fund (grant number EKF-780/19). | PMC10566543 | ||
Author Contributions | Hanna Enerbäck (Data curation [Equal], Formal analysis [Equal], Investigation [Equal], Software [Equal], Validation [Equal], Writing – original draft [Lead], Writing – review & editing [Equal]), Mai Lin Lövgren (Data curation [Equal], Validation [Equal]), Nicklas Strömberg (Methodology [Equal], Supervision [Supporting], Writing – review & editing [Supporting]), and Anna Westerlund (Conceptualization [Lead], Funding acquisition [Equal], Project administration [Equal], Resources [Equal], Supervision [Lead], Writing – review & editing [Supporting]) | PMC10566543 | ||
Conflict of interest | The authors declare that there is no conflict of interest. | PMC10566543 | ||
Data availability | Data are available on request. | PMC10566543 | ||
References | PMC10566543 | |||
Abstract | PMC10368966 | |||
Background | infection | INFECTION, RESPIRATORY SYNCYTIAL VIRUS (RSV) | Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available. | PMC10368966 |
Methods | RSV INFECTION | This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1–24 months, hospitalized with RSV infection. In Part 1, patients ( | PMC10368966 | |
Results | death | ADVERSE EVENTS | No safety or tolerability signals were detected for AK0529: grade ≥3 treatment‐emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A −4.0 (95% CI: −4.51, −2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with −2.0 (95% CI: −3.42, −1.82) in the placebo group. | PMC10368966 |
Conclusions | AK0529 was well tolerated in hospitalized RSV‐infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score. | PMC10368966 | ||
Clinical Trials Registration | NCT02654171.
Li‐Min Huang and Andreas Schibler contributed equally.
| PMC10368966 | ||
INTRODUCTION | respiratory infections, deaths | RESPIRATORY INFECTIONS, RSV INFECTION, RESPIRATORY SYNCYTIAL VIRUS (RSV) | Respiratory syncytial virus (RSV) is estimated to annually cause 30 million respiratory infections world‐wide, particularly in young children, with around three million associated hospital admissions and >60,000 in‐hospital deaths in children younger than 5 years.A promising target for RSV drug development is the class I viral trimeric fusion (F) glycoprotein, which mediates RSV entry in response to binding of the attachment (G) glycoprotein to a host receptor. Several molecules targeting F protein have been evaluated in clinical challenge models in adults as well as in children with an acute RSV infection but with limited success.AK0529 (ziresovir) is a potent, selective, and orally bioavailable RSV F protein inhibitor.Based on this profile, we performed a two‐part proof‐of‐concept Phase 2 study in infants aged 1–24 months hospitalized with RSV infection. | PMC10368966 |
METHODS | PMC10368966 | |||
Patient selection | RSV INFECTION, MAY | Study participants were infants aged ≥1–≤24 months, weighing >3 kg at screening, and within the 10th and 90th age percentiles (inclusive), requiring hospitalization for management of virologically confirmed RSV infection. They were continuously enrolled from May 2016 to April 2019 RSV seasons in the subtropical regions of Australia, Taiwan, Malaysia, Turkey, and Israel. | PMC10368966 | |
Study design | This was a double‐blind, placebo‐controlled, randomized, multicenter study with the primary objective to evaluate the safety and tolerability of single and multiple oral doses of AK0529. Secondary objectives were to evaluate the effect of AK0529 on Wang Respiratory Score, to determine the effects of treatment on viral load, and to characterize the pharmacokinetics (PK) of single and multiple AK0529 doses.The ethics committee at each trial center approved the trial. All subjects' parents or legal guardians provided written informed consent.The study consisted of two parts. In both parts, subjects were randomized in a 2:1 ratio to receive active treatment or placebo. Subjects were stratified by age (6 to 24 months in Cohorts 1 and 3, and 1 to <6 months in Cohorts 2 and 4).Part 1 was a single‐dose study with a 7‐day follow‐up. The doses administered to patients in Cohort 1 included 4, 2, and 1 mg/kg. The Safety Review Committee (SRC) reviewed PK and safety data after each of the sets of three patients, before further enrollment of subjects, and recommended 0.5 and 1 mg/kg as the doses for patients in Cohort 2.In Part 2, subjects received AK0529 or placebo over 5 days and were followed until day 14 post‐initial dose. The doses in Cohort 3 included 1 and 0.5 mg/kg bid. In Cohort 4, the doses included 2, 1 and 0.5 mg/kg bid.Details of the rationale for the dose selection, subject dosing, and safety review schemes in Parts 1 and 2 are detailed in the | PMC10368966 | ||
Study assessments | lethargy, wheezing, irritability | RESPIRATORY SYSTEM DISORDERS | The Wang Respiratory Score assesses the severity of respiratory rate, wheezing, retraction of respiratory muscles, and general condition on a scale from 0 to 3 except for the general condition, which is scored 0 for normal and 3 for irritability or lethargy. The sum score, ranging between 0 and 12 (most severe), reflects the severity of the respiratory system disorders in children. | PMC10368966 |
Safety | ADVERSE EVENTS | Safety and tolerability was evaluated by clinical assessment of safety data, including laboratory data, electrocardiographic data, vital signs, and adverse events (AEs). | PMC10368966 | |
PK | Individual plasma concentrations of the active drug were measured, and PK were determined using nonlinear mixed‐effect models. In all cases, when new data were available, the updated model was used for evaluation under the assumption of an allometric coefficient of 0.75 and incorporation of CYP maturation. Using a Population PK (Pop‐PK) analysis approach, AUC | PMC10368966 | ||
Statistical analysis | respiratory viral infections | RSV INFECTION, RESPIRATORY VIRAL INFECTION | Clinical safety and tolerability were assessed on the safety population, comprising all subjects who received ≥1 dose of study drug. Clinical variables were evaluated in the full analysis population, which included all subjects who received a dose of study drug and for whom ≥1 post‐treatment assessment was available. Pharmacokinetic analysis was performed on those subjects in the safety population for whom both pre‐ and post‐dose samples were available.All data are summarized by descriptive statistics with 95% confidence intervals for comparisons. As respiratory viral infections may coexist with potentially pathogenic respiratory bacteria that may affect the severity of RSV infection,In study Part 1, no formal sample size calculation was performed. For Part 2, it was calculated that a sample size of 16 patients in each active treatment group would provide >90% power to detect a 50% reduction (mean ratio of 0.5) in RSV viral load AUC with AK0529 as compared with placebo, using a one‐sided significance level of 0.05, two‐sample equal variance All analyses were performed using SAS® Version 9.3 (SAS Institute Inc., Cary, NC, USA). | PMC10368966 |
RESULTS | PMC10368966 | |||
Study population | The study flow is shown in Figure Study flow chart. Demographic characteristics. Percentages do not always add up to 100% because of rounding.One subject received unblinded treatment with AK0529 (2 mg/kg bid) on a compassionate use basis and was excluded from the full analysis population.Baseline Wang respiratory score and viral load in the groups treated with different doses of AK0529 or placebo. | PMC10368966 | ||
Reduction in viral load and S&S scores | ADENOVIRUS, VIRUS, COINFECTION, RHINOVIRUS, DISEASE, REMISSION | In Part 1, reductions in viral load at 24 h after a single dose AK0529 administration were <1 log(A) Median change in viral load from baseline to 96 h post‐dose in Part 2 (full analysis population). (B) Median change in Wang respiratory score by dose level in Part 2 (full analysis population). *In Part 1, median Wang Respiratory Score decreased from baseline to 24 h in a dose‐related manner (see plot in the (A) Relationships between viral load and Wang respiratory score: viral load vs. RSV S&S score, In a post‐hoc analysis, 8/11 patients (73%) receiving AK0529 2 mg/kg bid achieved disease remission by Day 5, as defined by Wang Respiratory Score ≤1. In contrast, only 5 out of 16 (31%) in the placebo group (one‐sided Sanger sequencing on Coinfection with ≥1 other respiratory virus was identified in 9/22 analyzed patients in Part 1 (40.9%), including three (13.6%) with ≥2 additional respiratory viruses. In Part 2, ≥1 other respiratory viruses were identified in 13 of 41 analyzed patients, including ≥2 additional respiratory viruses in three patients (7.3%). Human rhinovirus was the most frequently co‐detected virus in both populations, followed by adenovirus C and adenovirus B/E. | PMC10368966 | |
Safety | pneumonia, hyperkalemia | ADVERSE EVENTS, ADVERSE EVENT, PNEUMONIA | The safety profile of AK0529 is shown in Table Adverse event profile of AK0529 compared with placebo.Abbreviations: AEs, adverse events; SAEs, serious adverse events; TEAEs, treatment‐emergent adverse events.One case each of increased aspartate aminotransferase, increased transaminases, hyperkalemia.Two cases of unrelated pneumonia.One case of pneumonia, classified as SAE; one case of elevated transaminase.One case of pneumonia.Shifts evaluation for aspartate aminotransferase and alanine aminotransferase (safety population).Abbreviations: CS, clinically significant; For a subject with multiple shifts with different categories, only the worst shift category was counted, where the hierarchy for shift category was ordered from “Normal to abnormal CS” (worst) to “Abnormal CS to normal” (best). Cochran–Mantel–Haenszel test was used to calculate the Two serious TEAEs (pneumonia) were reported: one of Grade 4 | PMC10368966 |
PK | Pharmacokinetic parameters evaluated in Part 1 are shown in Table Predicted concentration‐time profiles for different single doses of AK0529 from Part 1 study.
Abbreviations: AUC, area under the plasma concentration‐time curve; Cmax, maximal concentration; CV, coefficient of variation; tThe 4 mg/kg dose group includes additional data from a single subject treated in a preceding phase 1b study (Study AK0529‐1002).In Part 2, an approximate dose proportionality was observed for mean C | PMC10368966 | ||
DISCUSSION | infection, pneumonia, ill | RSV INFECTION, PNEUMONIA, DISEASE, INFECTION, INFECTION TOE | The current Phase 2 study supports a favorable safety profile of the The results may appear moderate but need to be viewed in context. In a Phase II study with JNJ‐8678 in infants hospitalized with RSV, a greater reduction in RSV viral load than with placebo did not translate into observed clinical benefit, with no improvements in length of hospital stay or time to clinical stability.The safety profile of AK0529 was favorable, an important consideration given the age of the studied population. The two cases of pneumonia were deemed unrelated to the treatment. Increased transaminase level is associated with the disease severity of RSV infection,A problem with some candidate molecules has been the resistance mutations in RSV strains.Although of limited size, this Phase 2 study enrolled patients from five countries/regions on three continents during RSV seasons in four calendar years, suggesting that the results are representative of global patients and treatment conditions. A disadvantage is that the time from infection to first dose could not be captured. It is difficult to determine the time of infection in infants who are not able to communicate. Moreover, some of the participating centers were central hospitals treating severely ill patients transferred from local clinics with possibly limited initial records. On the upside, the results support the efficacy of AK0529 under conditions closely related to those of actual clinical practice and regardless of time from infection to treatment.Among other shortcomings, the limited follow‐up time meant that the question of rebound could not be addressed. The 96 h timepoint was not the pre‐defined primary timepoint for the analysis, and significance tests were not adjusted for multiple analyses. Differences in national healthcare and insurance policy prevented analysis of the potential impact of the therapy on the length of hospital stay. There was a limited information about the need for respiratory support (e.g., ventilation or nasal oxygen) at baseline, which may have affected the assessment of disease severity. There is an ongoing discussion around the relative performance of different sampling methods for respiratory viruses.In conclusion, this proof‐of‐concept study supported a relevant effect on viral load and clinical signs and symptoms with 2 mg/kg bid AK0529 in infants hospitalized with RSV infection. Further study on AK0529 is warranted. | PMC10368966 |
AUTHOR CONTRIBUTIONS | PMC10368966 | |||
CONFLICT OF INTEREST STATEMENT | RSV diseases | JZW is a co‐inventor of patents (WO2013020993A, 2012; CN105726488B, 2014) covering a compound targeting RSV diseases and a preparation method of the formula. ST and JZW are co‐inventors of a patent (WO2021083290A1; 2020) covering RSV fusion protein inhibitor composition and its use for the treatment and prophylaxis of RSV. FG, ST, GZ, and JZW are or were employees of and are shareholders in Ark Biosciences. JPD served as a compensated scientific consultant for Ark Biosciences and is a shareholder in the company. All other authors declare no competing interests. | PMC10368966 | |
ETHICS APPROVAL STATEMENT | The ethics committee at each trial center approved the trial. All subjects' parents or legal guardians provided written informed consent. All subjects' parents or legal guardians provided written informed consent. | PMC10368966 | ||
Supporting information |
Click here for additional data file. | PMC10368966 | ||
ACKNOWLEDGEMENTS | BRUCE, FRANK | The authors would like to acknowledge the contribution of Professor Stephen Allen of the Liverpool School of Tropical Medicine for leading the SRC, Wynne Cheng and Frank Hsu of Tigermed for project management and biostatistical work, Drs. Bruce Green and Fran Stringer of Model Answers for biometrics supports. We gratefully acknowledge editorial assistance by Pelle Stolt PhD, Basel, Switzerland. | PMC10368966 | |
DATA AVAILABILITY STATEMENT | As this is a study in pediatric patients, the raw data are not publicly available because of privacy and ethical restrictions. | PMC10368966 | ||
REFERENCES | PMC10368966 | |||
Background | AUD | DISORDER | Motivational enhancement therapy (MET) has shown to be efficacious as treatment of alcohol use disorder (AUD), in reducing alcohol consumption and related consequences. However, qualitative research on how patients perceive this treatment is lacking. The aim of this study was to explore how patients experience MET as a treatment for AUD. | PMC10357895 |
Methods | Fifteen patients (8/7 female/male) participated in semi-structured interviews after receiving MET at a specialized addiction outpatient clinic in Sweden. Data were analyzed by thematic analysis. | PMC10357895 | ||
Results | Five themes were identified: the therapist conveyed the MI-spirit, the therapist did not guide on how to reach the goal, participants were committed to change before starting treatment, participants were uncertain if treatment was enough to maintain change, and significant others were not wanted in sessions. Participants appreciated the supportive relationship with their therapist, but some experienced therapy as overly positive, with no room to talk about failure. Further, they experienced a low level of guidance in goal-setting. For some, this was empowering, while others requested more direction and advice. Participants perceived their motivational process to have started before treatment. MET was considered to be too brief. None of the participants brought a significant other to a session. | PMC10357895 | ||
Keywords | Open access funding provided by Karolinska Institute. | PMC10357895 | ||
Introduction | goal-related behaviors, AUD | DISORDERS | Motivation is essential for a person to achieve behavior change and maintain goal-related behaviors [Since the introduction of MI more than 30 years ago, several meta-analyses have been conducted to investigate its effectiveness [Motivational enhancement therapy (MET) is a manualized version of MI for the treatment of alcohol use disorders (AUD) that was introduced in the 1990s as one of three interventions investigated in Project MATCH [Although outcomes of MI and MET have been studied extensively, studies involving patient perspectives on the treatments are lacking [Taken together, MET is scientifically proven to be effective in terms of reducing alcohol consumption and related consequences. Despite this, patient experiences of MET are not well-investigated, more specifically as regards how the main aim of MET—to support and maintain change—is achieved from the patient perspective. In the current study, the aim was to investigate patient experiences and thoughts on participating in MET. Further, the aim was to explore which treatment features, if any, were perceived as helpful, and if patients experienced that MET treatment was sufficient to achieve the desired change in drinking behavior. | PMC10357895 |
Methods | PMC10357895 | |||
Participants and procedure | psychiatric | DISORDER | Participants were recruited within a randomized controlled trial (RCT) in Stockholm, Sweden, that investigated the efficacy of two psychological treatments: Behavioral Self-control Training (BSCT) and MET, including 250 individuals with AUD and a goal of controlled drinking. The primary outcome of the trial has been reported elsewhere. For detailed information on participants and study procedures in the RCT, see Ingesson Hammarberg, in press. The original trial was approved by the Regional Ethics Board in Stockholm (DNR: 2016/634-31/2). The current study was approved by the Regional Ethics Board, as an amendment to the original study. The trial was retrospectively registered in ISRCTN (14,539,251) (05/06/2018). The study was conducted in accordance with the Declaration of Helsinki and was reported in accordance with the Consolidated criteria for Reporting Qualitative research) (COREQ) checklist [All patients underwent assessment as part of the clinical trial protocol, including of level of alcohol consumption, alcohol-related consequences, and psychiatric diagnostics. Inclusion criteria were: a stated goal of controlled drinking, fulfilment of a diagnosis of alcohol use disorder, and age 18–70 years. Exclusion criteria were: fulfilment of any other substance use disorder except nicotine, severe psychiatric comorbidity, and severe somatic risk related to continuous alcohol consumption.Participants in this study were recruited during 2021, among those who had received MET and attended the 26-week follow-up in the RCT. If consenting, participants took part in an interview either via a video meeting platform or by telephone. All participants gave verbal and written consent to participate and to data being used in a scientific publication. The interviews were audio-recorded and then transcribed by the interviewers. None of the participants withdrew consent after being interviewed and there was no reimbursement for their participation. | PMC10357895 |
Motivational enhancement therapy | MET, as applied in this study, included four sessions, and was distributed over 12 weeks [ | PMC10357895 | ||
Therapists | Five MET therapists were involved in the current study. All had extensive training in MI and MET, with clinical experience in both MI and MET ranging from 10 to 20 years. Therapists attended regular supervision meetings and received regular feedback on their recordings in accordance with the Motivational Interviewing Treatment Integrity Code (MITI) protocol 4.2.1 [ | PMC10357895 | ||
Measures | PMC10357895 | |||
Baseline measures | Baseline measures, as well as sociodemographic data, were collected as part of the clinical trial protocol. Alcohol consumption was assessed using the timeline follow-back method [ | PMC10357895 | ||
Interviews | A semi-structured interview guide was developed by the research team. Four areas were covered: (1) The treatment experience, and if there were positive and negative features. (2) Whether the treatment was helpful and, if so, in what way? If not, in what way? (3) Was the treatment sufficient to achieve change regarding alcohol consumption? To what extent? In what way? (4) Thoughts about involving a significant other (SO) in the treatment. The guide was discussed after the first interview and was not changed thereafter.The interview guide allowed for participants to freely express opinions and permitted follow-up questions from the researcher. The approach to data was inductive, as research questions and interview guide were not chosen based on a specific theory or concept that we wanted to explore. Rather, they were based on our interests and clinical experiences on how patients perceived the therapeutic intervention. | PMC10357895 |
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