title stringlengths 1 1.19k | keywords stringlengths 0 668 | concept stringlengths 0 909 | paragraph stringlengths 0 61.8k | PMID stringlengths 10 11 |
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Authors’ contributions | All authors (SA, EH, IJ, LA and AF) contributed to conceptualizing the study. SA wrote the first draft and all authors participated in revising the final draft. SA and AF conducted the initial analyses. EH contributed with the statistical analysis. All authors contributed to validating the analyses and have approved the final manuscript. | PMC10585814 | ||
Funding | ALF | This work was supported by the Swedish Research Council for Health, Working Life and Welfare (reference number 2016–07418, 2017 − 00557 and 2019 − 01726) and was financed by grants from the Swedish state under the ALF agreement between the country councils and the Swedish government (ALFGBG-772191 and ALFGBG-932659).Open access funding provided by University of Gothenburg. | PMC10585814 | |
Data availability | As dictated by the ethical body that approved the study and the promise to participants in their informed consent, the raw study data cannot be shared publicly as the data contain potentially identifying or sensitive patient information. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10585814 | ||
Declarations | PMC10585814 | |||
Ethical approval and patient consent | Ethical approval was obtained from the Regional Ethical Review Board in Gothenburg, Sweden (DNr 497 − 17). Informed consent was obtained from all subjects and/or their legal guardian(s). All methods were carried out in accordance with relevant guidelines and regulations. | PMC10585814 | ||
Consent for publication | Not applicable. | PMC10585814 | ||
Competing interests | The authors declare no competing interests. | PMC10585814 | ||
References | PMC10585814 | |||
Objectives | orthodontic | Academic Editor: Vikram Dalal This study aimed to evaluate the effects of different cleaning regimes of acrylic-based removable orthodontic appliances on bacterial biofilm formation and whether the surface modification, i.e., polished acrylic fitting surface, reduces biofilm formation. | PMC10586913 | |
Materials and Methods | thirty-nine orthodontic, denture, orthodontic | This double-blind, parallel, randomized clinical trial involved thirty-nine orthodontic patients indicated for removable orthodontic appliances. The patients were allocated into three groups according to the cleaning method: brushing with a denture brush and chlorhexidine (CHX) toothpaste, Lacalut cleaning tablet, and a combination of both cleaning methods. Each patient wore an upper removable appliance containing eight wells fitted with eight detachable acrylic tiles (four polished and four unpolished) for seven days. Five types of oral microbiota were evaluated using selective growth media and biochemical tests. The biofilm cleaning efficacy was assessed using the colony-forming unit (CFU) and scanning electron microscopy (SEM). | PMC10586913 | |
Results | There was no significant difference among the three cleaning methods on the polished or unpolished tiles. However, in polished tiles, streptococci were significantly reduced in all cleaning methods, whereas staphylococci and | PMC10586913 | ||
Conclusions | Polishing the fitting surface of an acrylic-based orthodontic appliance reduced the tested bacterial biofilm formation and may enhance cleaning efficiency. Brushing and combination methods showed superior cleaning effects compared to cleaning tablets. This trial is registered with | PMC10586913 | ||
1. Introduction | orthodontic, malocclusions | ADHESION | People seeking orthodontic treatment have increased not only to correct their malocclusions but also to improve mastication, speech, appearance, overall health, comfort, and self-esteem [Maintaining good oral hygiene is integral to successful orthodontic treatment [This clinical trial was designed to compare the effectiveness of different cleaning methods, including brushing with chlorhexidine (CHX) toothpaste, the use of cleaning tablets, and a combination of both protocols on biofilm removal on acrylic-based removable orthodontic appliances, and to assess whether polishing the fitting surface has an impact on biofilm adhesion and growth. | PMC10586913 |
2. Methods | PMC10586913 | |||
2.1. Trial Design | This double-blind, parallel, randomized clinical trial was approved by the Ethical and Board Committee of College of Dentistry, University of Baghdad (issue no. 598/April 2022), and registered under protocol ID ClinicalTrials.gov: | PMC10586913 | ||
2.2. Participants | orthodontic | MINOR | Thirty-nine subjects were recruited from the Department of Orthodontics at the College of Dentistry. Those included 24 females and 15 males aged 16–31 (a mean of 23.1 years). Those patients fulfilled the following criteria [Patients who were clinically fit and healthy and had no history of systemic diseasesPatient who had been scheduled to wear an upper removable orthodontic appliance due to minor tooth discrepanciesThe presence of full upper permanent dentitionPatients who had no history of sensitivity to persulfate or chlorhexidineCaries-free patients with good oral hygieneThe exclusion criteria are as follows:Participants who were under steroid-based medications, broad-spectrum antibiotics, or antibacterial mouthwash two months before the experimentPatients who were smoking or tobacco eatersMouth breatherPregnant or lactating femaleThe study protocol was explained to the participants verbally and in writing, and written informed consent was obtained from each participant. | PMC10586913 |
2.3. Randomization | A computer random number generator developed a simple, nonstratified randomization of three groups ( | PMC10586913 | ||
2.4. Allocation Concealment | It was accomplished using an opaque and sealed pack marked with a treatment allocation code. Each pack contained the allocated cleaning materials and an instruction card that an independent person gave. | PMC10586913 | ||
2.5. Interventions | PMC10586913 | |||
2.5.1. Construction of Removable Appliance with Acrylic Tiles of Different Surface Textures | Acrylic tiles (5.5 mm × 1 mm) of two surface textures were made from an acrylic block of 1 mm thickness using a mould of silicone rubber (Rema® Sil silicone duplicating material, Dentaurum, Ispringen, Germany) [After obtaining the consent form, an impression was taken on the maxillary arch using alginate impression material (Hydrogum 5, Zhermack, Badia Polesine, Italy). The negative replica was then poured using type IV stone to make a study model and coated with a separating medium (Separating Agent, Shanghai New Century Dental Materials Co., Ltd., Shanghai, China). Eight detachable metal discs of 5.5 mm × 1.2 mm were distributed on the palatal side of the stone model (The acrylic tiles, with different roughnesses, were randomly seated and fixed into the wells using sticky wax (The appliance was sterilized using 115 V UV light in a UV sterilization hood (Dahian Labtech Co., Laminar hood, Korea) for 15 minutes [ | PMC10586913 | ||
2.5.2. Patient Grouping | denture | The patients were randomly divided into three groups:Lacalut cleaning tablet group: Patients were instructed to use one tablet (LacalutDent, Lacalut, Germany) dissolved in 150 ml of tap water. The appliance was soaked for 20 minutes and then washed with tap water.Brushing with CHX toothpaste group: Patients were instructed to clean the appliance with a denture brush (Foramen Denture Brush, Spain) loaded with CHX toothpaste (LacalutActive, Lacalut, Germany) for one minute and then washed with tap water.Combination group: Patients were instructed to clean the appliance using a brush and CHX toothpaste, similar to the brushing group, followed by soaking it in the cleaning tablet solution for 20 minutes. The appliance was then washed with tap water.The patients were asked to wear the appliance for seven days and follow the instructions and the sealed cleaning method assigned. | PMC10586913 | |
2.5.3. Sample Collection | STERILE | A CONSORT flow diagram illustrating subjects' flow during the clinical trial was followed (After seven days of wearing the appliance, three acrylic tiles of each roughness category were gently removed from their wells using a metal pin through the chimney-like structure without disturbing the biofilm. The tiles were held using a sterile tweezer and immersed twice in a 15 ml bijou tube containing phosphate buffer saline (Sigma-Aldrich) to remove the planktonic bacteria and then inserted into a 1.5 ml bijou tube containing 1 ml PBS and vortex mixed for 1 minute to disseminate the biofilm and create a homogenous solution. A ten-fold serial dilution was carried out using PBS, and 50 Bacteria were distinguished by colony morphology and were characterized by Gram reaction [ | PMC10586913 | |
2.5.4. Scanning Electron Microscope (SEM) | The fourth acrylic tile (of each roughness category) was removed from the appliance aseptically and immersed carefully in a Petri dish containing PBS (Sigma-Aldrich). The sample was prepared for SEM using a previously suggested protocol [ | PMC10586913 | ||
2.6. Statistical Analysis | Data from the colony-forming unit (CFU) using different cleansing methods were compared, following log transformation, using one-way analysis of variance (ANOVA). The polished and unpolished tiles were compared for biofilm formation on each cleansing method using independent | PMC10586913 | ||
3. Results | The results showed no significant difference among different cleaning methods regarding staphylococci, streptococci, and total anaerobic bacterial biofilm on polished tiles (Similarly, there was no significant difference among different cleaning methods regarding the tested bacterial biofilm on unpolished tiles (
The SEM micrographs of the polished and unpolished tiles revealed that the unpolished acrylic tiles showed a similar amount of bacterial biofilm, irrespective of the cleaning method. However, all cleaning methods in polished tiles were effective and demonstrated fewer biofilm aggregates ( | PMC10586913 | ||
4. Discussion | cleft lip, MPS, orthodontic, palate | ADHESION | This randomized clinical trial was designed to compare the effects of mechanical and chemical cleansing methods on bacterial biofilm attached to acrylic-based removable orthodontic appliances. It was reported that the prevalence of opportunistic pathogens was higher in PMMA-based intraoral devices such as feeding appliances in cleft lip and palate patients, orthodontic retainers, and prosthodontic prostheses [The sample size was estimated based on a pilot study of 8 participants' appliances for cultivated staphylococci counts, with a mean of 1200 CFU for the Lacalut cleaning tablet and 800 CFU for the brushing group. A total of 12 patients were needed per group to yield an alpha value of 0.05 with a study power of 80%. A 10% dropout was estimated, which renders the total sample of 39 patients. The sample size was comparable to many previously published randomized clinical trials conducted on biofilm formation on dentures and disinfection methods.This study showed no significant difference among the cleaning methods on bacterial biofilm in unpolished groups. A similar result was found in the polished groups. It was found that the acrylic resin, i.e., the autopolymerized acrylic resin in this study, was apron to bacterial adhesion due to several surface properties, including surface hydrophobicity, surface free energy, and surface roughness [However, previous clinical trials suggested that brushing reduced denture biofilm formation compared with immersion in a peroxide solution [Regarding the comparison of the polished and unpolished tiles, the data showed that the polished surface significantly facilitated Furthermore, the Lacalut cleaning tablet contains potassium monopersulphate (MPS), a broad-spectrum disinfectant that oxidizes the bacterial protein capsids and evacuates cell content; its action depends on the contact time and concentration [The SEM micrographs showed the superior cleaning results of the combination method, followed by the brushing and the cleaning tablet methods; this was true for the polished and unpolished surfaces; however, there was a dispersed distribution of the bacterial aggregates in the polished samples, which showed a relatively cleaner surface. This agreed with the finding reported by Al Groosh et al. [ | PMC10586913 |
4.1. Study Limitations | diabetes | DIABETES | There are limitations encountered in the current study. These include the microbial diversity between individuals and the response of bacterial species to individual cleaning methods.Furthermore, this study was conducted on clinically fit and healthy patients, and further investigation may widen the scope of its novelty, i.e., patients with diabetes, immune suppressive medications, or those with obturators such as “baby feeding plates,” orthodontic retainers, prosthodontic prostheses, etc. | PMC10586913 |
5. Conclusion | The study found that polishing the acrylic surface significantly reduced bacterial biofilm, regardless of the cleansing method used. Furthermore, brushing and the combination cleaning methods showed superior cleaning efficacy compared to the Lacalut cleaning tablet for all tested bacteria in polished acrylic samples. | PMC10586913 | ||
Acknowledgments | The authors would like to thank Ms. Samar Qahtan, the technical manager at the Orthodontic Department/College of Dentistry, University of Baghdad, for her help with the appliance fabrication. The authors would also like to thank ClinicalTrials.gov for providing a valuable platform for the registration and dissemination of this clinical trial information. They also acknowledge that the availability of this resource was instrumental in the execution of our study. This work was self-funded. | PMC10586913 | ||
Data Availability | The data used to support the findings of this study are available from the corresponding author upon request. | PMC10586913 | ||
Conflicts of Interest | The authors declare that they have no conflicts of interest. | PMC10586913 | ||
Authors' Contributions | orthodontic | DHA conceptualized and designed the study, interpreted the results, contributed to critical revision, and finally approved the manuscript. SIK collected data, analysed the study, performed statistics, and wrote the manuscript. All authors have approved the final version of the manuscript.Acrylic tiles made from polished and unpolished acrylic sheets.Construction of a modified acrylic-based orthodontic appliance. (a) Study model with metal discs; (b) fitting surface of the removable acrylic appliance with a chimney-like structure.Each appliance contained eight wells to house: four (5.5 mm) diameter polished tiles (yellow) and four similar diameter unpolished tiles (purple). The allocation of the polished tiles to the left or right sides, anterior or posterior of the removable appliance, was decided by a randomized number sheet; the unpolished tiles were subsequently inserted into the wells on the contralateral side.CONSORT flow diagram of subject randomization and selection criteria.Bar chart of streptococci and total anaerobic bacteria among groups on polished and unpolished tiles. Error bars represent the standard error of measurements for 13 patients in three separate sample runs (Bar chart of staphylococci among groups on polished and unpolished acrylic tiles. Error bars represent the standard error of measurements for 13 patients in three separate sample runs (SEM micrographs of retrieved acrylic tiles. (a–c) The unpolished acrylic tiles cleaned with the Lacalut cleaning tablet, brushing with CHX toothpaste, and a combination of methods, respectively. (d–f) The polished acrylic tiles cleaned with the Lacalut cleaning tablet, brushing with CHX toothpaste, and a combination of methods, respectively, using conventional laboratory polishing procedures.Comparison of bacterial biofilm on polished tiles among the three cleaning methods using the ANOVA test.Comparison of bacterial biofilm on unpolished tiles among the three cleaning methods using the ANOVA test.Comparisons of bacterial biofilm on polished and unpolished acrylic tiles of three cleaning methods using the independent
| PMC10586913 | |
Results | PMC10077489 | |||
Development of albuminuria and increased glomerular permeability in early DN is ameliorated by MR antagonism. | After receiving streptozotocin (STZ), rats were hyperglycemic at week 3 ( | PMC10077489 | ||
The effect of MR antagonism in preventing the diabetes-induced increase in glomerular permeability is dependent on the GEnGlx. | Hyaluronidase, a Glx-degrading enzyme, was infused in a subgroup of spironolactone-treated diabetic rats to remove the EnGlx to confirm the importance of GEnGlx preservation in this model ( | PMC10077489 | ||
Increased MMP activity in early DN is ameliorated by MR antagonism. | We have previously identified MMP2 and MMP9 as key Glx sheddases ( | PMC10077489 | ||
Exposing human GEnC to diabetic conditions resulted in MMP upregulation and GEnGlx damage that were both ameliorated by MR antagonism. | Secreted gelatinases MMP2 and MMP9 can be activated by cell membrane–bound membrane type 1 MMP, also known as MMP14 ( | PMC10077489 | ||
The GEnGlx is damaged in human DN. | Human renal biopsies were obtained from two centers (Bristol, United Kingdom; Bari, Italy) ( | PMC10077489 | ||
MR antagonism in human diabetes reduces urinary MMP activity. | Previously, Mehdi et al. confirmed that the addition of spironolactone to a regimen including maximal ACE inhibition improved renoprotection in DN ( | PMC10077489 | ||
Discussion | albuminuria, GEnGlx damage, diabetes, STZ-induced diabetic, diabetic, MR, glomerular dysfunction | DISEASE, DYSFUNCTION, ADVERSE EFFECTS, PEARLY DISEASE, DIABETES | Using a rat model of diabetes, we have demonstrated that upregulation of MMPs, GEnGlx damage, and glomerular dysfunction develop rapidly before other visible markers of DN. MR antagonism preserved the GEnGlx and restored GFB function. In vitro, using human GEnC exposed to a diabetic environment, we also observed upregulation of MMPs and glycocalyx damage, effects ameliorated by MR antagonism. In addition, we confirmed that GEnGlx damage occurs in human DN and may contribute to the disease phenotype. Finally, we have demonstrated that MR antagonism in human DN reduced MMP activity, with associated reductions in albuminuria. Together, these data suggest that alternative approaches to limit MMP activity and GEnGlx damage may reproduce the effect of MR inhibition while limiting side effects.STZ-induced diabetic rats provide a good model of early changes in DN (The GEnGlx plays an important role in GFB function, limiting albumin permeability (Hyaluronan is a key Glx component that is shed in diabetes (MR-induced MMPs are likely to contribute to Glx damage in DN. In mice, we have demonstrated increased MMP activity induced by excess aldosterone (MR is widely expressed by vascular endothelial cells, including GEnC, (In humans, the absence of GBM and podocyte changes in early disease, along with systemic endothelial and Glx dysfunction seen in both type 1 (In summary, we have shown that MR antagonism prevented damage to the GEnGlx and normalized glomerular albumin permeability in early DN. By applying potentially novel, validated techniques, we have demonstrated that GEnGlx damage may contribute to the disease phenotype in human DN. In addition, MR antagonism in DN reduced MMP activity, highlighting a mechanism of Glx protection. Alternative approaches to block MR-induced GEnGlx dysfunction, to reproduce the benefit of MR antagonists in DN without the adverse effects, warrant further investigation. | PMC10077489 |
Methods | PMC10077489 | |||
Animals. | Male Wistar rats (150–200 g, Charles River Laboratories) were maintained by the Animal Services Unit, University of Bristol. Animals were housed in a conventional facility with a controlled environment (21°C–24°C and 12:12 hour light/dark cycle). Timelines of the experimental protocols used are included ( | PMC10077489 | ||
Type 1 diabetic model. | diabetic rats, diabetic, diabetes | DIABETES | For induction of diabetes, randomized rats were injected i.p. with 50 mg/kg STZ (S0130; Sigma-Aldrich) by adding the appropriate volume of the drug at 25 mg/mL in 10 mM sodium citrate (pH 4.5). Comparisons were made with vehicle-treated rats (10 mM sodium citrate [pH 4.5]). Glycemia, by tail-tip blood droplet analysis using a glucometer (Accu-Chek Aviva; Roche), was measured 3 weeks after STZ, and rats with glycemia ≥ 15 mmol/L were considered diabetic and included in the study.To confirm whether MR antagonism could preserve the GEnGlx and limit the development of DN, from 4 weeks after STZ administration, randomized diabetic rats were given daily s.c. injections of spironolactone (S3378; Sigma-Aldrich) at 50 mg/kg made up in corn oil (C8267; Sigma-Aldrich) for 28 days, and comparisons were made with vehicle-treated diabetic rats (corn oil). This spironolactone dose has previously been shown to have no effect on BP (To determine the importance of GEnGlx preservation in this model, enzymatic degradation of the GEnGlx with hyaluronidase was used. Briefly, randomized diabetic rats treated with spironolactone were given hyaluronidase (H3506; Sigma-Aldrich), 200 units in 1 mL, via tail vein injection 1 hour before being culled for tissue collection.Body weight was monitored regularly after STZ, and rats were placed on hydrophobic sand to collect urine. Urinary albumin was quantified with a rat albumin ELISA (E111-125, Bethyl Laboratories), and creatinine was measured using an enzymatic spectrophotometric assay (Konelab T-Series 981845; Thermo Fisher Scientific). uACR and urinary protein/creatinine ratio (uPCR) were calculated as previously described ( | PMC10077489 |
Tissue collection. | For tissue collection, rats were anesthetized with isoflurane in 1 L/min oxygen. A midline laparotomy was performed, and the abdominal aorta was cannulated with PE-10 tubing (427400; Becton Dickinson) to flush both kidneys with Ringer solution (NaCl, 132 mM; KCl, 4.6 mM; MgSO | PMC10077489 | ||
Glomerular albumin permeability (Ps’ | The glomerular P | PMC10077489 | ||
Lectin staining. | FLUOR | MOA, WGA, and UEA-I lectins have binding specificities for carbohydrate sequences present in the glycocalyx. MOA lectin binds to nonreducing terminal galactose-α-1,3-galactose-carbohydrates, WGA lectin binds to the sialyloligosaccharides, N-Acetylglucosamine and N-Acetylneuraminic acid, and UEA-I binds to α-L-fucose. Lectins were labeled with biotin or FlTC: biotinylated MOA (Z8-BA-9001-1, TCS Biosciences, 2 mg/mL; 1:100); FITC-WGA (GTX01502; GeneTex; 5 mg/mL; 1:500); and biotinylated UEA-I (GTX01511; GeneTex; 2 mg/mL; 1:200):Paraffin-embedded kidney sections (5 μm) were dewaxed in Histo-Clear II (National Diagnostics) followed by rehydration in graded ethanol and a wash in PBS. All sections were incubated in blocking buffer (1% BSA in PBS containing 0.1% Tween) for 30 minutes. For biotinylated lectins, this was followed by endogenous biotin blocking using a streptavidin/biotin blocking kit (SP-2002; Vector Laboratories). After 2 washes, the sections were incubated with the biotinylated lectin (pH 6.8) overnight at 4°C. Buffer only was used as a negative control. After 4 washes, the sections were incubated with streptavidin–Alexa Fluor 488 (1:500, S32354; Thermo Fisher Scientific) (pH 6.8) for 1 hour at room temperature. For FITC-labeled lectins, the sections were incubated overnight at 4°C (pH 6.8). Then, for all sections, the nuclei were counterstained with 4′,6-diamidino-2-phenylindole (D1306; Thermo Fisher Scientific) and the cell membrane was labeled with R18 (1:1,000, O246; Thermo Fisher Scientific) for 10 minutes at room temperature. After a 2-minute wash in PBS, the coverslips were mounted in Vectashield mounting medium (H-1000; Vector Laboratories) and examined using either an AF600 LX wide-field fluorescence microscope (Leica Microsystems) or a Leica SP5-II confocal laser scanning microscope attached to a Leica DMI 6000 inverted epifluorescence microscope. | PMC10077489 | |
Fluorescent profile confocal peak-to-peak analysis. | Initially, the fluorescence profile peak-to-peak assessment was carried out, blinded using a manual methodology, as previously described ( | PMC10077489 | ||
PAS staining. | Rat paraffin-embedded kidney sections from perfused kidneys were stained using a periodic acid–Schiff (PAS) kit according to the manufacturer’s instructions. Images were quantified with ImageJ using the Haematoxylin PAS color deconvolution plug-in. Corrected total cell intensity values were calculated as follows: integrated density (area of glomerulus × background mean gray value). Ten glomeruli were analyzed per rat. | PMC10077489 | ||
TEM. | TEM | Perfusion-fixed right kidneys were used for TEM, as described previously, to measure GEnC, GBM, and podocyte parameters to identify effects on GFB ultrastructure that could explain changes in glomerular permeability ( | PMC10077489 | |
MMP activity. | AS-72017 | MMP2 activity was studied using the MMP2 Biotrack activity assay (RPN2631; GE Healthcare) and the SensoLyte Plus 520 MMP2 assay (AS-72224; AnaSpec). MMP9 activity was studied using the SensoLyte Plus 520 MMP9 assay (AS-72017; AnaSpec). The manufacturer’s instructions were followed in full. Urinary active MMP2 and MMP9 were normalized to creatinine. Glomerular active MMP2 and MMP9 were normalized to total protein using the Pierce BCA protein assay (23225; Thermo Fisher Scientific). The fold change relative to control was calculated to enable pooling of results from different experiments. | PMC10077489 | |
Cell culture. | Human CiGEnC ( | PMC10077489 | ||
Human renal samples. | TBMN | RENAL, EMERGENCY | Renal biopsy samples from 34 patients were obtained from the Histopathology Department of Southmead Hospital (Bristol, United Kingdom) and Aldo Moro University of Bari (Division of Nephrology, Dialysis and Transplantation, Department of Emergency and Organ Transplantation; Bari, Italy). Tissue was immersion fixed in 10% neutral buffered formalin and embedded in paraffin. Samples had been clinicopathologically diagnosed, including 19 patients with DN, 8 patients with TBMN and 7 histologically normal control patients ( | PMC10077489 |
Human urine samples. | diabetes | DIABETES | Urine samples from 35 patients were obtained from a double-blind, placebo-controlled trial conducted in patients with diabetes as previously described ( | PMC10077489 |
Statistics. | All statistics were calculated using Prism 8 (GraphPad). Normality was assessed visually and using the Shapiro-Wilk test. Where data was normally distributed, a 1-way ANOVA or Student’s 2-tailed | PMC10077489 | ||
Study approval. | All animal protocols were approved by the UK Government Home Office and conformed to the | PMC10077489 | ||
Author contributions | HLH, CJD, RDR | CJD | MC, GIW, RRF, SCS, and MJB designed research; MC, JKF, RDR, ASO, LKD, and MJB performed research; JS, CJD, SJH, PP, LG, HLH, and RDT contributed resources; MC, JKF, KLO, ASO, MG, LS, KHW, and MJB analyzed data; MC, SCS, and MJB wrote paper; and all authors approved the final version of the manuscript. | PMC10077489 |
Supplementary Material | PMC10077489 | |||
02/07/2023 | In-Press Preview | PMC10077489 | ||
03/08/2023 | Electronic publication | PMC10077489 | ||
Development of albuminuria and increased glomerular permeability in early diabetic nephropathy is ameliorated by MR antagonism. | ( | PMC10077489 | ||
Fluorescence profile peak-to-peak measurements confirm that glomerular endothelial glycocalyx damage is prevented by MR antagonism and correlates strongly with glomerular albumin permeability. | Rats were perfused with Ringer solution, and the left kidney was removed for lectin staining. ( | PMC10077489 | ||
The effect of MR antagonism in preventing the diabetes-induced increase in glomerular permeability is dependent on the glomerular endothelial glycocalyx. | ( | PMC10077489 | ||
Increased matrix metalloproteinase activity in early diabetic nephropathy is ameliorated by MR antagonism. | ( | PMC10077489 | ||
Exposing human GEnC to diabetic conditions resulted in MMP upregulation and GEnGlx damage, effects ameliorated by MR antagonism. | diabetic | Human conditionally immortalized glomerular endothelial cells (CiGEnC) were maintained in the presence of glucose, insulin, TNF-α, and IL-6 to mimic a diabetic environment. ( | PMC10077489 | |
The glomerular endothelial glycocalyx is damaged in human diabetic nephropathy. | ( | PMC10077489 | ||
Matrix metalloproteinase activity in human diabetes is reduced by MR antagonism. | Matrix metalloproteinase (MMP) activities were measured for the sheddases MMP2 and MMP9. ( | PMC10077489 | ||
Clinical and analytical data at the time of renal biopsy | PMC10077489 | |||
Clinical and analytical data at the time of urine sample | PMC10077489 | |||
Keywords | PMC10357344 | |||
Introduction | In recent years, improved price transparency of pharmaceuticals has emerged as an important yet highly debated approach to manage medicine prices. This approach is believed to contribute to expanded access to medicines through the reduction of medicine prices The importance of promoting price transparency has also been reflected in various initiatives and regulations aiming to enhance transparent pricing. One such example is the Medicines Transparency Alliance (MeTA) initiative by the World Health Organization (WHO), which sought to develop national-level multistakeholder platforms to share data on the selection, procurement, quality, availability, pricing, promotion and use of medicines [The underlying rationale for promoting price transparency is that it may improve economic efficiency, as conventional economic theory indicates; assist policymakers and researchers through reliable price information; empower buyers to negotiate more strategically; increase accountability of manufacturers and governments for prices; and promote cost-effective decision-making by prescribers and patients [At the same time, there are concerns that improving transparency may lead to an increase in prices for lower-income countries, as manufacturers might abandon differential pricing schemes and apply uniform pricing for all countries to refrain from the appearance of unfair pricing | PMC10357344 | ||
Methods | This systematic review was undertaken according to the principles of systematic reviewing embodied in the Cochrane Handbook and guidance document published by the Centre for Reviews and Dissemination (CRD) [As part of a wider review on ten pharmaceutical pricing policies, this paper only addresses policies promoting price transparency as a pricing approach. | PMC10357344 | ||
Search strategy and selection criteria | An extensive literature search was performed between September 5 and October 10, 2019, for relevant articles published from 2004 to the search date in a large number of databases including but not limited to Ovid MEDLINE (Ovid), Embase (Ovid), Social Science Citation Index, EconLit, and the NHS Economic Evaluations Database (NHS EED). A variety of grey literature sources were also searched. The main structure of the search strategy comprised concepts pertaining to 1) non-specific pharmaceutical pricing policies (e.g. terminology related to pricing/prices combined with terms for medicines) or to 2) pharmaceuticals and one of ten specific pricing policies, among which were policies promoting price transparency (e.g. terminology related to pricing/prices combined with terms for transparency, including related terms such as disclosure, rebates, sharing, and accountability). Supplementary search approaches included reference-list checking and contacting experts. | PMC10357344 | ||
Selection criteria | This systematic review only included studies that used robust experimental or observational study designs comparing policies promoting price transparency (see Definition of the policy intervention. | PMC10357344 | ||
Study selection | TB | A single researcher assessed all titles and abstracts identified from the database searches and removed the obviously irrelevant records based on titles and abstracts. Two reviewers independently screened the titles and abstracts of potentially eligible records, with disagreements adjudicated by a third reviewer. The full texts of studies identified as potentially relevant were then subject to an eligibility check by two members of the review team independently (TB and CL or IRJ and HAvdH) before data extraction. Disagreements about study selection were resolved by discussion, and if consensus could not be reached, a third reviewer (DT or AKM-T) was consulted. | PMC10357344 | |
Data extraction and quality assessment | Data from included studies was extracted by one member of the review team (IRJ or LT) using a standardized data extraction form, including information on study design, setting and subjects, interventions including implementation strategies, outcomes, and results including contextual factors. Extracted data was verified by a second reviewer (HAvdH or DT) for accuracy.The risk of bias in each included study was assessed by the extracting reviewer and checked by a second reviewer. Any disagreements were resolved by discussion until a consensus was reached. The assessment was done according to the EPOC guidelines, in which bias assessment criteria were adapted to study design The quality of the evidence was assessed by use of the GRADE methodology | PMC10357344 | ||
Data analysis | Substantial expected differences in the characteristics and contexts of included studies meant we did not aim to undertake a meta-analysis. Instead, we provided a narrative summary describing the quality of the studies, the relationship between interventions and patterns discerned in the data. | PMC10357344 | ||
Results | Electronic database and grey literature searches identified 43,693 records for all ten pricing policies combined. The review of relevant reference lists and other sources yielded a further 2,345 records. After removal of duplicates, 32,011 articles were screened by title and abstract, resulting in 1,000 potential articles to be included in the wider review. Nine of these articles were specific to policies promoting price transparency at first sight. After full-text screening, three scientific articles covering two policy measures were included in this section of the systematic review (Both studies identified had an interrupted time series design, one examining data from the United Kingdom Summary of included studies.ITS=Interrupted time series.The results of the risk of bias assessment are presented in Risk of bias assessment of included studies.Bias domains only applicable to ITS and RM studies. Moodley et al. | PMC10357344 | ||
Discussion | Following extensive searches, we found only two studies assessing an intervention promoting price transparency in a manner sufficiently robust for inclusion in this review. It is worth noting that the SEP, while introducing transparency in the private market, also included aspects of price control other than price transparency. With that, evidence on measures that exclusively promote price transparency is even more limited. Nevertheless, the results show that the majority of patient prices of both originator and generic medicines were reduced following a national measure that introduced transparency on the level of the manufacturer. Not only did this policy achieve the intended price reduction, it has also improved accountability of manufacturers through mandatory price disclosure. Findings on the impact of cost-feedback approaches to prescribers are considered inconclusive, due to inconsistent results for different therapeutics. Information about the effects on volume, availability or affordability is currently missing for all transparency initiatives. The 2020 WHO Guideline on Country Pharmaceutical Pricing Policies suggests that countries improve the transparency of pricing and prices, informed by the limited research evidence and additional qualitative information that was considered The 2015 WHO Guideline on Country Pharmaceutical Pricing Policies did not yet include policies promoting price transparency in its scope The WHA's resolution to advance the transparency of markets for pharmaceuticals was considered controversial [The strengths of our systematic review include the use of a rigorous methodological approach, following a pre-defined protocol Our study has several limitations. As noted before, the search resources included grey literature sources. Although important to include such resources, many of the databases have very limited search and exporting functionalities. For those resources, we had to use a more limited range of search terms. This pragmatic search approach is a limitation of the search methods, but should be seen within the wide range of search approaches described above. Another limitation might arise from the heterogeneity of price transparency measures, which may often be interwoven with other pricing policies or which may not be described as a transparency measure by the authors of the study. To minimize this limitation, a standard systematic review approach of using a highly sensitive search approach was used with a broad definition of price transparency policies and search terms, which would identify all types of transparency measures were used. Nevertheless, there is always the chance of missing relevant studies. However, we note that experts in the field were consulted to mitigate this risk. Additionally, the scoping review on transparency measures mentioned earlier, did not identify any studies that we had missed The evidence identified on price transparency measures may be limited in applicability, despite its broad relevance in both high- and low-income economies [Although opportunities for research on transparency measures seem to be limited due to a ‘Catch-22’ dilemma, it is crucial that when such opportunities do present, efforts of policy-makers and researchers are coordinated. This will help to ensure the collection of data for adequate monitoring of these policies. The conduct of small pilots may help to increase opportunities for evidence generation on the one hand and overcome the reluctance of policy-makers on the other. These future studies should focus on all levels that transparency measures may occur in, and not only on medicine prices or expenditures, but likewise on outcomes such as the volume, availability and affordability of medicines. There should also be a particular focus on unintended and potentially harmful effects of these policies, both in high- as well as in low-income settings. Additionally, the limited amount of evidence currently available is insufficient to elucidate what contextual factors and implementation strategies may influence the effects of such policies, and should be the object of further study. | PMC10357344 | ||
Conclusion | In conclusion, the lack of quantitative and comparative evidence assessing the impact of policies promoting price transparency is a clear call for further research. Collaborative pilots involving both national governments and researchers could help to align their interests and overcome the current inertia in evidence development. Additional evidence is needed to confirm the impact of a wide range of transparency measures on the management of medicine prices in countries all over the world. The evidence that is currently available, although from a single study, indicates that a national measure introducing price transparency along the supply chain may be effective in managing medicine prices. | PMC10357344 | ||
Role of the funding source | This systematic review was commissioned and funded by the World Health Organization [HQ/EMP/2019/002, 2019] under a grant from the United Kingdom Department for International Development (DFID). The review was part of the process for developing the 2020 WHO Guideline on Country Pharmaceutical Pricing Policies. The WHO secretariat and its advisors provided technical support for formulating the review protocol, performing specific searches on government websites, and translating several non-English publications. WHO, its advisors and DFID had no role in data analysis or interpretation. The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the WHO or DFID.Flow chart of study selection.The number of articles identified through database searching and screening by title and abstract shown in grey apply to the overall search; as per protocol the database search included search terms for all ten specific pricing policies among which policies promoting price transparency was one. The lower part of the flow chart shown in white is specific to the selection of studies on policies promoting price transparency. WoS=Web of Science.*Two articles are part of the same study, but were published separately. These references are considered | PMC10357344 | ||
Declaration of Competing Interest | This systematic review was commissioned and funded by the World Health Organization. | PMC10357344 | ||
References | PMC10357344 | |||
Supplementary materials | PMC10357344 | |||
Acknowledgements | TB | The authors are grateful to the members of the Guideline Development Group (GDG) and the World Health Organization (WHO) secretariat and its advisors for providing technical support while establishing the research protocol: Kiu Tay-Teo, Fatima Suleman, Lisa Bero, Sabine Vogler. Additionally, Zaheer Babar, Jaime Espin and Kalipso Chalkidou contributed with constructive remarks on an early draft of the protocol and the technical report. Colleagues at York Health Economics Consortium (YHEC) who contributed to the extensive search, document management and screening process include Ross Birtles, Mick Arber, Chris Bartlett, and James Mahon. We thank Lynn Al-Tayara (LT) for her role in extracting data and are grateful to the other members of our systematic review team: Christine Leopold (CL), Lizanne Arnoldy, Tom Buijs (TB) and Daniela Moye Holz.Supplementary material associated with this article can be found, in the online version, at doi: | PMC10357344 | |
2. Materials and Methods | PMC10536396 | |||
2.1. Study Design | arteria, ischaemic stroke | ISCHAEMIC STROKE | A randomised controlled monocentric study was conducted in a population of patients after their first ischaemic stroke in the arteria cerebri media basin who were admitted to a rehabilitation sanatorium. The study was approved by the Ethics Committee of the University of Ostrava Faculty of Medicine. All patients signed an informed consent. | PMC10536396 |
2.2. Participants | neurological disease, cardiovascular instability, cognitive impairment, Stroke, ischaemic stroke, epilepsy, dementia, low functional mobility, arteria | NEUROLOGICAL DISEASE, STROKE, EPILEPSY, ISCHAEMIC STROKE, EVENT, SEVERE VISUAL IMPAIRMENT | The study included patients after their first ischaemic stroke in the arteria cerebri media basin (time since the event <6 months) who were referred for rehabilitation for 4 to 5 weeks in a rehabilitation sanatorium in the Czech Republic, between November 2022 and March 2023. Patients were treated according to the European Stroke Organization (ESO) standard operating procedure based on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. All patients were treated pharmacologically prior to the start of rehabilitation, and during their stay in the rehabilitation facility, they underwent regular medical examinations at least once a week.The inclusion criteria for the study were those aged 40–79 years, in stable condition, with ability to participate, mini-mental state examination score <25 points, intact vision, preserved grip function of the thumb and index finger of the affected limb, and functional mobility according to Functional Ambulatory Category (FAC) 3–5.Study exclusion criteria included: age >40 and <79 years, decompensated state, cardiovascular instability, severe fatal and severe cognitive impairment, low functional mobility according to FAC 0–2, dementia with mini-mental state examination >24 points, severe visual impairment, and personal history of epilepsy. The selected patients had no other neurological disease that could affect the measurement results. All selected patients signed an informed consent to be included in the study. The study was approved by the Ethics Committee. | PMC10536396 |
2.3. Procedures | stroke, BBS, disability, cognitive deficits | STROKE | All patients underwent an initial examination (T0) by a trained occupational therapist on the first day after admission to the rehabilitation sanatorium. The mini-mental state examination (MMSE), the Barthel index (BI), the extended Barthel index (EBI), the Berg balance scale (BBS), and the WHO disability assessment schedule 2.0 (WHODAS 2.0) tests were performed. Mobility was assessed according to the FAC scale (0–5) [MMSE is the most widely used 10-item test to detect cognitive deficits, evaluating the patient’s orientation to time and space, short-term memory, numeracy, attention, speech, and constructive practical skills [BI is a tool used to assess functional capacity, the ability to perform basic activities of daily living after a stroke [EBI helps to assess the need for assistance in performing ADL where cognitive ability is a prerequisite [BBS assesses the patient’s static and dynamic balance [WHODAS 2.0 is an international standardised generic test that evaluates disability as defined by the International Classification of Functional Abilities [ | PMC10536396 |
2.4. Instruments Used | Oculus Quest 2 (Meta Quest 2) has 6 GB of RAM combined with the ultra-fast Qualcomm Snapdragon XR2 platform. It consists of a projection helmet and two controllers. The helmet houses two screens for the eyes with the ability to adjust focus and the addition of an eyeglass attachment. A fast switchable LCD display with low backlight persistence, 1832 × 1920 pixels per eye resolution, will allow visual fidelity of approximately 21 PPD (pixels per degree) without blurring or doubling artefacts. Adjustable straps are used to secure the helmet to the head. Both the right- and left-touch controllers have multiple control buttons, a joystick, and an adjustable fixation strap that attaches to the wrist to prevent the controller from potentially falling out of the hand. With built-in Bluetooth and an app on a mobile phone or tablet, the therapist can monitor what the patient sees and how effectively they perform each task. | PMC10536396 | ||
2.5. Intervention | hand pain, seizure, sudden instability | In addition to conventional therapy, the patients in the intervention group received training using the Oculus Quest 2 VR device. In total, there were a minimum of 10 and a maximum of 15 therapy sessions of 20 min per day, 3 times per week for 4 to 5 weeks. The total volume of active VR therapy averaged 270 min for the entire intervention. When determining the 20-min unit of time, we based this on the amount of time the patient spends with a physical or occupational therapist during the exercise unit. The standard therapeutic unit lasts 30 min, but this does not deduce the time the patient takes to talk to the therapist and assess their current condition, remove clothing and shoes, and assume a suitable position for exercise. The first three therapy sessions, which were aimed at familiarising the patient with the functions of the system controls using the First Steps for Quest 2 programme, lasted a maximum of 10 min. The patients were seated for the first two sessions and completed the third and subsequent sessions standing. From the fourth therapy, VITALIS Pro VR 0.4.1 software was used as part of the intervention. All patients completed the exercises in a total of 4 programmes: free painting, 2D tracing, 3D painting, and puzzles. In the “free painting” programme, they were asked to draw specific shapes; in 2D and 3D, they traced the shapes shown. The “puzzle” programme had three levels of difficulty and a hint option. The patients performed each task in three types of environments, namely forest, space, and sea. Each environment also conveyed different sound sensations to the patients. When performing tasks in the forest environment, patients heard birds singing; in the sea environment, it was the sound of waves; and in the space environment, it was computer music. Throughout the exercise, the study coordinator was present in the room and monitored the patient for symptoms indicating sudden instability, seizure, shoulder, arm, or hand pain. If the patient did not feel well at any time during the exercise, the coordinator instructed them to stop the task. Patients enrolled in the study received exercise in VR due to organizational reasons of the rehabilitation facility in the afternoon from 3 h after the completion of all treatments.As a part of conventional therapy, patients were indicated for individual neurophysiological-based physiotherapy 2 times a week for 30 min (total 240–280 min per stay). The other part consisted of occupational therapy aimed at targeted training of self-sufficiency, gross and fine motor skills, monomanual and bimanual activities, and improvement of movement coordination. Occupational therapy was performed twice a week for 30 min (240–280 min in total per stay). Furthermore, patients received twice-weekly bath with iodine–bromine + wrap, oxygen therapy, whirlpool bath, pool exercise, dry hot compresses, classical massage, mechanotherapy, CO | PMC10536396 | |
2.6. Statistical Methods | Basic descriptive statistics and statistical tests according to the type of data were used for statistical evaluation. The normality of the data was tested using the Shapiro–Wilk test, followed by a two-sample t-test and a non-parametric Mann–Whitney test, paired Wilcoxon test, and Spearman correlation coefficient. For qualitative data, the chi-square test was used; if the conditions for its use were not met, Fisher’s exact test was used. Statistical tests were evaluated at the level of significance of 5%. Stata version 17 was used for processing. | PMC10536396 | ||
4. Discussion | stroke, comorbidity, post-stroke, ’ illness | EVENTS, STROKE | New sophisticated virtual reality technologies implemented in the therapy of post-stroke patients have gained importance in recent years and are promising forms of technology that have been shown to increase patient satisfaction with post-stroke rehabilitation [In the studied patient group, statistically significant changes occurred in all domains of the quality of life and self-sufficiency questionnaire after VR-assisted therapy, and this change persisted four weeks after the end of therapy. Although all patients subjectively rated VR therapy as beneficial, motivating, and enjoyable, and the experimental group experienced improvements in their self-sufficiency, quality of life, and stability, statistical significance was not demonstrated when the test results were compared with those in the control group. Patients perceived and described VR exercise as effective, as immersion increased their motivation to complete meaningful activities, while completion of tasks allowed them to increase the intensity of purposeful repetitive movements. Self-sufficiency in activities that require coordinated hand and arm actions, such as dressing, shoeing, and showering, improved for all patients. After therapy, patients persisted with deficits in fine manipulative activities such as grasping and manipulating keys, coins, and buttons, which require good finger–thumb coordination, which may have been influenced by the programme and controllers not allowing repeated finger involvement in fine motor functional activities during the activity. Virtual reality programmes are designed to simulate objects and events in the real world [The patient’s ability to adapt to his/her new situation is also related to age, gender, education, and social class. Mobility and activities of daily living are the basis of the quality of life in patients after stroke. Performance in ADL becomes automated over the course of life, as activities are performed daily from a very early age, while the repertoire of ADL performance is shaped over the course of life, which also affects different cognitive and physical demands [The level of education, the level of comorbidity, as well as socioeconomic situation, occupational status, and potential return to work are also related to the quality of life. In our study, most patients were living in a relationship with a partner and all patients planned to return to their home environment. Hayes et al. (2003) reported in their study that up to 25% of patients after stroke remain in institutional care, and in their analyses, women were more dependent for ADL, less likely to go unassisted, and lived in nursing homes [However, as new VR technologies are increasingly being implemented in patient rehabilitation programmes and studies report that the use of VR in stroke rehabilitation contributes to improved motor function, self-sufficiency, muscle strength, and balance, further studies are needed to ensure that VR programmes are appropriately selected, properly timed, and produce a targeted treatment effect [The advantage of this study was the fact that the study had follow-up trials to monitor longer-term effects. Even after 4 weeks of therapy, the patients continued to experience a positive effect of therapy. The patients subjectively rated the therapy as motivating and effective. One limitation for our study is that some patients found VR tasks easy to perform after a certain period and would need incorporation of more challenging tasks into their therapy. Furthermore, the small sample size, which became even smaller due to the patients’ illness and the positivity of COVID-19, may also have affected the study results. The time since the stroke was not the same in all patients. The appropriate timing of physical activity is a topic of ongoing debate. Some patients prefer to remain temporarily at home after the stroke and postpone subsequent rehabilitation. This is a natural reaction of the patient who is forced to react to the change in his/her life situation, and his/her reaction depends on many factors, the degree of impairment of physical and mental functions, life experiences, personality, and attitude. Even spare capacity in subsequent rehabilitation facilities plays a role in early rehabilitation. | PMC10536396 |
5. Conclusions | post-stroke | The application of VR did not lead to significantly different changes compared to conventional therapy. Patients experienced improvements in self-sufficiency and quality of life, but these improvements were not different from the changes seen with conventional therapy. However, more randomised controlled trials are needed to determine the effectiveness of VR training on the quality of life and self-sufficiency in post-stroke patients. | PMC10536396 | |
Author Contributions | Formal analysis, D.P.; Funding acquisition, M.F.; Investigation, M.D.; Methodology, M.J.; Resources, L.H.; Software, H.T.; Supervision, Š.B.; Writing—review & editing, I.F. All authors have read and agreed to the published version of the manuscript. | PMC10536396 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Faculty of Medicine of the University of Ostrava, proceedings number: 12/2022, 12 December 2022. | PMC10536396 | ||
Informed Consent Statement | Patients included in the study signed an informed consent to be included in the study and for publication of the results of the study in a peer-reviewed journal. | PMC10536396 | ||
Data Availability Statement | All research data was securely stored in digital format and protected from loss and unauthorized access. Data may be shared with other researchers upon request. | PMC10536396 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10536396 | ||
References | BBS | Flow chart of study participants according to CONSORT.Explanatory notes: WHODAS 2.0—WHO Disability Assessment Schedule 2.0. The Basic sociodemographic and clinical characteristics of the experimental and control groups and their comparison.Explanatory notes: IQR—Interquartile range, Comparison of MMSE, WHODAS 2, BI, EBI, and BBS median (IQR) scores between two groups.Explanatory notes: MMSE—Mini-Mental State Examination, BI—Barthel Index, EBI—Extended Barthel Index, BBS—Berg Balance Scale, WHODAS 2—WHO Disability Assessment Schedule 2.0, IQR—Interquartile range, Comparison of WHODAS 2 median (IQR) scores between two groups.Explanatory notes: WHODAS 2.0—WHO Disability Assessment Schedule 2.0, ADL—Activities of daily living, IQR—Interquartile range, | PMC10536396 | |
Aims | hyperglycaemia, GDM, dysglycaemia | GDM, HYPERGLYCAEMIA, GESTATIONAL DIABETES MELLITUS | Gestational diabetes mellitus (GDM) is the most common type of hyperglycaemia in pregnancy. GDM is a risk factor of adverse perinatal outcomes, with the incidence rate increasing proportionally to the level of maternal dysglycaemia. Therefore, glycaemic control plays an important role in management of GDM. The aim of this study was to assess the efficacy of flash glucose monitoring (FGM) in GDM. | PMC10359198 |
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