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Funding | Open Access funding enabled and organized by Projekt DEAL. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. | PMC9970129 | ||
Declarations | PMC9970129 | |||
Disclosure | PD, Sebastián A. | Dr. med. Esther Giehl-Brown, Dr. med. Sandra Dennler, Dr. med. Sebastián A. Garcia, Dr. med. Danilo Seppelt, Dr. med. Florian Oehme, Dr. med. Johannes Schweipert, MHBA, Prof. Dr. med. Jürgen Weitz, MSc and PD Dr. med. Carina Riediger, MSc, have no conflicts of interest or financial ties to disclose. | PMC9970129 | |
References | PMC9970129 | |||
Background | febrile | Parents often contact out-of-hours services due to worry concerning febrile children, despite the children rarely being severely ill. As telephone triage of children is challenging, many children are referred to hospital assessment. This study investigated if video triage resulted in more children staying at home. Secondary aims included safety, acceptability and feasibility of this new triage tool. | PMC10464404 | |
Methods | death, febrile | In this prospective quality improvement study, nurse call-handlers enrolled febrile children aged 3 months-5 years to video or telephone triage (1:1), with follow-up within 48 h after call. The setting was an out-of-hours call-center for non-urgent illness in Copenhagen, Denmark, receiving over 1 million calls annually and predominately staffed by registered nurses. Main outcome measure was difference in number of children assessed at hospital within 8 h after call between video-and telephone triage group. Rates of feasibility, acceptability and safety (death, lasting means, transfer to intensive care unit) were compared between the triage groups. | PMC10464404 | |
Results | There was no difference in triage outcome (home care vs. hospital referral) or number of patients assessed at hospital between triage groups. However, more video triaged patients received in-hospital treatment, testing and hospitalization. | PMC10464404 | ||
Keywords | Open access funding provided by Royal Library, Copenhagen University Library | PMC10464404 | ||
Introduction | ’ worry, febrile, fever | SECONDARY | Telephone triage is used extensively during out-of-hours (OOH) healthcare and is a crucial tool in prioritizing both pre-hospital and in-hospital resources. Telephone triage is a challenging task, and children, the relatively most frequent group of callers, are inherently difficult to triage. This is mainly due to second-hand consultations via the parents, and the paucity of visual input, which complicates the assessment of the frequently unspecific symptoms in children [Furthermore, many parents have misconceptions about fever, such as dangerous side effects, measurement methods, the definition of fever, and how to manage it [Moreover, several studies have shown that non-verbal impressions such as tone of voice, breathing and pauses are a crucial part of call-handling [This present study investigated live video streaming (video triage) of febrile children at an OOH call-center. Previously, a study reported that video triage of young children with respiratory symptoms at the same call-center, was safe, feasible and acceptable to both parents and call-handlers [This present study investigated if the new triage tool video triage resulted in a higher proportion of patients staying at home the next 8 h after the call, while also identifying the most ill children and referring them to hospital. The study also investigated safety, feasibility and acceptability of video triage.Other secondary aims included if video triage reduced the parents’ DOW more than standard telephone triage, and if parental DOW was associated with the child being assessed at hospital. The study investigated parental DOW before and after call, and call-handlers’ DOW after the call. Moreover, secondary aims included an investigation of a possible reduction of the parents’ DOW when using video triage, and if the parental DOW was associated with the child being assessed at a hospital. As parental worry often is the reason for contacting healthcare services, it could potentially be of great interest if video triage could decrease parents’ worry, to prevent renewed contact and need of referral to hospital assessment. | PMC10464404 |
Methods | PMC10464404 | |||
Setting | injuries | EVENT, EMERGENCY | The study was conducted at the OOH Medical Helpline 1813 (MH1813) in Copenhagen, Denmark, which is open 24/7 for injuries and OOH for medical illness. An assessment at a hospital OOH in Denmark requires referral from either the Emergency Medical Services or an OOH service such as MH1813. Self-referral is largely discouraged. MH1813 provides service for a catchment population of 1.8 million citizens and is predominately staffed by registered nurses and supplemented by physicians who both answer calls and supervise. The call-handlers basically have two options: (1) telephone consultation with advice on self-care, possibly with a recommendation to contact their general practitioner (GP) the next workday (or renewed contact to MH1813 if needed), or (2) hospital referral, either to a low-acuity urgent care clinic, or to an emergency department, reflecting different grades of perceived urgency. Calls are forwarded to the ambulance services in the event of potentially life-threatening situations. MH1813 receives over 1 million calls annually of which 25% concern children under the age of 12 years [ | PMC10464404 |
Design | fever, ill | A prospective quality improvement study design was used, where a group of experienced nurse call-handlers invited parents of young children to participate. In all calls matching the inclusion criteria and where the parent consented to participation, the call-handlers were instructed to perform standard telephone triage in one call and video triage in the next call and so on, to get two comparable groups. In that way, the two groups would optimally only differ by triage method. After all included calls, the call-handlers filled out an electronic questionnaire about the call and their experiences and sent a questionnaire to the participating parents by text message. The study period lasted from September 1, 2019, to January 31, 2020. Children aged 3 months to 5 years with fever were eligible for inclusion. It was not mandatory that the parents had measured the temperature, even though they were encouraged to do so by the call-handlers. Exclusion criteria were foreign telephone number, previous participation in the project or neither Danish- nor English-speaking parent. The present study used a similar set-up as the previously described video triage study concerning respiratory symptoms [Moreover, the study also included the parents’ DOW before and after having talked to the call-handler, and both scores were reported in questionnaires In addition, the call-handlers rated their DOW of the child immediately after each call. DOW was registered in the survey question “On a scale from 1 to 5, where 1 is minimally worried and 5 is maximally worried, how worried are you that the child is seriously ill?”. The design of the study is illustrated in Fig. Study designThe remaining survey responses of both call-handlers and parents and the actual surveys can be found in a previous article [The technological set-up for video streaming was provided by GoodSAM: Instant-on-Scene ( | PMC10464404 | |
Outcome measures | death | ADVERSE EVENTS, DISEASES, MINOR, ADVERSE EVENT | Outcome data were derived from four sources: MH1813 patient records, questionnaire responses from parents and call-handlers, and the hospitals’ patient charts. The primary outcome of the study was to investigate if video triage could result in 10-percentage points more patients being able to stay at home during the first 8 h after the call. In 2018 56% children were triaged to stay at home. The time frame, the first 8 h after the call, was chosen to decrease the risk of including a natural deterioration that had nothing to do with the call and triage decision when including the patient in the study. If a longer time frame had been chosen, there’s a risk that a natural worsening could be interpreted as a wrongful triage decision at time of inclusion.The patients’ age, gender and triage outcome were retrieved from MH1813 patient records, and reason for contact was retrieved from the call-handlers’ questionnaire. Triage outcome was primarily divided into (1) the patient being advised to stay at home, possibly with contact to GP or MH1813 if necessary, or (2) into hospital referral. It was further registered if the children referred to hospital were referred to a pediatric emergency department (PED) or to a pediatric urgency care clinic (PUCC). This reflects the urgency perceived by the call-handler, as only suspected minor illnesses are to be assessed at PUCCs, where no possibility for treatment or extensive paraclinical testing exists. All included patients were followed-up in the region’s electronic hospital charts up to 48 h after the call. If a patient had been assessed at a hospital, the chart was read to identify time, location, International Statistical Classification of Diseases and Related Health Problems (ICD-10) diagnosis, treatment, and duration of the child’s stay at the hospital. ICD-10 diagnoses were gathered in groups of similar character. Adverse events, defined as transfer to intensive care unit, signs of lasting means or death were also identified in the hospitals’ patient charts. The follow-up was carried out 2–8 days after the call.The parental DOW was investigated before and after calls in the two study groups. It was studied if video triage reduced the parents’ DOW, and if the parental DOW was associated with the child being assessed at a hospital, both in total and in the two separate study groups. It was also investigated if DOW was associated to triage group.Safety was defined as the occurrence of adverse events (death, signs of lasting means or transfer to intensive care unit) and feasibility as the rate of successful video calls, and acceptability as how many parents that consented to participate in video triage. | PMC10464404 |
Statistical analysis | REGRESSION | Patients’ baseline characteristics (age, gender, triage response and symptom) were described with frequency (number, percentage), median and interquartile range (IQR). Differences in triage response, symptoms registered by call-handler and hospital outcome between the video and telephone triage groups were analyzed using chi square-test, Mann–Whitney test, logistic regression or multinomial logistic regression as appropriate. Logistic regression and multinomial logistic regression models were presented as odds ratio (OR) estimated with corresponding 95% confidence intervals (95% CI) and were also used for analyzing the association between DOW and hospital assessment.DOW-scorings were grouped in low (1 + 2) medium (3) and high (4 + 5) in the regression analyses, due to few observations in some categories. As DOW-scores were not normally distributed, they were presented as median with corresponding IQR (interquartile range). Differences in DOW-scores between groups were tested with Kruskal Wallis-test. Association between DOW-score and triage mode was studied using Fisher’s exact test. A 95% CI for proportions was calculated by Wilson Binominal Proportion Confidence Interval. P values less than 0.05 in two-sided tests were considered statistically significant. The statistical analyses were made with SAS Enterprise Guide 7.1 (SAS Institute, Cary, NC, USA), and Open Source Epidemiologic Statistics for Public Health (A sample size of 774 children divided into two groups was needed in order to detect a 10-percentage point increase in children triaged to stay at home, from 56% in the general pediatric MH1813-population in 2018 [ | PMC10464404 | |
Ethics | EMERGENCY | The study was a quality improvement study, and the Research Ethics Committee in the Capital Region of Denmark deemed approval was not indicated (Journal number H-19037554), and participant consent was hence not needed. All participating parents were however informed about the study and gave verbal consent. The managements of the hospitals in the Capital Region with pediatric departments or pediatric urgent care clinics approved access to the patient records, as well as the management of Copenhagen Emergency Medical Services. | PMC10464404 | |
Results | PMC10464404 | |||
Discussion | fever, Non-Danish, ill, worry, tonsillitis | EAR INFECTIONS, MINOR, SECONDARY, TONSILLITIS | Our primary aim was to investigate if video triage could enable more ill children to stay at home, while also efficiently identifying potentially severely ill children with the need for assessment at hospital. There was not a difference in the number of patients triaged to stay at home or in the number of patients assessed at hospital within the follow-up period of 48 h after the call. However, several findings pointed towards video having been used at the discretion of the call-handlers, and not in every other call, as instructed. As such, the video triaged children more often were assessed as potentially more ill by the call-handlers, as they more frequently were referred directly to a PED as opposed to a PUCC reserved for minor illnesses. Moreover, among the children assessed at hospitals, children from the video triage group more often received paraclinical testing or in-hospital treatment and were more often hospitalized as compared to the telephone triage group. Equivalently, the children in the telephone triage group assessed at hospitals received less severe diagnoses, but more prescriptions, probably due to them being assessed in PUCCs with illnesses that could be treated at home with e.g. antibiotics, such as uncomplicated tonsillitis and ear infections.Our secondary aims related to the parents’ DOW. DOW was higher in the video group than in the telephone group, and there was a significant association between DOW and triage mode, that is, the parents’ degree of worry might have influenced what triage mode that was used. The conversation with the call-handler had in itself a reassuring effect on the parental DOW, as DOW decreased significantly after the call in both groups. Furthermore, high parental DOW both before and after having talked to a call-handler was significantly associated with the child being assessed face-to-face at a hospital. Hence, children of worried parents were actively allocated to video triage. After the call, where the call-handler confirmed the parents’ worry by referring the child to a hospital, the parent had a persisting high worry.Decision-making is the final product and essential element of call-handling [A systematic review of unscheduled pediatric healthcare visits found that patients do not find these visits as clearly distinguished from planned visits as professionals, and parents do not necessarily take the appropriateness of visits into account, when choosing where and when to seek help [Several studies have tried to estimate appropriateness of referrals made by call-centers by assessing patient outcome [Feverish children are highly prevalent in OOH care, and challenging to assess, as harmless and severe causes may be hard to separate. Furthermore, parents often expect a physical examination. Video triage might be beneficial, as it provides visual assessment and can assist in finding the most severely ill children. Several parents stated that it was a relief not having to go to a hospital after video triage as somebody already had “seen their child” [Video triage in other symptoms and age groups should be the subject of future studies, both to identify in which cases that video triage is most useful, and also how to implement the video findings most optimally in the decision-making protocols used at many call-centers. Randomized studies are needed to find the impact of video triage on triage outcome and subsequent patient outcome.By including DOW, a simple and time-efficient score, in the triage process, the incorporation of parental feelings of worry in the decision-making can be ensured. As worry is a main reason to OOH contact, this is crucial. By investigating how DOW has changed at the end of the call, it is possible to conclude if the contact has resulted in increased reassurance and empowerment. If not, the underlying reasons should be sought corrected.Some limitations to the study were identified. Although the participating call-handlers had been instructed to include patients to the video- or telephone triage group in a 1:1 ratio to get two comparable groups, the results show that children with potentially more severe or complex symptoms and/or with parents displaying a high degree of worry more often received video triage than telephone triage. Previously, the study group reported that several of the participating study call-handlers stated that they could not do without video in some situations, and therefore switched to video triage even if the allocation strategy stated telephone triage [Non-Danish and non-English speakers were excluded, to test this new tool in a setting that felt achievable to both call-handlers and parents. We also did not want to affect the waiting times in a negative way, as might have been the case if there would have been difficulties explaining the video triage setup and tool. For future purposes though, these situations should be studied as well, as it is possible that much is to gain when using a visual aid when experiencing language barriers.Regarding DOW, parents were asked AFTER the call about their DOW both before and after having talked to a call-handler. Recall bias might have an impact on the “before-rating”. Also, as the numbers of parents rating their DOW as low (1 + 2) were rather small, this generated some wide 95% CI’s.Lastly, it would have been preferable if the study had been conducted as a randomized controlled trial, but this was not possible due to several reasons. Firstly, the call-handlers did not have sufficient time for thoroughly informing the parents and obtaining written informed consent, and an oral consent, although it would have been stored in the MH1813 electronic patient chart, would not legally suffice. Furthermore, it was not possible to change the computer set-up to randomly allocate calls to video or telephone triage, or to change the introduction speech of MH1813 as would have been desired in terms of informing about the study. Due to this limitation, the study cannot yield fully valid answers to the impact of video triage on triage and patient outcomes.Finally, to sum the findings up, the study did not find an increase of video triaged patients staying at home. Video triage of young children with fever was feasible, acceptable and as safe at telephone triage at this medical helpline. However, video triage was more often used in situations with complex or potentially severe symptoms and when parents rated worry as high. High parental degree-of-worry was associated to assessment at hospital and can be used as a method to incorporate the caller’s subjective notion of worry and urgency into the triage process. | PMC10464404 |
Author contributions | ABH | The study was designed by CG, DC, GL, FF, MSF and ABH. CG conducted the experimental work and collected data. Analysis of data was done by CG, DC, AKE and HGJ. Interpretation of data was conducted by CG, DC, HGJ, GL, ABH, FF and HGJ. CG drafted the initial manuscript. Revising and commenting of manuscript was done by all authors. All authors accepted the final version. | PMC10464404 | |
Funding | Open access funding provided by Royal Library, Copenhagen University Library. The study received unrestricted grants from the TRYG Foundation, the health research foundation of the Capitol Region and the Amager-Hvidovre Hospital research foundation. The funding bodies had no influence on study design or collection, analysis and interpretation of data or writing of manuscript. | PMC10464404 | ||
Availability of data and materials | The datasets used during the current study are available from the corresponding author on reasonable request. | PMC10464404 | ||
Declarations | PMC10464404 | |||
Consent for publication | Not applicable. | PMC10464404 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10464404 | ||
References | PMC10464404 | |||
Abstract | PMC9932240 | |||
Objectives | MARF, bone dehiscence, postoperative pain | PERIOSTEUM | One of the simplest methods to increase keratinized gingiva is the modified apically repositioned flap (MARF) technique. In this method, the periosteum remains exposed, which may lead to postoperative pain and discomfort. In the presence of bone dehiscence, bone resorption and gingival recession may occur. Hence, this study aims to use platelet‐rich fibrin (PRF) to promote wound healing in the MARF technique and overcome its disadvantages. | PMC9932240 |
Material and Methods | MARF | In this randomized controlled trial study, 10 patients (six males and four females with a mean age of 33.9 ± 11.13) with less than 2 mm of attached gingiva bilaterally were treated by the MARF + PRF membrane (test group), on the one hand, whereas, on the other hand, it was treated only by MARF (control group). Clinical parameters of keratinized gingiva include thickness, width, and vestibule depth before and 8 weeks after the intervention were measured. | PMC9932240 | |
Results | MARF | The attached gingival width increased significantly in both groups (1.7 mm in the MARF and 2.3 mm in the PRF) and this was greater in the PRF group ( | PMC9932240 | |
Conclusion | gingiva, MARF, reduced shrinkage, Postoperative pain | Using PRF with the MARF method significantly increased the width and thickness of the gingiva and reduced shrinkage compared to MARF only. Postoperative pain and vestibular depth changes were similar in both groups.
| PMC9932240 | |
INTRODUCTION | gingiva, Gingiva, bone dehiscence, postoperative pain | PERIOSTEUM | Gingiva is the part of oral mucosa that covers the alveolar processes of jaws and surrounds the neck of the teeth. The gingiva is divided anatomically into marginal (unattached), attached, and interdental areas (Newman et al., In this method, a horizontal incision is performed in the attached gingiva and a split‐thickness flap is raised and sutured apically. The periosteum remains exposed, the granulation tissue forms on top of the wound, and eventually, the keratinized tissue will mature. Leaving the periosteum naked may lead to postoperative pain and discomfort. In the presence of bone dehiscence, marginal bone resorption and gingival recession may occur, which is a contraindication of this technique.On the other hand, the patient's platelet derivatives have been used for many years to accelerate wound healing. Various generations have been introduced to date, the most widely used of which is the platelet‐rich fibrin (PRF) membrane (Choukroun et al., | PMC9932240 |
MATERIALS AND METHODS | PMC9932240 | |||
Study design | MARF | This study was designed as a randomized controlled trial with a split‐mouth design. To participate in the study, the following inclusion and exclusion criteria need to be fulfilled. This study was done to evaluate the clinical results of using PRF in combination with MARF to increase the attached gingiva around the teeth. | PMC9932240 | |
Inclusion criteria | gingiva | Inclusion criteria in the study were: patients with less than 2 mm of attached gingiva at the buccal site; less than 5 mm of vestibular depth (VD); and the presence of high frenum pull bilaterally in the mandible. | PMC9932240 | |
Exclusion criteria | SYSTEMIC DISEASE, PLAQUE | Exclusion criteria were systemic diseases, pregnancy and lactation, smoking, alcohol use, plaque index >20%, gingival recession Class 3 or 4 Miller, and PPD >5 mm.Patients were invited to participate in the study after being fully informed. Informed consent was obtained from all participants. The study was approved by the Ethical Committee of the Hamadan University of Medical Science. The approval ID is IR.UMSHA.REC.1400.114. | PMC9932240 | |
Participants and randomization | MARF, Blindness | MAY, BLINDNESS | The present study was performed in the periodontics department of the Dentistry School of Hamadan University of Medical Sciences from May to September 2021; 10 people who had less than 2 mm of attached gingiva and needed soft tissue augmentation on both sides were selected.The sample size was determined based on the assumption that the test group (MARF + PRF) and the control group (MARF) were equal. Mean and standard deviation indices were extracted from a similar study by Temmerman et al. (Each lower jaw was divided into two segments. Each side was randomized as control or test groups in a split‐mouth design, via a randomization table by a computer‐generated randomization list (STATA version 11). The treatment codes (test/control) were available in closed envelopes, which were sealed and opened just before the surgery by the surgeon. Blindness was not possible due to the nature of the procedure, and both the patient and the surgeon were informed about the treatment modality. | PMC9932240 |
Surgical procedures | CAVITY | Chlorhexidine 0.2% was used for rinsing the oral cavity before surgery. Local anesthesia (lidocaine 2% with epinephrine 1:80,000) was performed in the buccal area of the premolars by mental nerve block. | PMC9932240 | |
Control group (MARF) | PERIOSTEUM | A horizontal incision was made by a blade (no. 15) approximately 0.5 mm coronal to the mucogingival junction. The split‐thickness flap was elevated and the dissection was extended 5 mm in an apical direction. The coronal part of the flap would contain a band of keratinized tissue. The extension of the incision depends on the teeth involved so that at least one and a half teeth are extended on each side (mesiodistal). This extension allows the flap to be repositioned apically. The flap is sutured to the periosteum in the apical position by resorbable sutures (Vycril® 4.0; ETHICON, Cincinnati, Ohio, USA). A homogeneous layer of periosteum with no elastic or fibers remained on the bone. A periodontal dressing without eugenol (COE‐PAK™; GC Corporation, Alsip, Illinois, USA) was used on top to protect the wound (Figure | PMC9932240 | |
Test group (PRF) | MARF | STERILE, PERIOSTEUM | Patient's blood was collected into 10 ml sterile silica‐coated plastic tubes without anticoagulants (VACUETTE; Greiner Bio‐OneOne GmbH, Kremsmünster, Austria). At least two tubes were prepared, and the tubes were centrifuged immediately in a fixed‐angle centrifuge (Arman Teb Noor, Iran, Tabriz). According to studies by R. Miron et al. (The MARF was done exactly as mentioned before. Several layers of PRF membranes (two or three layers) were placed on the exposed periosteum and were fixed by sutures around the teeth and finally dressed with a periodontal dressing (COE‐PAK™; GC Corporation, Alsip, Illinois, USA) (Figure All patients were prescribed 0.2% chlorhexidine mouthwash twice a day for 4 weeks, and ibuprofen 400 mg four times a day or as needed. The periodontal dressing and sutures were removed after 1 week. The patient was prohibited from doing any mechanical cleaning in the surgical area such as brushing and flossing for 4 weeks (Carnio et al., | PMC9932240 |
Primary outcomes: Width and thickness of keratinized tissue | tooth | CAVITY, PERIOSTEUM | The patient's oral cavity was examined by a specialist with Williams Probe (Hu‐Friedy; Chicago, USA) to evaluate the clinical parameters. The evaluated parameters such as probing pocket depth (PPD), keratinized tissue width, VD, and gingival thickness (GT) were measured at the baseline, and after 8 weeks. GT measurements were taken using an endodontic spreader (#30) from 2 mm of the buccal gingival margin as shown in Figure (a) Preoperative view. The first premolars with an attached gingiva width less than 2 mm. (b) A horizontal incision half a millimeter above the mucogingival junction line, with one‐and‐a‐half tooth extension. (c) Absorbable suture is used to secure the flap in the apical position. (d) Placement of periodontal dressing to protect the wound. (e) Eight weeks postop.(a) Preoperative view. The first premolars with an attached gingiva width of less than 2 mm. (b) A horizontal incision half a millimeter above the mucogingival junction line, with one‐and‐a‐half tooth extension. (c) Absorbable suture is used to secure the flap in the apical position. (d) Placing and securing three layers of platelet‐rich fibrin membrane to the periosteum. (e) Periodontal dressing to protect the wound. (f) Eight weeks postop.Preoperative measurement of gingival thickness | PMC9932240 |
Secondary outcomes: Postoperative pain and wound shrinkage | postoperative pain, pain | SECONDARY | A secondary objective of the study was to assess postoperative pain. A visual analog score (VAS) questionnaire was used to evaluate the amount of pain, ranging from 0 (no pain) to 10 (worst pain), and the patients were asked to fill out the questionnaire on the VAS scales on the day after surgery.To assess the wound shrinkage, the amount of apical placement of the flap at the surgery was compared to the newly attached gingiva gained after 8 weeks. Wound shrinkage was calculated as follows:
| PMC9932240 |
Statistical analysis | The data were checked for normality in distribution using a normal quantile plot. The confidence level was determined at 95%. The patient was used as a statistical unit. After a rejection of normality, a paired | PMC9932240 | ||
RESULT | Postoperative pain, MARF, platelet‐rich, postoperative pain | PERIOSTEUM | Ten patients participated in this trial. The mean age was 33.9 ± 11.1 years old and the male/female ratio was 6:4. None of the subjects dropped out during the 8‐week follow‐up. One side of each patient was randomly assigned to the test (MARF + PRF) or control (MARF) group, while the contralateral side was assigned to the other group. A flow diagram of the study participants is provided (Figure Flow diagram of the studyPPD at baseline and follow‐up were almost the same and there was no difference in either group.At baseline, the average width of the attached gingiva was 1.15 ± 0.52 for the test group and 0.8 ± 0.82 for the control group. The mean increase in the attached gingiva after 8 weeks was 1.7 mm in the MARF group and 2.3 mm in the PRF group, which was significantly higher in the PRF group compared with the MARF group (At baseline GT was 0.79 ± 0.16 and 0.74 ± 0.22 mm for the test and control groups, respectively. After 8 weeks, the GT was 1.09 ± 0.09 in the PRF group and 0.86 ± 0.16 mm in the MARF group. GT is increased by 0.11 mm in the MARF group and 0.29 mm in the PRF group, with a significant statistical difference between those values (The VD at baseline and follow‐up are recorded in Table Clinical measurements at baseline and 8‐week postop (mean ± SD) and clinical parameter change (Δ) from baseline to 8 weeks postop
Abbreviations: AG, attached gingiva; GT, gingival thickness; MARF, modified apically repositioned flap; PPD, probing pocket depth; PRF, platelet‐rich fibrin; VD, vestibular depth.Postoperative pain is assessed by using the VAS questionnaire a day after surgery. The VAS values associated with PRF and MARF groups were almost the same and were not different in either group (Wound shrinkage was measured by comparing the apicocoronal dimension of the exposed periosteum with the newly attached gingiva 8 weeks postop. The wound shrinkage was 51.1% in the control group and 30.9% in the test group, which was significantly higher in the MARF group (Table Comparison postoperative pain and shrinkageAbbreviations: MARF, modified apically repositioned flap; PRF, platelet‐rich fibrin. | PMC9932240 |
DISCUSSION | postoperative pain, Postoperative pain, pain, MARF, bone dehiscence, Inflammation, LSCC | INFLAMMATION, ALMEIDA | A gingival width of 2 mm is sufficient to maintain healthy gingiva (Wennstrom & Lindhe, The apical repositioning flap introduced by Friedman increases the risk of bone resorption (Lang & Löe, In a 1‐ to 11‐year follow‐up study, Carnio et al. (The MARF and PRF groups resulted in a significant increase in keratinized tissue. MARF is an effective and efficient method to increase keratinized tissue and the attached gingival width. The main limitation of this technique is the presence of at least 0.5 mm of attached gingiva before surgery so that the wound is surrounded by keratinized tissue. The presence of bone dehiscence is another contraindication (Swarna et al., Alaood et al. (Free gingival grafting is the most common method for increasing keratinized tissue and attached gingiva (Miller, Temmerman et al. (Postoperative pain was also slightly reported in both groups, with no significant difference. Inflammation peak and maximum postoperative pain occur within the first 24 h following surgery. Since the PRF membrane acts as a biological dressing, it was expected to be effective in reducing postoperative pain. Several studies demonstrate that PRF decreases postoperative pain (de Almeida Barros Mourão et al., Another possible reason is using silica‐coated blood collection tubes. Silica in the tube causes negative effects on periosteal cells (Masuki et al., In the PRF group, wound shrinkage was significantly lower than in the MARF group. These values were reported to be 30.9% for the PRF group and 51.1% for the MARF group. PRF group shrinkage values are comparable to those of Temmerman et al. (According to the shrinkage results, for obtaining at least 2 mm of new keratinized tissue, we suggest a 4 mm apically repositioned flap in MARF and a 3 mm repositioned flap in the MARF + PRF method.Recent advances in the field of platelet derivatives lead to the use of low‐speed centrifugation concept (LSCC) and horizontal centrifugation. LSCC results in an increased growth factor concentration. Therefore, enhancing the growth factor concentrations improves the potential of tissue regeneration and wound healing capacity of the fluid PRF‐based matrices (Choukroun & Ghanaati, Due to recent improvements in platelet derivatives, further clinical studies are necessary to evaluate LSCC and horizontal centrifugation to enhance clinical results. | PMC9932240 |
LIMITATION | Pain | This study was limited to the mandibular premolar area due to the split‐mouth design. Also, a small sample size may be subject to selection bias. Wound shrinkage will continue for months and the complete shrinkage assessed needs long‐term follow‐ups. Pain assessment one day after surgery may lead to bias.To substantiate our findings, further and multicentered studies are needed. | PMC9932240 | |
CONCLUSION | gingiva, MARF, reduced shrinkage, Postoperative pain | DEHISCENCE | Using PRF with the MARF method significantly increased the width and thickness of the gingiva and reduced shrinkage compared to MARF without PRF. Postoperative pain scores and VD changes were similar in the test and control groups. Increasing the GT may allow PRF to be used in the presence of bone dehiscence. | PMC9932240 |
AUTHOR CONTRIBUTIONS | PMC9932240 | |||
CONFLICT OF INTEREST | The authors declare no conflict of interest. | PMC9932240 | ||
ETHICS STATEMENT | The study protocol was registered on the IRCT registry, with Registration reference: IRCT20211124053173N1. | PMC9932240 | ||
ACKNOWLEDGMENTS | The authors would like to thank the dental research center and vice chancellor of research at the Hamadan University of Medical Sciences for their support. This research was fully funded by the research center, Hamadan University of Medical Sciences. | PMC9932240 | ||
DATA AVAILABILITY STATEMENT | The applicant has unlimited access to the data after sending the request via email to the corresponding author. | PMC9932240 | ||
REFERENCES | PMC9932240 | |||
Subject terms | beta-cell dysfunction, diabetes | SECONDARY, INSULIN RESISTANCE, TYPE 2 DIABETES, INSULIN SENSITIVITY, DIABETES | In early type 2 diabetes, the strategy of “induction” with short-term intensive insulin therapy followed by “maintenance” with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin.ClinicalTrials.Gov NCT02192424In early type 2 diabetes, “induction” with short-term insulin therapy followed by “maintenance” with metformin can stabilize beta-cell function. The authors show that initial reversibility of beta-cell dysfunction followed by preserved hepatic insulin sensitivity determine sustained stabilization. | PMC10374648 |
Introduction | deterioration of pancreatic beta-cell function, T2DM | TYPE 2 DIABETES | The natural history of type 2 diabetes (T2DM) is characterized by the progressive deterioration of pancreatic beta-cell function over timeHere we show that one such strategy is the administration of initial short-term IIT (as induction therapy) followed by metformin (as maintenance therapy), an approach that has been shown to stabilize beta-cell function for 2-years in some patients but not others | PMC10374648 |
Results | T2DM | The RESET-IT Main trial (ClinicalTrials.Gov NCT02192424) was a multi-centre, parallel arm trial in which adults with T2DM were randomly assigned to receive induction therapy with a 3-week course of IIT, followed by maintenance therapy consisting of either (i) metformin alone or (ii) metformin with intermittent 2-week courses of short-term IIT administered every 3-months for 2-years. As recently reported | PMC10374648 | |
Characteristics at Baseline and after 3-weeks Induction | Table Baseline characteristics of study population stratified into (i) participants who had sustained stabilization of beta-cell function for 2 years and (ii) those who did notContinuous variables presented as mean followed by standard deviation in parentheses (if normal distribution) or median followed by interquartile range (if skewed distribution). Categorical variables presented as proportions. Groups were compared by Analysis of Variance (normally distributed variables), Kruskal-Wallis test (skewed variables), or Chi-Square test (categorical variables). All tests were two-sided, with no adjustment for multiple comparisons. Bold indicates During the 3-weeks of induction IIT, glycemic control was similar in the 2 groups, as evidenced by the profile of mean capillary glucose measurements across the day (Supplementary Fig. Characteristics after 3-weeks of induction intensive insulin therapy (IIT) in (i) participants who had sustained stabilization of beta-cell function for 2 years and (ii) those who did notContinuous variables presented as mean followed by standard deviation in parentheses (if normal distribution) or median followed by interquartile range (if skewed distribution). Groups were compared by Analysis of Variance (normally distributed variables), Kruskal-Wallis test (skewed variables), or Chi-Square test (categorical variables. All tests were two-sided, with no adjustment for multiple comparisons. Bold indicates | PMC10374648 | ||
Characteristics during maintenance phase | adiposity | ADIPOSITY | We next examined the maintenance phase (from 3-weeks to 2-years). Of note, the stabilization and non-stabilization groups did not differ in the maintenance therapy to which participants were randomized (Table Characteristics at completion of maintenance therapy at 2-years in (i) participants who had sustained stabilization of beta-cell function and (ii) those who did notContinuous variables presented as mean followed by standard deviation in parentheses (if normal distribution) or median followed by interquartile range (if skewed distribution). Groups were compared by Analysis of Variance (normally distributed variables) or Kruskal-Wallis test (skewed variables). All tests were two-sided, with no adjustment for multiple comparisons. Bold indicates We first examined progressive changes over time in the glucose response to the OGTT in the 2 groups (Supplementary Fig. Comparison of the absolute changes in metabolic parameters between 3-weeks and 2-years showed differences between the groups in adiposity (BMI: | PMC10374648 |
Changes over time in metabolic variables. | ( | PMC10374648 | ||
Determinants of sustained beta-cell stabilization | analysesTwo-sided | REGRESSION | Finally, we performed logistic regression analyses to identify independent determinants of the stabilization of beta-cell function at 2-years (Table Logistic regression analyses of (dependent variable) stabilization of beta-cell function over 2 years: (A) core model derivation and (B) sensitivity analysesTwo-sided We next performed sensitivity analyses to evaluate the robustness of these findings from the core Model III (Table On additional sensitivity analyses, we repeated the core logistic regression analyses by replacing ISSI-2 with each of the other 3 measures of beta-cell function. The significant predictors from the core model above persisted when ISSI-2 was replaced as the measure of beta-cell function with insulinogenic index/HOMA-IR, ΔCpeptide | PMC10374648 |
Discussion | weight gain, weight loss, T2DM, beta-cell dysfunction | REGRESSION, INSULIN RESISTANCE, INSULIN SENSITIVITY, GESTATIONAL DIABETES | In this study, we show that 55 of 99 patients with T2DM achieved sustained stabilization of beta-cell function over 2-years in response to induction IIT followed by metformin maintenance. These individuals had poorer beta-cell function than their peers at baseline but experienced greater recovery thereof in response to 3-weeks of induction IIT. Over the subsequent 2-years, they had greater stability of weight/adiposity, hepatic insulin sensitivity and ALT compared to their peers, and ultimately exhibited better beta-cell function and glycemic control. Logistic regression analyses revealed 3 independent predictors of the sustained stabilization of beta-cell function: the change in ISSI-2 during induction IIT and the changes in HOMA-IR and ALT during maintenance. It thus emerges that the initial reversibility of beta-cell dysfunction during induction and the subsequent preservation of hepatic insulin sensitivity during maintenance are underlying determinants of sustained stabilization of beta-cell function in response to short-term IIT and metformin.Two elements of these data point to the role of reversible beta-cell dysfunction. First, it is notable that those who ultimately achieved stabilization 2-years later had poorer (not better) beta-cell function than their peers at baseline. Second, in response to induction IIT, they experienced a greater improvement in beta-cell function than did their peers. Importantly, when both of these variables were included in the optimal model (Model V in Table After addressing reversible beta-cell dysfunction with induction therapy, the next challenge is maintaining this beneficial effect. In this regard, current thinking holds that improving insulin sensitivity (e.g. through weight loss) can off-load the secretory demands placed on the beta-cells and thereby reduce their functional deterioration in T2DM. Conversely, weight gain may increase insulin resistance and hasten beta-cell demise. In this context, it is notable that, during maintenance from 3-weeks to 2-years, there were differential changes over time in BMI between the stabilization and non-stabilization groups, with evidence of a decrease in the stabilization group (Fig. This emerging role of hepatic insulin sensitivity is supported by earlier observations. First, in women with recent gestational diabetes, worsening hepatic insulin resistance in the 1It is notable that, while the change in HOMA-IR from 3-weeks to 2-years superseded the changes in Matsuda, BMI and waist, consideration of the concomitant change in ALT yielded the optimal model of sustained stabilization of beta-cell function (Model V in Table An additional limitation is the relatively modest sample size (In conclusion, treatment with 3-weeks of induction IIT followed by metformin maintenance achieved stabilization of beta-cell function over 2-years in 55 of 99 participants. These individuals had poorer beta-cell function than their peers at baseline but experienced greater functional recovery thereof in response to induction IIT, suggestive of reversibility of beta-cell dysfunction. Their subsequent changes in HOMA-IR and ALT during the ensuing 2 years emerged as significant predictors of sustained stabilization of beta-cell function, coupled with the initial beta-cell response to induction IIT. Thus, the initial reversibility of beta-cell dysfunction during induction and the subsequent preservation of hepatic insulin sensitivity during maintenance are physiologic changes associated with the sustained stabilization of beta-cell function in response to short-term IIT and metformin. | PMC10374648 |
Methods | This multi-centre clinical trial was approved by the research ethics boards of Mount Sinai Hospital (Toronto, ON), Western University (London, ON), and Hamilton Health Sciences (Hamilton, ON), which were sites where the study took place. The trial was registered at ClinicalTrials.Gov NCT02192424. It was conducted in accordance with Good Clinical Practice and the principles of the Declaration of Helsinki, and all participants provided written informed consent. The study protocol has been previously described in detail, along with reporting of the primary outcome | PMC10374648 | ||
Study population | T2DM, liver disease | LIVER DISEASE | Inclusion criteria included age 30–80 years and duration of T2DM ≤ 5 years. Before the trial, participants could be treated with either metformin or lifestyle only. Exclusion criteria included treatment with anti-diabetic medication other than metformin, estimated glomerular filtration rate <50 ml/min, and known liver disease or transaminases > 2.5-fold above normal. | PMC10374648 |
Randomization and Interventions | Participants stopped metformin (if applicable) and fasted overnight prior to the baseline visit, at which they completed a 2 h 75 g oral glucose tolerance test (OGTT). At this visit, they received instruction on healthy lifestyle practices for managing T2DMThese 2 treatment protocols have been described in detail previously in ref. Following the 3-week OGTT, participants began maintenance therapy consisting of either (i) metformin or (ii) metformin + intermittent IIT. In both arms, metformin was initiated at 1000 mg/day for 2 weeks, followed by 2000 mg/day or maximal tolerated dose thereafter. In the intermittent IIT arm, a 2-week course of IIT was administered every 3-months with the same glucose targets as during induction, as previously described in detail in ref. | PMC10374648 | ||
Physiologic Indices on OGTT | INSULIN SENSITIVITY/RESISTANCE | The serial 2 h 75 g OGTTs enabled assessment of physiologic indices reflecting insulin sensitivity/resistance and beta-cell function. Participants fasted overnight prior to each OGTT, with metformin held on the morning of the test. During each OGTT, venous blood samples were drawn at fasting and at 30-, 60-, 90- and 120-min post-challenge. Glucose, insulin and C-peptide were measured from these samples, as previously described in ref. | PMC10374648 | |
Outcomes | SECONDARY | The primary and secondary outcomes of the trial have been previously reported in detail | PMC10374648 | |
Statistical Analyses | Statistical analyses were conducted with R 4.2.2, with two-tailed | PMC10374648 | ||
Reporting summary | Further information on research design is available in the | PMC10374648 | ||
Supplementary information |
Supplementary InformationPeer Review FileReporting Summary | PMC10374648 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-40287-w. | PMC10374648 | ||
Acknowledgements | MOP 133701, Diabetes | GILBERT, DIABETES | RR holds the Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at Mount Sinai Hospital. SBH holds the Diabetes Canada Chair in Diabetes Management at Western University. SMR holds the Brian W. Gilbert Chair in Primary Health Care at Western University. HCG holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. This study was supported by the Canadian Institutes of Health Research (CIHR) (MOP 133701) (RR). The funder had no role in study design, data collection and analysis, or writing of the manuscript. | PMC10374648 |
Author contributions | R.R. and B.Z. designed the study. R.R., A.E., S.B.H., S.R., H.C.G., N.M., C.K.K. and B.Z. implemented the study and acquired the data. R.R. led overall study implementation. A.E. oversaw research coordination. J.P. performed the statistical analyses. R.R. wrote the manuscript. R.R. and J.P. verified the data. All authors contributed to interpretation of the data and critical revision of the manuscript. All authors approved the manuscript. R.R. is the guarantor of this work. | PMC10374648 | ||
Peer review | PMC10374648 | |||
Data availability | De-identified data can be made available under restricted access from the corresponding author (Ravi.Retnakaran@SinaiHealth.ca), for academic purposes, subject to a material transfer agreement and approval of the Mount Sinai Hospital Research Ethics Board. Individual participant data that underlie the results reported in this article can be made available by this mechanism, after de-identification, to achieve the aims in the approved proposal. Access is controlled in this way because of the clinical nature of the data. The study protocol can also be made available in this way. This data access mechanism will be available beginning 9 months and ending 36 months following publication of this article. We will attempt to respond to requests within 3 months, pending Research Ethics Board capacity to do so within this time frame. Source data for figures have been provided with this paper. | PMC10374648 | ||
Code availability | The code used for the statistical analyses is available at Github at the following link: | PMC10374648 | ||
Competing interests | N.M., Nordisk | R.R. reports grants from Boehringer Ingelheim, grants and personal fees from Novo Nordisk, personal fees from Sanofi, personal fees from Eli Lilly, outside the submitted work. SBH reports grants and personal fees from Sanofi, grants and personal fees from Novo Nordisk, grants and personal fees from AstraZeneca, personal fees from Eli Lilly, personal fees from Janssen, grants and personal fees from Abbott, outside the submitted work. S.M.R. reports personal fees and non-financial support from Boehringer Ingelheim, Janssen, Eli Lilly, Sanofi, Bayer and AstraZeneca; grants, personal fees and non-financial support from Abbott, and Novo Nordisk; personal fees from Western University, Schulich School of Medicine and Dentistry and The Federation of Medical Women of Canada; grants from the Canadian Institute of Health Research, outside the submitted work. N.M. reports grants and non-financial support from AstraZeneca, grants and non-financial support from Merck, grants and non-financial support from Sanofi, outside the submitted work. H.C.G. reports research grants from Eli Lilly, AstraZeneca, Merck, Novo Nordisk and Sanofi; honoraria for speaking from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, DKSH, and Zuellig; and consulting fees from Abbott, Covance, Eli Lilly, Novo Nordisk, Sanofi, Pfizer and Kowa. C.K.K. reports research grants from Boehringer Ingelheim. J.P., A.E., and B.Z. have nothing to disclose. | PMC10374648 | |
References | PMC10374648 | |||
Purpose | hematotoxicity | GLIOBLASTOMA | In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. | PMC9886607 |
Methods | hematotoxicity, HAE | ADVERSE EVENTS, ADVERSE EVENT, REGRESSION | Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. | PMC9886607 |
Results | HAE | REGRESSION | HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. | PMC9886607 |
Conclusion | HAE | Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. | PMC9886607 | |
Trial registration | NCT01149109. | PMC9886607 | ||
Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC9886607 | ||
Introduction | HAE, Glioblastoma, hematologic adverse | GLIOBLASTOMA, PRIMARY BRAIN TUMOR | Glioblastoma is the most common malignant primary brain tumor in adults and has a detrimental prognosis despite standard-of-care treatment with surgery, radiotherapy, and temozolomide chemotherapy [The aim of the present study is to provide a detailed analysis of patterns, predictors and prognostic effect of high grade hematologic adverse event (HAE) in the CeTeG/NOA-09 trial. | PMC9886607 |
Methods | PMC9886607 | |||
Study design, participants and treatment | HAE, neutropenia, leukopenia, anemia, lymphopenia | ADVERSE EVENT, NEUTROPENIA, THROMBOPENIA, LEUKOPENIA, ADVERSE EVENTS, ANEMIA, LYMPHOPENIA | The CeTeG/NOA-09 study design has been published previously [HAE were defined as thrombopenia, leukopenia, lymphopenia, neutropenia, or anemia of grade 3 or higher. All adverse events were rated according to the Common Terminology of Clinical Adverse Events (CTCAE) version 4.0 and documented using pre-specified clinical reporting forms. | PMC9886607 |
Statistical analysis | HAE | REGRESSION | Standard descriptive statistics were used for all presented data. Group differences were analyzed with Fisher’s exact test for categorical variables, and Mann-Whitney U test for continuous and ordinal variables as normal distribution could not be assumed.Survival analysis was performed using Cox regression to analyze the impact of HAE and a delay of chemotherapy courses by 2–6 weeks. Given the time-dependent nature of HAE and delayed chemotherapy courses, i.e. an increasing cumulative incidence in patients receiving longer treatment, a landmark analysis was performed [Uni- and multivariable logistic regression was performed to predict HAE during the concomitant phase of chemotherapy using previously published parameters [ | PMC9886607 |
Results | PMC9886607 | |||
Patterns of hematologic adverse events grade 3 or higher | lymphopenia, HAE, hematotoxicity, neutropenia | ADVERSE EVENTS, NEUTROPENIA, LYMPHOPENIA | The prevalence of HAE was higher in patients treated with CCNU/TMZ compared to treatment with TMZ alone without reaching statistical significance (36.4% (24 of 66) vs. 28.6% (18 of 63), respectively, p = 0.36) as reported before [
Swimmer plot with individual patient data on applied chemotherapy courses and hematotoxicity. Crosses indicate hematological adverse events CTCAE grade 3 or 4, triangles indicate discontinuation of chemotherapy due to hematotoxicity or a resulting delay of more than 6 weeks. The duration of HAE in the concomitant phase of chemotherapy was longer in the TMZ arm (concomitant: median 20 days, IQR 13–36.5, n = 13) compared to the CCNU/TMZ arm (1st course: median 10 days, IQR 2–24, n = 15) without reaching statistical significance (p = 0.10). We observed the opposite for HAE during adjuvant courses; the median duration in TMZ was 6.5 days (IQR 4.5–13.25), compared to CCNU/TMZ with 20 days (IQR 11.25–51.5, p = 0.004). For all HAE episodes combined, the median duration was 11.5 days (IQR 5.25–22.75) in the CCNU/TMZ arm and 13 days (IQR 6.75–23.25) in the TMZ arm, respectively (p = 0.46). The duration of lymphopenia grade 3 or 4 was longer under CCNU/TMZ treatment, but this observation was based on a low number of cases (Table
Median duration and interquartile range (IQR) of hematotoxicity grade 3 or 4 episodesHigh risk neutropenia, defined as CTCAE grade 4 neutropenia > 7 days [ | PMC9886607 |
Risk of recurring hematotoxicity | HAE | EVENTS | Among patients experiencing HAE, the median number of events was 1 (range, 1–4), with no difference between treatment arms (TMZ: 1 [range 1–4], CCNU/TMZ: 1 [range 1–4], p = 0.40). The risk of repeat HAEs during later courses among patients receiving at least one further course of chemotherapy after first HAE was 42.9% (15 of 35), numerically larger with CCNU/TMZ (47.6%, 10 of 21) compared to TMZ (35.7%, 5 of 14, p = 0.73). | PMC9886607 |
Impact of hematotoxicity on chemotherapy and survival | hematotoxicity, HAE | Chemotherapy was completed (i.e. concomitant + 6 adjuvant courses of TMZ or 6 courses of CCNU/TMZ) in 40.6% (26 of 66) of patients receiving CCNU/TMZ and 59.4% (38 of 63) of patients receiving TMZ, as reported before [According to protocol, chemotherapy was stopped if a course was delayed by more than 6 weeks. More patients stopped chemotherapy due to hematotoxicity or resulting delay under CCNU/TMZ (19.7%, 13 of 66) than TMZ (6.3%, 4 of 63, p = 0.0358, Fig. The occurrence of HAE was not associated with shorter survival in the entire cohort (hazard ratio [HR] 1.06, 95% CI 0.73–1.54, p = 0.76) nor for both arms separately (TMZ: HR 1.08, 95% CI 0.63–1.85, p = 0.79, CCNU/TMZ: HR 1.03, 95% CI 0.61–1.75, p = 0.91).Survival was also similar in patients with a delay of 2–6 weeks for any course of chemotherapy compared to patients without such a delay, both in the entire cohort (HR 0.70, 95% CI 0.43–1.16, p = 0.17) and for both arms separately (TMZ: HR 0.59, 95% CI 0.29–1.21, p = 0.15; CCNU/TMZ: HR 0.82, 95% CI 0.40–1.66, p = 0.58). | PMC9886607 | |
Discussion | HAE, hematologic adverse, toxicity, lymphopenia, glioma, hematotoxic, hematotoxicity | LYMPHOPENIA, EVENTS, GLIOMA | The present study provides a detailed comparative analysis of high grade hematotoxicity in the CeTeG/NOA-09 trial. No hematologic adverse event grade 5 was reported and the overall frequency of HAE showed a non-significant tendency to be higher with CCNU/TMZ as compared to TMZ [HAE patterns differed between the treatment arms: compared to TMZ, more patients developed HAE during later courses in the CCNU/TMZ arm. HAE in the TMZ arm lasted longest after concurrent treatment, while HAE from CCNU/TMZ were more prolonged during later courses. Most likely, the 6-week long exposure to TMZ during the concomitant phase of radiochemotherapy (employing > 1/3 of the total maximum temozolomide dose given during therapy) translates to a longer lasting nadir than the adjuvant 5/28 courses. On the other hand, CCNU/TMZ courses with increasing intensity of the CCNU/TMZ treatment scheme and potentially cumulative and prolonged toxicity of CCNU may explain the more frequent HAE onset in later courses. Consequently, more patients in the CCNU/TMZ arm compared to TMZ discontinued chemotherapy due to hematotoxicity or a resulting delay of > 6 weeks.In line with previous reports, the occurrence of HAE was not associated with shorter survival in our analysis [The duration of HAE was similar between treatment arms with the exception of lymphopenia, which lasted longer in CCNU/TMZ than in TMZ. However, this observation was based on a small number of observations and lymphopenia is often perceived as a less threatening HAE due to the possibility of chemoprophylaxis for pneumocystis jirovecii pneumonia [Comparing HAE rates to former studies, one has to consider the different follow up schemes for blood tests. The present study required mandatory weekly blood tests to attribute hematotoxic events to the suspected causative chemotherapeutic drug and guide dose adjustment. This careful follow-up could explain the higher rate of HAE during standard TMZ treatment of 29%, compared to 16% upon monthly examination in the landmark EORTC 22981/26981-NCIC CE3 trial [We also evaluated the prediction of hematotoxicity employing previously published baseline factors found to be predictive in glioma patients receiving TMZ chemotherapy [The association of female gender and increased risk of HAE has been reported for temozolomide in glioma treatment [In addition to clinical factors, little is known about the contribution of genetic factors to hematotoxicity susceptibility. Lombardi et al. found a methylated | PMC9886607 |
Author contribution | JW, CS and UH designed the analysis. JW performed data analysis and wrote the first draft of the manuscript. CS and UH supervised the work. All authors contributed to data acquisition, commented on previous versions and read and approved the final manuscript. | PMC9886607 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. The trial was funded by the German Ministry for Education and Science (Grant No. 01KG1005). | PMC9886607 | ||
Data availability | The dataset is available from the corresponding author upon reasonable request. The data are not publicly available due to privacy restrictions. | PMC9886607 | ||
Declarations | PMC9886607 | |||
Conflict of interest | Janssen-Cillag, Novocure | UH has received lecture and/or advisory board honoraria from Medac, Novartis, Daichii-Sankyo, Noxxon, AbbVie, Bayer, Janssen, and Karyopharm. CS has received lecture or advisory board honoraria from AbbVie, Bristol-Myers Squibb, HRA Pharma, Medac, Roche, and Seagen. GT has received lecture, consultant or advisory board honoraria from AbbVie, Bayer, Boehringer Ingelheim, Medac, Novartis, Novocure) and research grants from Roche Diagnostics and Medac. JS has received lecture and/or advisory board honoraria or travel cost reimbursement from Abbvie, Medac, Med-Update, Roche, Novocure and Seagen. MGs reports personal fees from Roche, Novartis, Daichi Sankyo, Novocure, Bayer, frm Janssen-Cillag, Merck, Kyowa Kirin, Seagen, and grants from Novocure. FSG reports advisory board honoraria from Novocure. GT has served on advisory boards of AbbVie, Bayer, Boehringer Ingelheim, received consulting fees from AbbVie, Bayer; received speaker fees from Medac and Novocure. FR has received lecture and/or consulting honoraria from Stryker, Brainlab, Spineart, Icotec, royalties from Spineart and research support from Icotec. The other authors declare they have no financial interests. | PMC9886607 | |
Informed to consent | All procedures performed in studies involving human participants were in accordance with the ethical standards of the Helsinki Declaration and its later amendments and the Guidelines for Good Clinical Practice. The study was approved by the Ethics committees of all participating centers.Written informed consent was obtained from all individual participants included in the study. | PMC9886607 | ||
References | PMC9886607 | |||
1. Introduction | OA, inflammation, osteoarthritis, arthritis, pain, joints | RHEUMATOID ARTHRITIS, INFLAMMATION, JOINT DISEASES, OSTEOARTHRITIS, ARTHRITIS, DISEASES | Methylsulfonylmethane (MSM) is a food ingredient present in small amounts in many foods, and its anti-inflammatory effects have been reported. We conducted a randomized, double-blind, placebo-controlled trial of oral consumption of MSM on mild pain of the knee joint in healthy Japanese participants. A total of 88 participants were enrolled in this study and randomly assigned to MSM consumption (Sulfur composes 34% of methylsulfonylmethane (MSM), a food ingredient [Discomfort in joints is caused by local destruction and inflammation of the joint(s), and the acute phase of discomfort often becomes a chronic state and may progress to more severe diseases, such as osteoarthritis (OA) and rheumatoid arthritis. To prevent the progression of joint problems, daily dietary care is essential. Thus, many dietary components that maintain a normal healthy state of joints have been investigated [MSM has been suggested as a supplement for the prevention of OA due to its pleiotropic effects that help in joint protection. MSM has been shown to promote osteoblast differentiation via the Jak2/STAT5b pathway [The chondrogenic and anti-inflammatory effects of MSM and the incorporation of the ingested MSM-derived sulfur into the cartilage suggest an application of MSM for the prevention or treatment of inflammation-related joint diseases. In animal models, therapeutic effects of MSM on experimental arthritis have been reported, i.e., the score of arthritis in the models was improved in the MSM treatment groups [ | PMC10346176 |
2. Materials and Methods | PMC10346176 | |||
2.1. Study Aim | knee pain | This study aimed to determine the effect of oral consumption of MSM on knee joint quality of life (QOL) in mild knee pain participants. | PMC10346176 |
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