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Relationship between sleep health improvement and individual attributes. | (Notes) 1. Robust standard errors in parentheses.2. ***, **, and * indicate statistical significance at the 1%, 5%, and 10% levels.3. The purpose at the start of the program (multiple responses) and major changes in work and life during the program period are used as control variables but are omitted from the table. | PMC10553342 | ||
5. Discussion and conclusion | major loss, insomnia, sleep deficiency, ’ behavior | EVENTS | Using a randomized controlled trial of a sleep improvement program in a firm’s workforce, this paper examined the extent to which improved sleep health increases work productivity. The results of the analysis revealed the following. First, participants in the sleep improvement program showed a statistically significant improvement in sleep health compared to the control group after accounting for a variety of work and lifestyle factors that may affect sleep. Second, the treatment group also exhibited a statistically significant improvement in work productivity, which was fully explained by the effect through sleep improvement. The total effect sizes for productivity improvement were similar whether the ANCOVA or 2SLS estimation methods that capture the effect through diligent participation or sleep improvement were used. Although it is possible for anyone to experience worsening sleep due to various changes and events in their work and personal lives, promoting sleep health through the use of information technology such as sensing devices may help improve sleep deficiency and restore productivity. However, the results of this paper also reveal that the effect is heterogeneous depending on individual characteristics such as age and willingness and perseverance to improve sleep health. When implementing proactive corporate health interventions, it is important to plan ahead, identifying groups of employees who might benefit most from interventions and incorporating additional nudges to support those who have difficulty changing their behavior.Currently, many developed countries are experiencing an aging population. Japan has the oldest population in the world, with the proportion of people aged 65 and over recorded at 28.7% of the total population in 2020, and this proportion is projected to rise to 35.3% by 2040. To cope with the aging of the population, the government is requiring companies to try to retain their employees until the age of 70 under the revision Act on Stabilization of Employment of Elderly Persons from April 2021. There is concern that as the number of people with sleep problems increases with age (see, for example, Léger et al. [As this paper has shown, poor sleep health leads to a decline in productivity, which is a major loss for the economy. The problem, however, is that when a person experiences chronically poor sleep, he or she may feel it is normal, and it becomes difficult for the person to recognize the decline in productivity. Additionally, even if the person is aware of productivity loss, companies may not be able to detect presenteeism. A person can see a doctor if he or she has extreme insomnia, but few people will see a doctor for a slight loss of productivity if it does not interfere with their daily lives. As a result, people tend to neglect their daily sleep, and even if they want to get a good night’s sleep, they are unlikely to actively gather information to improve their sleep health or examine related bad habits that negatively affect sleep. Companies should understand that the importance of sleep health is not easily recognized by individuals and may consider implementing proactive health management, such as providing sleep improvement measures or subsidizing the cost of sleep technology for employees.Finally, we discuss the limitations of our paper. First, we conducted an RCT on white-collar day workers as the main target group, and productivity improvements through sleep improvement were confirmed for those workers. However, it is not clear whether similar improvements can be expected for shift workers and blue-collar workers in various industries, such as construction, manufacturing, and transportation. It is necessary to verify the results by expanding the target occupations. Second, this paper targets workers who are interested in improving their sleep, and the sample size is not large (approximately 200 workers). It is necessary to examine the results of a larger sample including those who have sleep problems but are not interested in the sleep health measures or those who are strongly resistant to the interventions. Third, the effects of the RCT analyzed in this paper were based on data immediately after the program was implemented, and it is unclear how long the changes in the participants’ behavior to improve their sleep might last. Even if the advice given by the sleep app was temporarily beneficial, the improved behaviors may be reversed as soon as individuals stop using the app or sleep measurement device. Fourth, it is also necessary to examine whether productivity gains due to improved sleep are a temporary phenomenon or whether they persist. It will be important to monitor changes over time by conducting multiple follow-up surveys of RCT subjects. Fifth, the usage of actigraphy data recorded by the sleep device in the treatment group is another future challenge. We created the third sleep health score ( | PMC10553342 |
Supporting information | TRANSFORMATION | (PDF)Click here for additional data file.This paper is a part of a joint research project combining the studies “Research on Work Style Reform and Health Management” (Sachiko Kuroda) and “Productivity Effects of Personnel Policies and the Transformation of Employment Systems” (Hideo Owan) at the Research Institute of Economy, Trade and Industry (RIETI). We thank Masaya Takahashi (National Institute for Occupational Safety and Health (NIOSH)), Makoto Yano (RIETI), Masayuki Morikawa (RIETI), Kotaro Tsuru (Keio University), and participants of the Discussion Paper study meeting of the RIETI for their helpful comments on this paper. | PMC10553342 | |
References | PMC10553342 | |||
Subject terms | meniscal injury, meniscus injury | Immunity-and-matrix-regulatory cells (IMRCs) derived from human embryonic stem cells have unique abilities in modulating immunity and regulating the extracellular matrix, which could be mass-produced with stable biological properties. Despite resemblance to mesenchymal stem cells (MSCs) in terms of self-renew and tri-lineage differentiation, the ability of IMRCs to repair the meniscus and the underlying mechanism remains undetermined. Here, we showed that IMRCs demonstrated stronger immunomodulatory and pro-regenerative potential than umbilical cord MSCs when stimulated by synovial fluid from patients with meniscus injury. Following injection into the knees of rabbits with meniscal injury, IMRCs enhanced endogenous fibrocartilage regeneration. In the dose-escalating phase I clinical trial (NCT03839238) with eighteen patients recruited, we found that intra-articular IMRCs injection in patients was safe over 12 months post-grafting. Furthermore, the effective results of magnetic resonance imaging (MRI) of meniscus repair and knee functional scores suggested that 5 × 10 | PMC10618459 | |
Introduction | meniscus injuries, meniscus injury, Meniscus injuries, injuries | Meniscus injuries are the second most commonly occurring injuries to the knee.Stem cell-based regenerative therapy is an emerging and promising option for healing meniscus injury.To date, one double-blinded randomized controlled trialIn the present study, we found that hESCs-derived-IMRCs present strong immunomodulatory and pro-regenerative profiles when stimulated by synovial fluids from patients with meniscus injury. Endogenous fibrocartilage regeneration was observed in meniscal defect rabbits after IMRCs engraft. Following additional safety assays in cynomolgus monkeys, we conducted a phase I, dose-escalation clinical study (NCT03839238) and found that intra-articular injection of IMRCs in patients is safe with promising outcomes for meniscus injuries. To our knowledge, this is the first-in-human Phase I clinical study of IMRCs in meniscus injuries. | PMC10618459 | |
Results | PMC10618459 | |||
IMRCs possess a stronger immunomodulatory and pro-regenerative profile than UCMSCs | PROLIFERATION | In this study, IMRCs derived from hESCs were generated through the passage of migrating cells acquired from human embryoid bodies (hEBs) using serum-free reagents (Supplementary Fig. IMRCs activated by synovial fluid enhanced chondrocytes proliferation and differentiation. In order to obtain a more comprehensive understanding of IMRCs at the protein level, we conducted a focused ELISA analysis involving 48 biologically relevant chemokines and cytokines in response to synovial fluid stimulation (Supplementary Table | PMC10618459 | |
IMRCs have a good safety profile for administration in vivo | Toxicity | The IMRCs used in this study were the same batch as before, and the detailed karyotyping and in vivo tumorigenicity assays had been described in our previous article.Toxicity test after cell transplantation. The study design, macroscopic observation, histological analysis and representative immunohistochemical staining 8 weeks after cell transplantation. | PMC10618459 | |
Intra-articular injection of IMRCs repairs punch defects in the rabbits’ meniscus | fibrous | The efficacy of this IMRCs-based therapy was further evaluated. At week 8 post-injection, samples of the entire meniscus of rabbits were collected for macroscopic observations and assessed using a semi-quantitative scale according to the previous report.Strongly positive Safranin-O staining (red) of extracellular matrix and glycosaminoglycan content was observed in the regenerated tissues in the IMRCs group at week 8, similar to the natural meniscus tissue (Supplementary Fig. Masson trichrome-stained sections were used to assess collagen distribution, orientation, and characterization of the matrix components. In a normal meniscus, a large number of collagen fibers were arranged in parallel. Meanwhile, chondrocytes, including some clusters of chondrocytes, were usually located in rows between fibrous bundles (Supplementary Fig. The histochemical staining of type I collagen (Col-1) and type II collagen (Col-2) fibers showed that Col-1 was lower in and around the repair foci, but Col-2 of repair foci was observed in the IMRCs group (Fig. We further performed semi-quantitative histological scoring of the regenerated meniscus tissue using a modified Pauli scoring system, | PMC10618459 | |
A phase I dose-escalating trial of IMRCs in the treatment of meniscus injury | PMC10618459 | |||
Intra-articular injection of IMRCs is safe | pain | ADVERSE EVENTS, BLOOD, BLOOD CLOTTING | All participants tolerated the injection procedure well, with no serious adverse events (SAE) associated with IMRCs during the post-procedure period. Four of the 18 patients (22.2%) experienced symptoms of mild adverse events (AEs), including joint pain after injection in 1 case of the mid-dose group and local swelling sensation in the knee joint in 3 cases of the high-dose group (Supplementary Table Blood tests, including complete blood count, basic metabolic panel, blood enzyme tests, blood clotting tests, human lymphocyte subsets and inflammatory cytokines, were almost in the normal reference range and showed no significant change after injection (Supplementary Table Clinical trial shows the safety profile of IMRCs by blood tests at six time points post-injection. | PMC10618459 |
Radiological analysis shows that IMRCs enhance meniscus repair | meniscus injury | The efficacy of IMRCs was assessed using MRI according to the Stoller’s classification standard of meniscus injury.Clinical trial shows efficacy outcomes of IMRCs in MRI analysis and knee function scores after IMRCs injection. Data from meniscus MRI images at week 1, 4, 8, 12 and 48 after IMRCs injection demonstrated that 6 (33.33%), 10 (55.56%), 11 (61.11%), 15 (83.33%) and 14 (81.25%) had healed meniscus. The meniscus repair rate at week 12 was significantly higher than that at week 1 (33.33% vs. 83.33%, Meniscal volume was calculated by quantitative MRI evaluation using 3D Slicer software. Overall, meniscus volume improved after intra-articular injection of IMRCs in all three groups, which increased from 4288 mm | PMC10618459 | |
Intra-articular injection of IMRCs relieves pain and improves knee function | pain | OSTEOARTHRITIS | The pain intensity was assessed on a 10-point Visual Analogue Score (VAS). In a total of 18 cases, the VAS (described as mean ± SEM below) decreased from 3.50 ± 0.40 before treatment to 1.69 ± 0.33 at week 48 after IMRCs injection, and the VAS pain intensity in patients was significantly decreased compared to the baseline (week 1, The knee function was assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, the Lysholm knee score, and the American Knee Society (AKS) knee score. The WOMAC score in 18 cases decreased from 14.94 ± 1.83 baseline to 10.81 ± 5.29 at week 48, a tendency that indicated improved outcome of knee function (Fig. | PMC10618459 |
Discussion | TGF-β1, meniscus injury, avascular | The meniscus has limited healing capacity, especially the avascular zone that occupies two-thirds of the meniscus. We have shown that intra-articular injection of hESCs-derived IMRCs enables the endogenous regeneration of injured meniscus in rabbits. This is likely achieved by modulating the injured environment as the IMRCs possess strong immunomodulatory and pro-regenerative gene profiles in response to the synovial fluids from patients with meniscus injury. Our phase I clinical trial showed that intra-articular injection of IMRCs is not only safe but also beneficial based on improvement in symptoms and MRI imaging. Our dose-escalation study further identified an optimal dose for treatment, setting the foundation for further clinical studies.Many pre-clinical studies suggested MSC-based regenerative treatment is a promising option to overcome poor intrinsic healing capacity, including synovial-derived MSCs (S-MSCs),The substantial pro-regenerative capacity of the IMRCs prompted us to examine their properties and compare them with other types of MSCs, especially UCMSCs. In previous vitro studies, the levels of IL-6, MCP-1, PEG2, and TGF-β1 in UCMSCs supernatants were increased, and UCMSCs were able to significantly reduce the production of IL-6 and IL-12 when activated by M1 macrophages.With the safety profiles in rabbits and monkeys, we conducted the phase I clinical trial. Our results show that intra-articular injection of IMRCs is safe, similar to previous reports using various types of MSCs,Importantly, we identified an ideal dose (5 × 10Taken together, despite the small sample size and absence of the control group, this study provides robust evidence that IMRCs are safe for meniscus injury and can promote meniscus regeneration and healing, as well as sufficient proof-of-concept (POC) data to justify further randomized, double-blind controlled clinical trials. | PMC10618459 | |
Materials and methods | PMC10618459 | |||
Cell culture | The IMRCs were prepared as described previously, and they have been verified in accordance with the requirements of China’s National Institutes for Food and Drug Control (NIFDC). | PMC10618459 | ||
Cell co-culture with synovial fluid stimulation | At the fourth passage, cells were digested and plated onto 12-well plates. IMRCs and UCMSCs were seeded at a density of 1 × 10 | PMC10618459 | ||
Cytokine analysis | The supernatants of IMRCs and UCMSCs were collected after synovial fluid stimulation for 24 h. The samples were analyzed by 48-plex Bio-Plex Pro Human Cytokine Assay (Bio-Rad, Hercules, CA, USA; 1200728), following the guidelines provided by the manufacturer. | PMC10618459 | ||
Preparation and analysis of RNA-seq libraries | Total RNA was extracted from IMRCs and UCMSCs using Trizol (Invitrogen, Waltham, MA, USA; 15596018). Subsequently, RNA-seq libraries were prepared with the NEBNext | PMC10618459 | ||
Animals | All animal experiments were conducted according to protocols approved by the Animal Care and Use Committee of Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology (Registration number: TJH-201806001). 26 New Zealand white rabbits that were 6 months old and weighed 2.5-3.0 kg were obtained from Wanqian Jiaxing Biotechnology Co., Ltd., Hunan, China. After arrival, all rabbits were acclimated to the animal facility at least 7 days before the experiments were initiated. The rabbits were housed in single cages and kept in a 12-hour light/12-hour dark cycle at 22 ± 2 °C with water and food ad libitum. | PMC10618459 | ||
Animal surgery and post-surgery care | STERILE | All rabbits fasted for 12 h before surgery. In sterile settings, a knee arthrotomy was performed under general anesthesia (RDW Life Science Co., Ltd., isoflurane, R510-22-10). Anesthesia was supplied with a small oxygen mask through a veterinary isoflurane tank (RDW Life Science Co., Ltd., R580). The anesthesia was induced at 4-5% with full airflow and maintained at 3-3.5%. The surgical area was shaved and rinsed with an antiseptic fluid. A sterile skin biopsy punch machine (Integra Life Sciences Production Corporation, 33-31 A) was used to create a 1.5 mm full-thickness, cylindrical, vertical defect at the anteromedial part of the right leg medial meniscus. The operated knee was bandaged with a loose non-elastic bandage and left mobile in their cages for 24 h after surgery. Antibiotics and antiviral medicine were given immediately after surgery and continued for three consecutive days post-surgery (benzylpenicillin Sodium, North China Pharmaceutical Group Co., Ltd.; Aciclovir, Hubei Wushi Pharmaceutical Co., Ltd.). The antibiotics and antivirals were dissolved in normal saline; the dosages were as follows: benzylpenicillin Sodium 200,000 units/day, Aciclovir 2 ml/day (one vial dissolved in 5 ml normal saline). | PMC10618459 | |
Cell transplantation and immunosuppression in rabbits | To evaluate their safety over both short and long durations, we conducted a series of biosafety experiments following the ‘Guidelines for Human Somatic Cell Therapies and Quality Control of Cell-based Products’ issued by the China Food and Drug Administration (CFDA).The IMRCs stored in a liquid nitrogen tank were thawed in a cell thawing system (Biocision, BCS-602) for 2-3 min at 37 °C. After thawing, a single dose of 1.0 × 10 | PMC10618459 | ||
Tissue harvesting and processing in rabbits | dehydration, overdosage | DEHYDRATION | The rabbits were sacrificed by overdosage with isoflurane 8 weeks after IMRCs injection with anesthesia. After sacrificing, the organs and whole meniscus were placed in 4% ice-cold PFA. Images of the whole meniscus were taken on the same day of harvesting and further completed the dehydration, paraffin embedding, and sectioning of the tissues. | PMC10618459 |
Macroscopic observation and semiquantitative scoring | Tissue growth was assessed macroscopically using naked-eye observation and entire meniscus images were obtained under a microscope (Guangzhou Micro-shot Technology Co., Ltd., MZ62). The meniscus defect filling and quality of repair were assessed. The defect repair and other features of repair were scored with a semiquantitative scale adopted from Rudert et al, | PMC10618459 | ||
Histological evaluation and immunohistochemistry staining of the regenerated tissue | toxicity | SECONDARY | All the tissues were sliced with microtome at 4 μm thickness. To detect meniscus cells (chondrocytes) in the neo-meniscus and analyze collagen distribution, matrix stainability and matrix contents, glycosaminoglycan, H&E staining, Masson’s trichrome and Safranin-O staining were used. For toxicity analysis, H&E staining was used to examine the morphology of key organs. Immunostaining for type I & II collagen in the regenerated meniscus was carried out to show the expression and distribution of collagen. Sections were incubated with the following primary antibodies: Collagen I Antibody (Col-1) (1:100; GeneTex, GTX26308), Anti-Collagen Type II (Ab-1) mouse mAb (II-4C11) (1:200; Sigma-Aldrich, CP18-100UG). Immunostainings were finished using Goat anti-mouse secondary antibody (1:1000; Servicebio, G1214).For quantification of histology for regenerated meniscus, Pauli’s scoring system was used as the previous report, | PMC10618459 |
Fluorescence in situ hybridization (FISH) analysis for existing of IMRCs | Human DNA-specific reference probes linked to fluorescent molecules, i.e., FISH analysis was used to detect human cells in the rabbit meniscus and internal organs according to previous reports. | PMC10618459 | ||
Dose-escalating clinical trial design and ethical considerations | meniscus injury | The study is an open-label, dose-escalation phase I clinical trial conducted from January 2019 to December 2020 that investigated the role of human embryonic stem cells-derived mesenchymal stem cells (IMRCs) in the treatment of meniscus injury (ClinicalTrials.gov Identifier: NCT03839238). The protocol was approved by the ethics committee of the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (certificate of approval number: TJ-IRB20180901). According to the suggestion of the National Health Commission, we extended the follow-up time from 12-week to 48-week and obtained updated approval from the ethics committee (updated certificate of approval number: TJ-IRB20190911). This study was conducted according to the Declaration of Helsinki and Good Clinical Practice principles. All patients provided written informed consent. | PMC10618459 | |
Participants Eligibility | 25 patients were screened. Eligible trial subjects were adults (18-65 years old) with Grade I-II meniscus injury according to the Stoller classification standard | PMC10618459 | ||
Allocation and Interventions | Eighteen patients enrolled in our study were sequence assigned to three groups: 6 patients in each of the three-group received 1 | PMC10618459 | ||
Outcome measures | PMC10618459 | |||
Primary outcome | Cancer | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT, CANCER | Safety was measured by the documentation of local and systemic adverse events. A combination of vital signs, physical examination, and blood test (including the routine manual complete blood count, biochemistry, liver, kidney function, electrolytes, coagulation, cellular immunity, lymphocyte function and cytokines) and urine laboratory tests were used at 1, 4, 8, 12, and 48 weeks. Adverse events were categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 scale (NCI-CTCAE 4.0). | PMC10618459 |
Statistical analysis | SPSS 23.0 software was used for the statistical analysis. Outcome measures were analyzed based on the intention-to-treat population. Data are reported as means ± SEM. An unpaired t-test was used to assess efficacy before and after injection, and a one-way analysis of variances was used for the comparison in three groups. Two-tailed Mann-Whitney tests were used for those with unequal sample sizes and outcome measures that were not normally distributed. To identify clinical function changes between baseline and 1, 4, 8, 12, and 48 weeks follow-up for self-reported knee scores, the two-way ANOVA was performed. Within-group differences were analyzed per the Mann-Whitney U and Wilcoxon signed-rank tests, respectively. Statistical significance was determined at | PMC10618459 | ||
Supplementary information |
Supplementary MaterialsSupplementary Table 2These authors contributed equally: Liangjiang Huang, Song Zhang, Jun Wu, Baojie Guo | PMC10618459 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41392-023-01670-7. | PMC10618459 | ||
Acknowledgements | This work was supported by the Natural Key Research and Development Program (No: 2021YFA1101604), the key Research and Development program of Hubei province (2022BCA028), the international cooperation project of China Manned Space Program, and program for Tongji Hospital Academic Frontier Youth Team(2019A20). We thank radiological engineer Dong Liu for performing the knee MRI scan. We thank the team of statistician Yao Chen for the initial design and final statistical analysis. We thank Prof. Shyh-Chang Ng and Dr. Chunchu Deng for English language assistance in the final manuscript. | PMC10618459 | ||
Author contributions | H.C., J.H., and B.Y.H. conceived the project and supervised the experiments. L.J.H., Y.J.L.(Yajie Li), and Y.Y.L. conducted the injection operation and patient care. S.Z., J.W., B.J.G., Z.W.L., and S.Z.A.S. performed the animal safety experiments. T.T.G., W.J.L., and Y.T. participated in stem cell differentiation and expansion. B.H. and G.T.K. conducted the radiological images review. L.J.H., Z.Y.F., X.L.H., and L.W. assisted with the experimental protocol design. L.J.H., L.F.X., J.Q.F., S.Y., and B.Z. organized the data collection. Y.J.L.(Yujuan Li) and Y.J. conducted the PET/CT scan. Y.N.X., Y.H.(Ying Huang), and Y.H.(Yan Huo) completed the safety testing of stem cells. H.C. and J.W. wrote the paper. G.H.F., W.L., and Q.Z. provided useful suggestions and comments on the project. All authors have read and approved the article. | PMC10618459 | ||
Data availability | The data used in the current study are available from the corresponding authors upon reasonable request. Participants data without names and identifiers will be made available after approval from all corresponding authors. Please refer to Supplementary Materials and Methods for further details regarding the materials and methods used. | PMC10618459 | ||
Competing interests | The authors declare no competing interests. | PMC10618459 | ||
References | PMC10618459 | |||
Background | NCT03592264 | SOLID TUMORS | Report of a Phase 1 dose-escalation study of OBI-3424 monotherapy in patients with advanced solid tumors (NCT03592264). | PMC10180615 |
Methods | A classic 3 + 3 design was used to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of OBI-3424 administered intravenously, as a single agent, at doses of 1, 2, 4, 6, 8, or 12 mg/m | PMC10180615 | ||
Results | toxicities, Dose-limiting | Dose-limiting hematologic toxicities at 12 mg/m | PMC10180615 | |
Conclusions | The RP2D is 12 mg/m | PMC10180615 | ||
Subject terms | PMC10180615 | |||
Introduction | NSCLC, tumor, cancers, cancer, prostate | TUMOR, CANCERS, CANCER, PROSTATE, HEPATOCELLULAR CARCINOMA, NSCLC | Aldo-keto reductases (AKRs) are a superfamily of NAD(P)(H)-dependent oxidoreductases that primarily catalyze the reduction of aldehydes and ketones to their corresponding alcohols [AKR1C3 is expressed in various normal human tissues, including sex hormone-dependent (e.g., testis, breast, endometrium, and prostate) and sex hormone-independent (kidney and urothelium) tissues [In a population-level survey of 2490 patients across 19 cancer types, in which tumor tissue microarrays were used to assess AKR1C3 overexpression, the highest frequency was noted in hepatocellular carcinoma, followed by bladder, breast, prostate, renal, gastric, cervical, colon, and non-small cell lung (NSCLC) cancers [OBI-3424 is a highly potent DNA-alkylating prodrug that is selectively activated by AKR1C3 (Fig. | PMC10180615 |
Reduction of OBI-3424 by AKR1C3 in the presence of NADPH to produce the cytotoxic agent OBI-2660. | NSCLC, human hepatocellular carcinoma, death | SOLID TUMORS, CYTOTOXICITY, NSCLC | In the presence of NADPH, reduction of OBI-3424 is mediated by AKR1C3 to release the cytotoxic moiety OBI-2660, which is an aziridine bis-alkylating agent, leading to crosslinking of DNA at the N7 (or O6) position of guanine and subsequent cell death. AKR1C3 aldo-keto reductase family 1 member C3.In a study using 11 human hepatocellular carcinoma cell lines and 10 human NSCLC cell lines, OBI-3424 exhibited enhanced cytotoxicity in the cell lines with AKR1C3 overexpression compared with the cell lines with low (protein expression ≤0.21 and RNA expression ≤0.19 LogWe report the results of a Phase 1, first-in-human, sequential dose-escalation study of OBI-3424 in patients with advanced solid tumors. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of OBI-3424 as a single agent. | PMC10180615 |
Methods | Cancer | CANCER | The study was conducted at two centers in the United States: The University of Texas MD Anderson Cancer Center and The Ohio State University Comprehensive Cancer Center. All patients provided written informed consent at the time of enrollment stating that they were aware of the investigational nature of the study. The study was approved by the institutional review boards of both institutions and conducted in accordance with the ethical principles of the International Council for Harmonization Guideline for Good Clinical Practice, the Declaration of Helsinki, and applicable local regulations. The study was registered at | PMC10180615 |
Patients | cancers, Tumors, active malignancies, infection, hematologic, hepatic, and renal function | CANCERS, BRAIN METASTASES, DISEASE, SOLID TUMORS, TUMORS, INFECTION, NONMELANOMA SKIN CANCER, ONCOLOGY, IN SITU CANCER | Eligible patients were ≥18 years of age and had histologically or cytologically confirmed advanced solid tumors for which standard treatments were exhausted or were no longer effective; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) guidelines; Eastern Cooperative Oncology Group performance status of 0–1; and adequate hematologic, hepatic, and renal function. Patients were excluded if they had received radiotherapy to >25% of the bone marrow or had symptomatic brain metastases; other active malignancies (except for adequately treated nonmelanoma skin cancer, in situ cancer, or other cancers whose natural history or treatment did not have the potential to interfere with the safety or efficacy assessment of the study); active infection; radiotherapy, surgery, chemotherapy, targeted therapy, hormonal therapy, or an investigational drug/device within 28 days of the study start date; or concomitant use of strong CYP3A4 inhibitors/inducers or naproxen. A complete list of the inclusion and exclusion criteria is provided in the | PMC10180615 |
Study design | toxicities, treatment-emergent adverse, DLTs, tumor | TUMOR | A standard “3 + 3” dose-escalation design was used. The primary endpoints were incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs), determination of the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D), and characterization of the OBI-3424 pharmacokinetic profile. Secondary endpoints were tumor response as assessed by RECIST v1.1, and AKR1C3 expression in available tumor samples. | PMC10180615 |
Treatment | OBI-3424 was administered by intravenous infusion over 30 min. The starting dose of OBI-3424, 1 mg/m | PMC10180615 | ||
Patient monitoring | tumor, bleeding, Tumor, neutropenia, fatigue, toxicity, diarrhea, thrombocytopenia, fever, nausea,, Cancer | ADVERSE EVENT, TUMOR, BLEEDING, TUMOR, NEUTROPENIA, FEBRILE NEUTROPENIA, THROMBOCYTOPENIA, EVENTS, CANCER | Safety assessments were performed at least once every 3 weeks throughout the study treatment period and included physical examination, measurement of vital signs, clinical laboratory tests, 12-lead electrocardiography, and urinalysis. Cell counts, concomitant medication review, and collection of TEAEs were done weekly. TEAEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.Radiologic assessments of tumor response by computed tomography scan were conducted at baseline, every two cycles for the first six cyles, and at the end of every four cycles thereafter. Tumor response was measured using RECIST v1.1 [A DLT was defined as the occurrence of any of the following events, within the first cycle of treatment, that was considered to be at least possibly related to OBI-3424: grade 4 neutropenia lasting ≥7 days; febrile neutropenia; grade 4 thrombocytopenia; grade 3 thrombocytopenia with ≥grade 2 bleeding requiring platelet transfusions; any other grade 3 or 4 nonhematologic toxicity (except grade 3 fatigue, nausea, vomiting, or diarrhea that resolved to grade 1 or baseline level within 72 h; grade 3 fever [in the absence of neutropenia]; grade 3 asymptomatic laboratory abnormalities that resolved to grade 1 or baseline level within 72 h or were not clinically significant; and asymptomatic grade 3 elevations in liver enzymes that resolved to grade 1 or baseline level within 7 days); and persistent aspartate aminotransferase/alanine aminotransferase levels of >3× the upper limit of normal with concomitant bilirubin value of >2× the upper limit of normal that was not clearly related to something other than the study drug. The period for DLT observation was 21 days from the first dose of OBI-3424. | PMC10180615 |
Pharmacokinetics | OBI-3424 (prodrug) and OBI-2660 (active metabolite) concentrations were analyzed from blood samples collected on day 1 of cycle 1 before, 15 min after the beginning of, and at the end of the infusion and 15, 30, 60, and 90 min and 2, 4, 6, and 8 h after the end of the infusion. Human plasma samples were analyzed by a validated method using liquid chromatography with tandem mass spectrometric detection. Plasma pharmacokinetic parameters were estimated with noncompartmental analysis using Phoenix WinNonlin Software (v8.3). | PMC10180615 | ||
Pharmacodynamics and biomarkers | tumor, tumors | TUMOR, TUMORS | Optional tumor tissue samples were collected prior to screening to measure AKR1C3 expression. OBI worked with the in vitro diagnostics company NeoGenomics Laboratories, Inc. (Aliso Viejo, CA, USA) to develop a validated immunohistochemistry (IHC) assay, which is being used to identify patients whose tumors have “high AKR1C3 expression” for inclusion in clinical trials with OBI-3424. Data from tissue microarrays or whole sections are summarized in Fig. | PMC10180615 |
AKR1C3 expression level in 10 tumor tissue types. | tumor, SCC squamous cell carcinoma, Tumor, HCC hepatocellular carcinoma, HNSCC head and neck squamous cell carcinoma, CRC colorectal carcinoma | TUMOR, TUMOR | AKR1C3 aldo-keto reductase family 1 member C3, CRC colorectal carcinoma, HCC hepatocellular carcinoma, HNSCC head and neck squamous cell carcinoma, IHC immunohistochemistry, SCC squamous cell carcinoma. Tissue slides were considered evaluable if hematoxylin and eosin staining showed ≥100 viable tumor cells. AKR1C3 expression levels on consecutive tumor tissue slides were analyzed using the validated automated IHC assay on the Leica BOND-III platform (Leica Biosystems, Deer Park, Illinois, USA). Slides were incubated with anti-AKR1C3 antibody (Sigma-Millipore mouse monoclonal antibody, clone NP6.G6.A6, 1.2 µg/mL, 1:2000 dilution in BOND primary antibody diluent) or isotype control (Leica BOND ready-to-use negative control [mouse]) for 30 min. The Sigma-Millipore antibody has previously been validated against the following cell line controls: HCT 116 (negative control), genetically modified HCT 116 transfected with a derivative of plasmid F527-V5 EFα promoter to overexpress AKRIC3, Nalm (low endogenous expression), and TF1 (high endogenous expression) [Reagents from the BOND Polymer Refine DAB Kit were used to perform the following steps on the Leica BOND-III IHC platform. Tumor AKR1C3 expression was evaluated using the H-score system [ | PMC10180615 |
Statistical analysis | The sample size in the current study was determined empirically, and there was no formal hypothesis testing. Categorical and continuous data were summarized with frequencies and percentages or descriptive statistics, respectively. All patients who received ≥1 dose of OBI-3424 ( | PMC10180615 | ||
Results | PMC10180615 | |||
Dose-limiting toxicity and maximum tolerated dose | In Schedule A, OBI-3424 was well tolerated at doses of up to 8 mg/m | PMC10180615 | ||
Hemoglobin level and platelet count changes with treatment. | Change in ( | PMC10180615 | ||
Pharmacokinetics | Mean plasma concentration versus time profiles of single doses of OBI-3424 and its active metabolite (OBI-2660) at doses ranging from 1 to 14 mg/m | PMC10180615 | ||
Pharmacodynamics | tumor | TUMOR | Thirty-two of the 39 patients provided archival (28/32) or fresh biopsy (4/32) tumor tissue specimens for AKR1C3 expression testing using the validated, automated IHC assay (NeoGenomics). Among the 32 specimens, 6 tumor tissue specimens did not have sufficient viable tumor cells and were non-evaluable. AKR1C3 H-scores by patient are listed in Fig. Antitumor activity in patients treated with OBI-3424 at postbaseline scans. | PMC10180615 |
Antitumor activity | tumor | DISEASE PROGRESSION, TUMOR, CHOLANGIOCARCINOMA | Thirty-three of 39 patients were evaluable for tumor response by RECIST v1.1. Six patients were not evaluable because of early discontinuation due to disease progression (A patient with cholangiocarcinoma, treated with OBI-3424 at 10 mg/mReasons for discontinuation of the study drug for all patients were as follows: disease progression ( | PMC10180615 |
Discussion | nausea, T-cell ALL, tumor, cancers, fatigue, epithelial carcinomas, thrombocytopenia, thrombocyopenia, anemia, B-cell ALL, hepatocellular tumors, ALL, hepatocellular cancer, advanced/metastatic pancreatic cancer, cholangiocarcinoma | TUMOR, CANCERS, PANCREATIC TUMORS, DISEASE, THROMBOCYTOPENIA, B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA, ANEMIA, CHOLANGIOCARCINOMA | In this first-in-human, dose-escalation, Phase 1 study, OBI-3424, a small-molecule prodrug, was tolerated at doses of up to 14 mg/mThe most common TEAEs were anemia (64%), thrombocytopenia (49%), nausea (26%), and fatigue (21%). Three patients experienced serious TEAEs; all 3 experienced grade ≥3 anemia and 2 of the 3 also experienced grade ≥3 thrombocyopenia. The occurrence of transient thrombocytopenia is consistent with published data on AKR1C3 overexpression in normal bone marrow. In a recent study, 20 normal archival bone marrow samples from patients with B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL were evaluated for AKR1C3 expression by IHC, protein Western blotting, and quantitative reverse-transcriptase PCR. An H-score was used to quantify the percentage of nuclear immunoreactivity for AKR1C3 with varying disease involvement. T-cell ALL samples had higher H-scores (172–190) than B-cell ALL samples (30–160). Follow-up IHC assessment of normal marrow specimens revealed that AKR1C3 is expressed in a subset of normal bone marrow cells that morphologically resemble erythroid lineage cells [OBI-3424 exhibited linear, dose-proportional pharmacokinetics at doses ranging from 1 mg/mThe best response to treatment with OBI-3424 was a partial response. One patient with cholangiocarcinoma had a partial response with 33% tumor reduction by local assessment while receiving OBI-3424 at a dose of 10 mg/mAKR1C3 is overexpressed in 90% of hepatocellular tumors and in 50% of pancreatic tumors, and there is a significant unmet need for better treatments in these cancers, especially for patients whose disease has progressed after surgery and/or systemic chemotherapy. Thus, a Phase 2 study of single-agent OBI-3424 is currently enrolling patients with locally advanced/metastatic pancreatic cancer, hepatocellular cancer, or other epithelial carcinomas with tumoral AKR1C3 overexpression. | PMC10180615 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41416-023-02280-4. | PMC10180615 | ||
Acknowledgements | We thank the investigators, coordinators, and study site personnel, as well as the patients and their families for participation in this study. We also acknowledge Leslie Chu, PhD, and Donald Young, MS, whose work was funded by OBI Pharma Inc, for assistance in writing this article. | PMC10180615 | ||
Author contributions | All authors contributed to the concept and design of the study; the acquisition, analysis, and interpretation of data; the drafting and revising of the manuscript; and the final approval of the manuscript submission. | PMC10180615 | ||
Funding | This study was funded by OBI Pharma Inc., Taipei City, Taiwan. | PMC10180615 | ||
Data availability | The data generated in the current study are available within the article and its supplementary data files. | PMC10180615 | ||
Competing interests | Diaccurate, Cancer | CANCER | Dr. AMT has received clinical trial research funding (through her institution) from OBI Pharma USA Inc., IMMATICS, Parker Institute for Cancer Immunotherapy, Agenus, Tempus, Tvardi, Boston Biomedical, and Karus Therapeutics. Dr. AMT has served in a consulting or advisory role for Vincerx, Diaccurate, and BrYet. Dr. CFV has no conflicts of interest to report. Dr. RW has no conflicts of interest to report. Dr. C-SS is an employee of OBI Pharma Inc. Dr. PH was an employee of OBI Pharma Inc. at the time the study was conducted. Dr. TEP was an employee of OBI Pharma USA Inc. at the time the study was conducted. | PMC10180615 |
Ethics approval and consent to participate | All patients provided written informed consent at the time of enrollment stating that they were aware of the investigational nature of the study. The study was approved by the institutional review board of both institutions and conducted in accordance with the ethical principles of the International Council for Harmonization Guideline for Good Clinical Practice, the Declaration of Helsinki, and applicable local regulations. The study was registered at | PMC10180615 | ||
Consent for publication | Not applicable. | PMC10180615 | ||
References | PMC10180615 | |||
Objective | rhinopharyngeal obstruction | To analyze the reliability of estimating the percentage of rhinopharyngeal obstruction by the adenoid using nasofibroscopy and its correlation with clinical symptoms. | PMC10493505 | |
Methods | OSA, rhinopharyngeal obstruction | SLEEP APNEA, OBSTRUCTIVE SLEEP APNEA | Cross-sectional observational study was conducted, involving 80 patients between 4 and 14 years old, recruited from Santa Casa of São Paulo general otorhinolaryngology outpatient service during the years of 2020 and 2021. All patients underwent nasal endoscopy examination, and the recorded videos were randomly assigned to four evaluators in two different sessions, with a minimum interval of 1 month. The evaluators estimated the percentage of rhinopharyngeal obstruction caused by the adenoid. Intra- and inter-evaluator correlations were established by comparing the reports from each evaluator. The data were compared to the Pro Image J Software report, that also estimates a percentage of obstruction by computer graphics. To correlate the grading of obstruction with clinical symptoms, all patients completed the OSA (Obstructive Sleep Apnea) 18 questionnaire, a validated tool for assessing sleep apnea in children. The questionnaire data were then compared to the average scores assigned by the evaluators. | PMC10493505 |
Results | Satisfactory intra- and inter-rater correlations were observed, and the results were consistent with the Pro Image J Software. However, no correlation was found between the percentage of obstruction and the severity of clinical symptoms. | PMC10493505 | ||
Conclusion | rhinopharyngeal obstruction | Nasofibroscopy demonstrates good reliability in assessing a percentage of rhinopharyngeal obstruction caused by adenoids. However, there is no correlation between the degree of obstruction of the rhinopharynx and the clinical symptoms. | PMC10493505 | |
Level of evidence | 4. | PMC10493505 | ||
Keywords | PMC10493505 | |||
Introduction | rhinopharyngeal obstruction, Adenoid hypertrophy, hypertrophy, nasal obstruction, adenoid hypertrophy | SLEEP APNEA, ADENOID HYPERTROPHY, TONSILLAR HYPERTROPHY, HYPERTROPHY, ADENOID HYPERTROPHY | Adenoid hypertrophy is one of the most common alterations of the upper airways in childhoodNasofibroscopy is considered the gold standard exam for assessing adenoid hypertrophy, enabling direct visualization of the rhinopharynx and adenoid lymphoid tissue.Unlike tonsillar hypertrophy,The limitations of the technique, as well as the subjectivity in interpreting adenoid hypertrophy diagnosed by nasopharyngoscopy, can impact clinical reasoning and lead to management decisions based on imprecise information. We did not find studies correlating the degree of adenoid hypertrophy with the intensity of symptoms such as nasal obstruction or nocturnal snoring. Additionally, we found no studies that define a specific percentage of rhinopharyngeal obstruction caused by the adenoid that suggests the need for adenoidectomy. Several studies have evaluated the correlation between hypertrophy of the palatine tonsils and respiratory symptoms,Thus, this study seeks to assess the reliability of estimating degree of rhinopharyngeal obstruction by the adenoid through nasofibroscopy and to correlate it with the intensity of nasal clinical symptoms, nocturnal snoring, and sleep apnea. | PMC10493505 |
Methods | upper airway infection, rhinopharyngeal obstruction, nasosinusal complaints, OSA, palate, congenital diseases, craniofacial malformations | OBSTRUCTIVE SLEEP APNEA, DOWN SYNDROME, IMMUNODEFICIENCIES, TONSILLAR HYPERTROPHY, NEUROMUSCULAR DISEASES, CONGENITAL DISEASES | Cross-sectional observational study that analyzes the reliability of adenoid evaluation by nasofibroscopy and correlates the degree of rhinopharyngeal obstruction with clinical symptoms.The study was approved by the Ethics and Research Committee (CAAE 29266820.1.0000.5479). Data were stored on the RedCap platform.The patients were screened at the various outpatient clinics of the Department of Otorhinolaryngology at Santa Casa of São Paulo over the years 2020 and 2021.Patients of both sexes, between 4 and 14 years old, with nasosinusal complaints and/or nocturnal snoring, who would undergo nasofibroscopy for clinical investigation, were selected. Patients who presented craniofacial malformations, Down Syndrome, congenital diseases, neuromuscular diseases, immunodeficiencies, current symptoms of upper airway infection, obstructive nasal septum deviation, and patients with Grade III or IV tonsillar hypertrophy were excluded. Patients who did not tolerate the examination or who presented poor quality videos that made it impossible to visualize the adenoid were also excluded.After being instructed about the risks and benefits of participating in the study and agreeing to participate, patients and family members signed the informed consent and assent and answered a clinical and demographic questionnaire (Annex 1). To determine the clinical outcome, they answered the OSA 18 (Obstructive Sleep Apnea) questionnaire (Annex 2),All patients underwent nasofibroscopy, in a sitting position, with a flexible fiberoptic nasofibroscope (OlympusTM ENFP4, 3.5 mm), with 250-watt halogen light, under topical anesthesia in both nasal cavities (4% lidocaine gel). Parents were informed how the exam would be performed and decided whether the children would be sitted alone or on their laps. No other immobilization method was used, and the examination was interrupted at any sign of discomfort. All videos ensured that the choana region was filmed during inspiration, with the palatal musculature relaxed, the moment for better assessment of rhinopharyngeal obstruction by the adenoid. The exam was recorded and edited in order to preserve the patient's identification.The group of evaluators was composed of four independent otorhinolaryngologists, with a minimum of five years of clinical experience, who are not study authors and did not have access to research protocol data. All were instructed to choose the moment for the best evaluation of the choana, soft palate relaxed during inspiration and the fiber being located in the distal position of the inferior turbinate. The video clips were sent to the evaluators, numbered by codes and without identification, in two different moments (T1 and T2) with an interval of at least one month between them. In the second evaluation, the order of the videos was randomized to avoid the influence of the first evaluation. The examiners did not have access to the grading attributed by themselves in the first evaluation, nor the grading attributed by the other evaluators. In each analysis, examiners were instructed to subjectively estimate a percentage of rhinopharyngeal obstruction by adenoid tissue.In addition to the subjective classifications, the videos were also digitally evaluated using the Pro Image J Software, which estimates the degree of rhinopharyngeal obstruction by the adenoid. In this software, a fifth evaluator delimited the area occupied by the adenoid and the choana area, as shown in Nasal endoscopy to evaluate the rhinopharynx using the Pro Image J Software. (A) Area of the choana estimated by Software Pro Image J. (B) Area of adenoid tissue estimated by Software Pro Image J. | PMC10493505 |
Statistical analysis | obstruction of the rhinopharynx, Obstruction of the rhinopharynx, rhinopharyngeal obstruction | The sample size was calculated based on Pearson's correlation, adopting a significance level of 5%, test power of 80%, and an initial correlation between obstruction of the rhinopharynx by adenoid and clinical symptoms of 0.4 was assumed, resulting in a minimum sample of 50 patients.Intra-rater reliability (between T1 and T2) was established by Pearson's correlation, being considered high when Once the high intra-rater reliability was accepted, the mean response of the patient of each rater was used for the inter-rater reliability study, through the Intraclass Correlation Coefficient (ICC). It was adopted as a reliable ICC greater than 0.7.Pearson's correlation was used to study the relationship between: (1) Subjective measurement of rhinopharyngeal obstruction by the adenoid, and objective measurement, by Pro ImageJ Software; (2) Obstruction of the rhinopharynx by the adenoid, both subjectively and objectively, and the intensity of the clinical symptoms determined by the OSA-18.To explore the relationship between potential risk factors that could influence correlation between rhinopharyngeal obstruction by the adenoid and the impact on quality of life (OSA-18), Pearson's correlation was used for qualitative risk factors, and Student's | PMC10493505 | |
Results | adenoid hypertrophy, obstruction of the rhinopharynx, inferior turbinate hypertrophy, XXX | ADENOID HYPERTROPHY, ALLERGIC RHINITIS | Eighty patients from the General Otorhinolaryngology outpatient clinic of XXX were screened. Among them, 29 were not included in the analysis (Flowchart representing the selection criteria applied to the study patients.The demographic and clinical characteristics of the included patients are described in Clinical and demographics characteristics.The intra-rater correlation coefficient was calculated based on T1 and T2 scores with Pearson's ratio. The 4 evaluators showed good individual correlation Scatter diagrams representing intra-rater correlation at T1 and T2.Inter-rater reliability was calculated using the Intraclass Correlation Coefficient (ICC) with an ICC result of 0.768 (95% IC 0.725‒0.875).For each evaluator, the average of the results between T1 and T2 was calculated and compared to the findings of the Software Pro Image J, through Pearson's correlation. All showed correlation Scatter diagram comparing the estimated percentage of obstruction of the rhinopharynx by the adenoid, established by the average of the evaluators at T1 and T2, compared to the estimated percentage of obstruction established by the Software Pro Image J (Objective).Of the 51 participants, 22 patients had a low impact on the quality of life assessed by the OSA-18, 15 had a moderate impact and 14 had a high impact. The final OSA-18 score was correlated to the average of the results of adenoid hypertrophy between T1 and T2 of the four evaluators using Pearson's correlation (Correlated to the average of the results of adenoid hypertrophy between T1 and T2 of the four evaluators using Pearson's correlation.Moreovere, when evaluated the degree of obstruction of the rhynopharynx by the OSA-18 categories, no significant difference was observed between the three categories (Distribution of the degree of obstruction of the rhinopharynx, given by the average of the evaluators, with the three categories of quality of life, determined by the OSA-18 questionnaire.Allergic rhinitis, inferior turbinate hypertrophy, age, current nasal treatment, and BMI were associated with OSA-18, with | PMC10493505 |
Discussion | rhinopharyngeal obstruction, rhinorrhea, otitis, adenoid hypertrophy, respiratory complaints, obstruction of the rhinopharynx), obstruction by the adenoid, nasal obstruction, palate, airway infection, adenoid, hypertrophic adenoids, tonsil hypertrophy | HYPERTROPHIC, OTITIS, SLEEP APNEA, ALLERGIC RHINITIS, ADENOID HYPERTROPHY, TONSIL HYPERTROPHY, COMPLICATIONS | Although nasofibroscopy is considered the gold standard exam in the diagnosis of adenoid hypertrophy, most studies use classifications that are not currently used in clinical practice.In the study, all four evaluators demonstrated a good correlation between T1 and T2 times (R > 0.7). However, although it is a good correlation, it is not excellent (R > 0.9). This could be improved if the evaluators were instructed to use anatomical parameters, for example, to determine the degree of obstruction by the adenoid tissue. We purposely refrained from providing such instructions in order to maintain the dynamics of clinical practice in the office.Another observation pertains to the comparison between the Pro Image J software and the evaluators (objective vs. subjective). All showed a good correlation (R > 0.7), but this correlation varied between 0.93 and 0.7. Due to the limited number of examiners (only four), it was not possible to determine the reasons for this variance.Once the method's reliability was confirmed, we assessed the correlation between the percentage of obstruction and the severity of clinical symptoms using the OSA-18 questionnaire. No correlation was observed, meaning that a more obstructed adenoid did not necessarily result in a more compromised quality of life. Evaluating the impact of the adenoid on these symptoms in isolation is challenging due to the multifactorial nature of sleep apnea, where several other factors may be involved. To ensure sample homogeneity and enhance the internal validity of the study, we applied strict inclusion criteria, excluding significant factors that could interfere with the impact of adenoids, such as tonsil hypertrophy and rhinorrhea/upper airway infection. Furthermore, we performed a linear model analysis of covariance to account for additional factors that might have influenced the results, including BMI, allergic rhinitis, current nasal treatment, and hypertrophic turbinates. Among these factors, only BMI exhibited a significant difference, indicating that higher BMI scores were associated with higher OSA-18 scores.On the other hand, the strict inclusion criteria resulted in the exclusion of 14 patients who experienced rhinorrhea during the examination. Additionally, 12 patients were unable to tolerate the procedure, as it is not our service's protocol to use any patient restraint methods. For future studies, we intend to conduct pre-tests to evaluate patients' tolerance to nasal manipulation, ensuring their inclusion.One of the main limitations of this study is the lack of objective examination to compare with the results evaluated by the examiners. However, the Pro Image J software, despite not being an objective method (it depends on a researcher to delimit the structures), is the best comparison parameter we had available since it is based on the gold standard method (nasofibroscopy) and avoids the limitations of imaging exams. Radiography and computed tomography of the cavum can show great variability in the assessment of adenoid size according to the incidence of the examination or whether the palate muscles are contracted at the time of examination, in addition to exposure to radiation and cost.This study has the potential to impact the clinical practice of otorhinolaryngologists and optimize diagnosis, interpretation and, mainly, procedures. The presented results confirm that the classification of adenoid hypertrophy through a percentage estimate is a reliable, reproducible and consistent method, supporting its use in clinical practice. However, the absence of correlation between the intensity of rhinopharyngeal obstruction by the adenoid and the clinical symptoms evaluated by the OSA-18 call an alert for the way of interpreting this exam. The nasofibroscopic evaluation of adenoid hypertrophy is a complementary exam and, therefore, must complement a reasoning based on the clinical history and the physical exam in order to arrive at an adequate conduct. According to the results of this study, it is not possible, for example, to conclude that adenoid hypertrophy above a certain percentage, regardless of clinical symptoms, is indicative of the need for more invasive therapies, such as adenoidectomy. Thus, adenoidectomy should be indicated based on persistent respiratory symptoms refractory to clinical treatment, corroborated by the nasofibroscopic finding of adenoid hypertrophy.Cassano et al. evaluated 7621 children with adenoid hypertrophy and observed that among those with Grade IV (100% obstruction of the rhinopharynx), there was a strong correlation with clinical repercussions such as sleep apnea and recurrent otitis. Among in 881 patients (54.7%) belonging to the Grade III group (>75% obstruction of the rhinopharynx), medical treatment was effective in controlling nasal obstruction and related pathologies and complications; and therefore, did not require surgical intervention. This finding supports the observations of our study and the approach of our team, which recommends more invasive therapeutic alternatives for patients with more severe clinical involvement, rather than relying solely on the presence of hypertrophic adenoids on examination. It is important to note that Cassano et al.'s study included patients with other conditions that can impact sleep quality, such as tonsil hypertrophy and nasal secretions.Finally, we reinforce the importance of anamnesis and physical examination in the evaluation of respiratory complaints in children and we understand that nasofibroscopy is a reliable complementary exam, but that by itself it is not capable of determining the intensity of symptoms or prognosis. | PMC10493505 |
Conclusion | rhinopharyngeal obstruction | ADENOID HYPERTROPHY | The findings of this study allow us to conclude that the evaluation of the percentage of rhinopharyngeal obstruction by the adenoid, through nasofibroscopy, is a reliable, consistent, and reproducible method for the evaluation and classification of adenoid hypertrophy. However, no correlation was observed between the degree of rhinopharyngeal obstruction by the adenoid and the intensity of clinical symptoms. | PMC10493505 |
Conflicts of interest | The authors declare no conflicts of interest. | PMC10493505 | ||
References | PMC10493505 | |||
Supplementary data | The following are Supplementary data to this article:Supplementary material related to this article can be found, in the online version, at doi: | PMC10493505 | ||
Background | critically ill | CRITICALLY ILL | Intention-to-treat analyses of POINCARE-2 trial led to inconclusive results regarding the effect of a conservative fluid balance strategy on mortality in critically ill patients. The present as-treated analysis aimed to assess the effectiveness of actual exposure to POINCARE-2 strategy on 60-day mortality in critically ill patients. | PMC10626740 |
Methods | REGRESSION | POINCARE‑2 was a stepped wedge randomized controlled trial. Eligible patients were ≥ 18 years old, under mechanical ventilation and had an expected length of stay in ICU > 24 h. POINCARE-2 strategy consisted of daily weighing over 14 days, and subsequent restriction of fluid intake, administration of diuretics, and/or ultrafiltration. We computed a score of exposure to the strategy based on deviations from the strategy algorithm. We considered patients with a score ≥ 75 as exposed to the strategy. We used logistic regression adjusted for confounders (ALR) or for an instrumental variable (IVLR). We handled missing data using multiple imputations. | PMC10626740 | |
Results | A total of 1361 patients were included. Overall, 24.8% of patients in the control group and 69.4% of patients in the strategy group had a score of exposure ≥ 75. Exposure to the POINCARE-2 strategy was not associated with 60-day all-cause mortality (ALR: OR 1.2, 95% CI 0.85–1.55; IVLR: OR 1.0, 95% CI 0.76–1.33). | PMC10626740 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13054-023-04701-5. | PMC10626740 | ||
Keywords | PMC10626740 | |||
Background | cancers, critically ill, ARDS, septic shock | CANCERS, CRITICALLY ILL, HEMODYNAMIC INSTABILITY, SEPTIC SHOCK, ARDS, ACUTE RESPIRATORY DISTRESS SYNDROME | Among critically ill patients in intensive care units (ICU), early and aggressive fluid resuscitation is indicated to tackle hemodynamic instability [Higher mortality was reported in critically ill patients with a positive fluid balance in various clinical settings, such as septic shock, acute respiratory distress syndrome (ARDS), cancers, and post-operative settings [POINCARE-2 stepped-wedge randomized controlled trial aimed to assess the effectiveness of a conservative strategy on 60-day all-cause mortality in a broad population of critically ill patients [The present as-treated analysis aimed to assess the effectiveness of actual exposure to POINCARE-2 strategy on 60-day mortality in critically ill patients. | PMC10626740 |
Methods | PMC10626740 | |||
Design and setting | CRITICALLY ILL | The POids INtensive CARE 2 (POINCARE-2) trial was a stepped wedge cluster randomized controlled trial implemented in 12 French ICUs [Critically ill patients who were admitted to one of the 12 recruiting ICUs were allocated either to the control group (and received standard of care during the control period) or to the strategy group (and received the POINCARE-2 strategy during the intervention period). They were followed up for 1 year.Additional file | PMC10626740 | |
Population and sampling | trauma | Eligible patients were ≥ 18 years old, under mechanical ventilation (through endotracheal intubation), admitted to one of the 12 participating ICUs between 48 and 72 h prior to inclusion, and with an expected length of stay after inclusion of > 24 h.Main exclusion criteria were clinical condition or unavailability of bedside scale impeding weight assessment, multiple trauma, history of ICU stay > 24 h immediately preceding the index ICU admission, pregnancy, expected withdrawal of life-sustaining therapy < 7 days after admission, patient refusal to personal data collection (and/or use), history of ICU stay in one of the 12 recruiting ICUs during the study period, and patients under guardianship. | PMC10626740 | |
Assessment of exposure to the strategy | To assess exposure of patients to the strategy under scrutiny, we developed a dedicated score. This score was based on the amount of deviation from the algorithm on which the strategy relied (Additional file Additional file | PMC10626740 | ||
Outcomes | myocardial infarction, patent mesenteric ischemia, RIFLE, hypotension, renal damage, hypokalemia, VFDs | HYPERNATREMIA, EVENT, MYOCARDIAL INFARCTION, EVENTS | The main outcome was vital status at Day 60 (alive vs deceased). Secondary outcomes included mechanical ventilator-free days (MVFDs) and vasopressor-free days (VFDs), defined as the cumulative number of days alive with no mechanical ventilation (or no prescription of vasopressor, respectively) between Day0 and Day28; renal replacement therapy-free days (RRTFDs), defined as the cumulative number of days alive with no renal replacement therapy between Day0 and Day60; occurrence of at least one unexpected harmful event (arterial hypotension, i.e. arterial systolic pressure < 90 mmHg, between Day2 and Day14; hypernatremia, i.e. serum sodium level > 155 mmol/L, between Day2 and Day14; hypokalemia, i.e. serum potassium level < 2.8 mmol/L, between Day2 and Day14; or acute ischemic events, i.e. myocardial infarction and/or patent mesenteric ischemia, between Day3 and discharge); and renal damage, defined by a worsening in the RIFLE criteria between Day3 and Day14, as compared to the higher RIFLE criteria during the first two days of hospitalization [ | PMC10626740 |
Statistical analysis | PMC10626740 | |||
Descriptive analyses | EVENTS, SECONDARY | We first described the distribution of the score of exposure to the strategy in our sample, overall and by group. We then described patients’ characteristics at admission, overall, and stratified on (1) the quartile of score of exposure to the strategy, and (2) both the ICU and the group, using mean (standard deviation [SD]) or median (interquartile range [IQR]) for continuous variables, and counts (percentages) for categorical variables.Then, we described survival time, vital status at Day 60, and total number (%) of events for each secondary outcome, overall and stratified on (1) the quartile of the score of exposure to the strategy, and (2) both the ICU and the group. | PMC10626740 |
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