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Declarations | PMC10303338 |
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Ethics approval and consent to participate | Ethics approval for this study was provided by the St. Michael’s Hospital Research Ethics Board (Toronto, ON) and all participants provided informed consent. | PMC10303338 |
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Consent for publication | Not applicable. | PMC10303338 |
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Competing interests | HT | CDM has received advisory board honoraria/consulting fees from Amgen, AstraZeneca, BioAge, Boehringer Ingelheim, and PhaseBio, and honoraria for DSMB membership from Beth Israel Deaconess Medical Center, Cerus and Takeda. HT reports personal fees from the Canadian Medical and Surgical Knowledge Translation Research Group. KAC has received research grants to his institution from Astra Zeneca and Boehringer Ingelheim, received support for travel to scientific meeting from Boehringer Ingelheim and Astra Zeneca and Merck and honoraria for speaking engagements and ad hoc participation in advisory boards from Astra Zeneca, Boehringer Ingelheim, Merck and Janssen. SV reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, and Sanofi. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. | PMC10303338 |
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References | PMC10303338 |
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Background | HDN | The mosquito landing rate measured by human landing catches (HLC) is the conventional endpoint used to evaluate the impact of vector control interventions on human-vector exposure. Non-exposure based alternatives to the HLC are desirable to minimize the risk of accidental mosquito bites. One such alternative is the human-baited double net trap (HDN), but the estimated personal protection of interventions using the HDN has not been compared to the efficacy estimated using HLC. This semi-field study in Sai Yok District, Kanchanaburi Province, Thailand, evaluates the performance of the HLC and the HDN for estimating the effect on | PMC10318828 |
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Methods | HDN | Two experiments to evaluate the protective efficacy of (1) a VPSR and (2) ITC, were performed. A block randomized cross-over design over 32 nights was carried out with both the HLC or HDN. Eight replicates per combination of collection method and intervention or control arm were conducted. For each replicate, 100 | PMC10318828 |
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Results | HDN | For the VPSR, the protective efficacy was similar for the two methods: 99.3%, 95% CI (99.5–99.0) when measured by HLC, and 100% (100, Inf) when measured by HDN where no mosquitoes were caught (interaction test p = 0.99). For the ITC, the protective efficacy was 70% (60–77%) measured by HLC but there was no evidence of protection when measured by HDN [4% increase (15–27%)] (interaction test p < 0.001). | PMC10318828 |
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Conclusions | bite, HDN | INTERACTIONS | Interactions between mosquitoes, bite prevention tools and the sampling method may impact the estimated intervention protective efficacy. Consequently, the sampling method must be considered when evaluating these interventions. The HDN is a valid alternative trapping method (relative to the HLC) for evaluating the impact of bite prevention methods that affect mosquito behaviour at a distance (e.g. VPSR), but not for interventions that operate through tarsal contact (e.g., ITC). | PMC10318828 |
Keywords | PMC10318828 |
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Background | malaria, HLCs, HDN | MALARIA, DISEASE, DISEASES | The human-mosquito contact rate is an essential parameter for determining disease risk in a given area and reducing human-mosquito exposure is essential for reducing the risk of diseases such as malaria [Human landing catch set-up in the temporary structureIn response to these challenges, a variety of possible alternative, ‘exposure-free’, collection methods been developed and evaluated against HLCs to examine mosquito landing rate equivalencies under semi-field and field conditions [The HDN is a collection method that consists of a person sitting underneath two untreated nets, thereby preventing any human-mosquito contact (Fig. Human-baited double net trap structureThere are two promising tools designed to protect the user from mosquito bites. First, spatial repellents (SRs), in particular, volatile pyrethroid spatial repellents (VPSRs) work by preventing human-vector contact primarily through non-contact irritancy (also referred to as non-contact excitorepellency or spatial repellency), landing inhibition, feeding inhibition, and sublethal incapacitation [Therefore, this study hypothesizes that the utility of the HDN may differ when the collector uses interventions that act primarily through contact irritancy versus spatial repellency in the vapour phase. In a semi-field system (SFS) in Sai Yok District, Kanchanaburi Province, Thailand, this study aims to assess whether the HDN can be used as a replacement collection method for the gold standard HLC in an outdoor setting to measure the protective efficacy against | PMC10318828 |
Methods | PMC10318828 |
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Study site | This evaluation was conducted in Kasetsart University’s SFS in Pu Teuy Village, Sai Yok District, Kanchanaburi Province, Thailand. Experimental chambers (9 × 4 × 3 m) of the SFS structure were positioned at least 20 m apart to minimize any spillover effect where the chamber containing the intervention impacts the behaviour of mosquitoes in the chamber containing the control. Temporary open structures (2 × 2 × 2 m), designed to mimic typical temporary shelters used by people in forested settings across southeast Asia, were constructed inside each experimental chamber (Fig. Bamboo temporary, open structures at Kasetsart University (KU) | PMC10318828 |
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Mosquito bite prevention interventions | HDN | Two interventions were included in this evaluation. The first is a transfluthrin-based VPSR that was hung from the open structure’s eaves. For this evaluation, two units of this product were hung from two opposite sides of the open structure, per manufacturer’s instructions. Note, due to limited space in the chambers, the HDN structure was not placed over the open structure and was tested without the presence of the temporary shelter. Thus, the VPSR devices were hung from the HDN’s opposing poles supporting the outer net. As the product manufacturer recommends replacing the product once every 30 days, the product was replaced after two experimental blocks (of eight days) to minimize possible waning efficacy. The second intervention was etofenprox treated ranger uniforms (Eto R). The ranger uniforms were hand-treated with etofenprox at Kasetsart University according to the manufacturer’s instructions: the bottle was held 15–20 cm away from garment to allow spraying on fabric for a treatment level of 2.0 g/m | PMC10318828 |
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Experimental design | The evaluation was conducted over 32 nights using a block randomized cross-over design with 16 nights of collection for each of the two interventions (Fig. Experimental design of the trap evaluation. | PMC10318828 |
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Mosquitoes and mosquito collection | HDN, a mouth | KU’s HLCs were conducted for 45 min during each hour of the six-hour replicate, allowing for a 15-min break per collection hour. To conduct the HLCs, a collector sat on a chair in the centre of the temporary structure and collected mosquitoes with a mouth aspirator as mosquitoes landed on the lower leg between the knee and the ankle, before the mosquitoes were able to bite (Fig. The HDN consists of a person sitting underneath two untreated, white nets: the first net is sealed against the ground and protects the human from direct mosquito exposure, and the second, larger net is placed directly over the inner net (Fig. | PMC10318828 |
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Data analysis | The OR of the released | PMC10318828 |
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Discussion | HDN, bite | This study evaluated the performance of two different mosquito trapping methods, the HLC and the HDN, for estimating the effect on mosquito landing rates of two intervention types characterized by contrasting modes of action. The study results indicated that the primary mode of action of each intervention had a substantial impact on how the HDN performed in comparison to the HLC to evaluate the protective efficacies of the VPSR and the etofenprox-treated clothing. The VPSR works primarily through non-contact irritancy; mosquitoes move away from the VPSR or become incapacitated at a distance from the VPSR, without coming into physical contact with the treated substrate. In contrast, Eto R primarily works through contact irritancy, requiring tarsal contact with the treated surface for mosquitoes to be affected by the active ingredient.When evaluating the VPSR intervention, the direction of the estimated effects of the intervention on mosquito landing is similar when measured by HLC and by HDN. However, the HDN intervention arm collected zero mosquitoes, which meant that a precise effect could not be estimated. This observation suggests that a larger number of replicates than the eight included in this study would be necessary when using the HDN to estimate the impact of a VPSR. However, given the magnitude of the observed efficacy, it can be concluded that the HDN remains a suitable collection method for evaluating the protective efficacy of VPSRs.When evaluating the Eto R intervention, there was no evidence of an effect of Eto R on mosquito landing obtained via HDN. In contrast, when using the HLC, the estimated effect of Eto R demonstrated a strong reduction in mosquito landing. The HDN is not a suitable collection method for ITCs likely because this intervention functions primarily through contact irritancy, which requires mosquitoes to physically land on the treated material worn by the collector to then be repelled by the active ingredient [To date, mosquito landing is the accepted endpoint to evaluate the impact of bite prevention tools on human-vector exposure [While there is the opportunity to conduct HLCs in a safe manner using disease-free mosquito populations in the SFS, there remains a pressing need to validate alternative methods to HLCs for evaluating ITCs and VPSRs, particularly outside the SFS, as many countries do not permit HLCs in the field. A limitation of this study is that this evaluation was conducted with a single species (Finally, this study could be further strengthened by conducting evaluations throughout the life of the VPSR intervention so that more reliable estimates of comparative efficacy can be made as the product wanes in efficacy and, presumably, more mosquitoes are captured. As VPSR efficacy wanes and more mosquitoes are attracted to the host, it is possible the estimated protective efficacy via HDN indicates less protection against mosquito landing than the estimated protective efficacy via HLC. This is because the HDN’s inner netting enclosure might further concentrate the VPSR’S active ingredient within the netting enclosure around the collector, interfering with the long-range activity of this intervention, thus further decreasing the number of attracted mosquitoes compared to the HLC [ | PMC10318828 |
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Conclusion | bite, irritancy | This study indicates that HDNs may be a suitable replacement for HLC for evaluating VPSRs in the field. However, for evaluating ITCs and other similarly acting interventions that function through short range modes of action and tarsal contact (such as, topical repellents), there are no known, validated alternative trapping methods to the HLCs. Therefore, other field collection methods should be evaluated to identify alternatives that would enable field evaluations of mosquito bite prevention products functioning through contact irritancy on mosquito landing in areas where HLCs are not possible. | PMC10318828 |
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Acknowledgements | The authors thank the data collectors for their diligent work collecting mosquitoes throughout the study. | PMC10318828 |
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Author contributions | Project conceptualization: SJM, NFL, TC; Project design: SJM, NFL, EV, AR, TC, DM; Project implementation and data collection: TC, MS; Data entry: MS; Data analysis: EV, AR, SJM; Drafting manuscript: EV; Revising and substantially contributing to manuscript: EV, AR, SJM, MS, TC, NFL, DM, AT. | PMC10318828 |
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Funding | This study was funded by the Australia Department of Foreign Affairs and Trade (DFAT) through the Innovative Vector Control Consortium (IVCC), Liverpool, United Kingdom (Grant number A134328). The funding body had no role in the study design, collection, data analysis, data interpretation, or drafting of manuscript. | PMC10318828 |
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Availability of data and materials | Data supporting the analysis, outcomes, and conclusions of this article are available upon request to the corresponding author. | PMC10318828 |
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Declarations | PMC10318828 |
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Ethics approval and consent to participate | Ethics approval for the study was approved by the Research Ethics Review Committee for Research Involving Human Research Participants, Kasetsart University (No. CAO63/035) and field research station was provided by the Royal Thai Armed Forces Development Command, Ministry of Defense and the Kasetsart University Research and Development Institute, Thailand [No. FF (KU) 14.64]. | PMC10318828 |
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Consent for publication | Not applicable. | PMC10318828 |
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Competing interests | The authors declare they have no competing interests. | PMC10318828 |
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References | PMC10318828 |
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2. Materials and Methods | PMC10255291 |
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2.1. Participants | stroke, mental disorder, cardiac disease, diabetes | CHRONIC RENAL FAILURE, JOINT DISORDER, HYPERLIPIDEMIA, GYNECOLOGICAL DISEASE, STROKE, CARDIAC DISEASE, HYPERTENSION, DIABETES | We recruited middle-aged and elderly community-dwelling adults from Japan. Ninety-eight participants were recruited through advertisements published in the local press and posters at community health and recreation centers. Thirty-two individuals who were performing habitual exercise; were taking anti-hyperlipidemic, anti-hypertensive, or anti-hyperglycemic medication; or had a history of stroke, diabetes, hypertension, hyperlipidemia, cardiac disease, chronic renal failure, gynecological disease, joint disorder, or mental disorder were excluded from this study. Sixty-six healthy middle-aged and older sedentary participants volunteered to participate in this study. All the participants voluntarily provided written informed consent before participating in the study. This study was approved by the Ethics Committee of Ritsumeikan University and conducted in accordance with the Declaration of Helsinki. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; UMIN000045605). | PMC10255291 |
2.2. Study Design | After informed consent for participation in the study was obtained, allocation was performed using computer-generated random numbers for each sex. In this study, using a randomized controlled intervention trial with a double-blind study design, participants were randomly divided into four groups: the sedentary-control and placebo intake (Sed and PL) group, the sedentary-control and | PMC10255291 |
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2.3. Resistance Training Intervention | Participants performed resistance training sessions using elastic bands (THERABAND, The Hygenic Corporation, Akron, OH, USA) in each participant’s home in the evening (7:00–8:00 p.m.); sessions took place 3 days per week on non-consecutive days for 12 weeks. Participants were supervised by experienced trainers in all training sessions with a remote control using Zoom (Zoom Video Communications, San Jose, CA, USA) to ensure proper intensity, exercise technique, rest intervals, and progression during each exercise session. Each session lasted 60 min and constructed of 5-min warm-ups, 50-min resistance elastic band exercises, and 5-min cool-downs. The resistance exercise protocol using an elastic band was designed for 10 exercises for the trunk and limb muscle groups, including the arms, shoulder, abdomen, back, and legs, according to the guidelines of the American College of Sports Medicine [ | PMC10255291 |
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2.5. Outcome Measures | PMC10255291 |
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2.5.1. Body Composition | Body weight and height were measured to the nearest 0.1 cm and 0.1 kg, respectively. Body mass index (BMI; kg/m | PMC10255291 |
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2.5.2. Physical Activity, Energy Intake, and Nutritional Status | The physical activity levels were assessed using the short form of the International Physical Activity Questionnaire (IPAQ-SF), as previously described [ | PMC10255291 |
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2.5.3. Muscle Quantity and Quality Indexes | To assess the muscle thicknesses of the anterior and posterior femoris muscles and the echo intensity of the rectus femoris muscle, we used a B-mode ultrasound device with 3.4–8.0 MHz linear-array probe (Vscan dual probe, GE Healthcare, Chicago, IL, USA). Ultrasound images consistently set the following parameters: frequency 8.0 MHz; gain 60 dB; depth 6–10 cm. All participants were scanned perpendicularly on the anterior and posterior thigh surfaces, halfway between the lateral condyle of the femur and the greater trochanter, in the anatomical standing position, with their arms and legs extended and relaxed. Three images of the anterior and posterior femoris muscles were obtained for each measurement site and stored on a personal computer. Images obtained from an ultrasound device regarding muscle thickness and echo intensity were analyzed using ImageJ (version 1.52a; National Institutes of Health, Bethesda, MD, USA), as previously reported [As indices of muscle function, 6-m normal walking speed, single-leg stand test, five times sit-to-stand test, and handgrip strength were assessed before and after each intervention, as previously reported [ | PMC10255291 |
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2.5.4. Cardiometabolic Parameters | DBP) blood pressures | All participants sat quietly for 30 min, and brachial systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) were measured in duplicate in the sitting position at rest (HEM-7120, OMRON Healthcare, Kyoto, Japan).The sample in serum was immediately collected via centrifuge (1500× | PMC10255291 |
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2.6. Statistical Analysis | All values were expressed as mean ± standard deviation (SD). Statistical analysis of each parameter was carried out using two-way analysis of variance (ANOVA) for repeated measures (time × group). One-way ANOVA was used to compare the differences in changes from baseline to 12 weeks among the four groups. A post hoc comparison test was used to correct for multiple comparisons (two-tailed Fisher’s post hoc test) when the analyses revealed significant differences. The relationships between changes in serum C1q levels and echo intensity in the rectus femoris from baseline to 12-week interventions were determined via Pearson’s correlation coefficients. Statistical significance was defined as (The required sample size for using repeated-measures ANOVA to examine comparisons between the four groups before and after the 12-week intervention with α set at 0.05 and power at 0.80 was 48 participants (12 in each group), as calculated using G*Power (ver. 3.1.9.6). | PMC10255291 |
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3. Results | PMC10255291 |
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3.1. Participant Characteristics and Nutritional Status | The participant flowchart for this study is shown in No significant differences in age, height, body weight, BMI, percent body fat, daily physical activity, or daily total energy intake were observed among the four groups before and after the intervention (Additionally, no significant differences in the main nutritional statuses were observed among the four groups before and after the intervention ( | PMC10255291 |
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3.2. Muscle Quantity and Quality Indices | No significant differences were observed in anterior and posterior femoris muscle thickness, echo intensity for the rectus femoris, normal walking speed, single-leg stance test, five times sit-to-stand test, and grip strength before and after the interventions among the four groups (Furthermore, changes in the posterior femoris muscle thickness from baseline to 12 weeks in the Sed and Dio, and RT and Dio groups were significantly higher than those in the Sed and PL group; however, these changes did not differ between the Sed and PL, and RT and PL groups (Changes in the serum C1q levels from baseline to 12 weeks did not differ among the Sed and PL, Sed and Dio, and RT and PL groups, whereas changes in the serum C1q levels in the RT and Dio group were significantly lower than those in the Sed and PL, and Sed and Dio groups ( | PMC10255291 |
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3.3. Cardiometabolic Parameters | TG | No significant differences in SBP, DBP, HR, Total-Cho, HDL, TG, or HbA1c before and after the interventions were observed among the four groups ( | PMC10255291 |
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4. Discussion | fibrosis | FIBROSIS | Our main findings demonstrated that in healthy middle-aged and older adults, 12-week In the present study, 12-week Aging accelerates muscle fibrosis, which results in decreased muscle quality [This study revealed that, among the cardiometabolic risk factors, HbA1c decreased in the sedentary and low-intensity resistance-trained groups with In this study, 12-week resistance training with and without In middle-aged and older adults, performing high-intensity exercise is difficult and places a heavy burden not only on the joints and muscles, but also on the circulatory system. In contrast, low-intensity exercise is easier to continue; however, its effects may be more limited. In this study, This study had five limitations. Firstly, we believe that the effects of resistance training with | PMC10255291 |
5. Conclusions | In this study, we revealed that 12-week | PMC10255291 |
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Author Contributions | Conceptualization, M.I.; Data curation, K.I. (Keiko Iemitsu), S.F., M.U., K.I. (Kenichiro Inoue) and M.I.; Formal analysis, K.I. (Keiko Iemitsu), Y.S. and M.I.; Funding acquisition, M.I.; Investigation, K.I. (Keiko Iemitsu), S.F., M.U., K.I. (Kenichiro Inoue) and M.I.; Methodology, Y.S. and M.I.; Project administration, M.I.; Supervision, M.I.; Visualization, K.I. (Keiko Iemitsu) and M.I.; Writing—original draft, K.I. (Keiko Iemitsu), S.F. and M.I.; Writing—review and editing, K.I. (Keiko Iemitsu), S.F., M.U., K.I. (Kenichiro Inoue), Y.S. and M.I. All authors have read and agreed to the published version of the manuscript. | PMC10255291 |
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Institutional Review Board Statement | The present study was performed in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Ritsumeikan University (approval number: BKC-2021-006; approval date: 30 June 2021). | PMC10255291 |
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Informed Consent Statement | Informed consent was obtained from all the subjects involved in the study. | PMC10255291 |
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Data Availability Statement | The data presented in this study are available upon request from the corresponding author. | PMC10255291 |
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Conflicts of Interest | The authors declare no conflict of interest. | PMC10255291 |
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References | anterior femoris muscle thickness | Participant flow chart.Change in anterior femoris muscle thickness ((Comparison of subject characteristics before and after interventions.Data are means and SD. Sed+PL: sedentary-control and placebo intake group, Sed+Dio: sedentary-control and Nutritional status before and after interventions.Data are means and SD. Sed+PL: sedentary-control and placebo intake group, Sed+Dio: sedentary-control and Comparison of muscle quantity and quality before and after interventions.Data are means and SD. Sed+PL: sedentary-control and placebo intake group, Sed+Dio: sedentary-control and Comparison of cardiometabolic parameters before and after interventions.Data are means and SD. Sed+PL: sedentary-control and placebo intake group, Sed+Dio: sedentary-control and | PMC10255291 |
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Objective | EPITHELIAL OVARIAN CANCER | Academic Editor: Dawei Cui The aim of this study was to explore prognostic factors, develop and internally validate a prognostic nomogram model, and predict the cancer-specific survival (CCS) of epithelial ovarian cancer (EOC) patients with pelvic exenteration (PE) treatment. | PMC10449593 |
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Methods | A total of 454 EOC patients from the Surveillance, Epidemiology, and End Results (SEER) database were collected according to the inclusion criteria and randomly divided into the training ( | PMC10449593 |
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Results | In the training cohort, age, histological type, Federation of Gynecology and Obstetrics (FIGO) stage, number of examined lymph nodes, and number of positive lymph nodes were found to be independent prognostic factors of postoperative CSS. A practical nomogram model of EOC patients with PE treatment was constructed based on these selected risk factors. Time-dependent ROC curves and KM curves showed the superior predictive capability and excellent clinical stratification of the nomogram in both training and validation cohorts. In the internal validation, the C index, calibration plots, and DCA in the training and validation cohorts confirmed that the nomogram presents a high level of prediction accuracy and clinical applicability. | PMC10449593 |
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Conclusion | Our nomogram exhibited satisfactory survival prediction and prognostic discrimination. It is a user-friendly tool with high clinical pragmatism for estimating prognosis and guiding the long-term management of EOC patients with PE treatment. | PMC10449593 |
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1. Introduction | Ovarian cancer, aggressive disease | OVARIAN CANCER, RECURRENCE, EPITHELIAL OVARIAN CANCER, METASTASES | Ovarian cancer (OC) is an aggressive disease characterized by its occult property and high rate of recurrence, making iterative cytoreduction a potentially beneficial approach. Among OC cases, epithelial ovarian cancer (EOC) accounts for approximately 90% of cases and represents the most prevalent histological type [While previous studies have demonstrated that several clinical parameters, such as age, distant metastases, and histological type, are important prognostic factors for EOC patients, however, their impact on the postoperative survival in patients undergoing PE treatment remains inconclusive [Nomogram is a user-friendly visualization tool of models to predict and quantify patient survival [ | PMC10449593 |
2. Patients and Method | PMC10449593 |
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2.1. Study Cohort Selection | Patient information was obtained using SEER | PMC10449593 |
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2.2. Variable Collection and Reclassification | tumor | TUMOR | The diagnosis and treatment process of EOC patients in the SEER database in the past period were reviewed to identify prognostic factors for CSS. We obtained the following variables of selected patients from the SEER database directly: age at diagnosis, race, year of diagnosis, marital status, histological type, tumor grade, tumor laterality, FIGO stage, clinical AJCC | PMC10449593 |
2.3. Statistical Analysis | All statistical analysis was performed using | PMC10449593 |
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3. Results | PMC10449593 |
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3.1. Demographic and Clinical Characteristics | The detailed process of patient selection is shown in | PMC10449593 |
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3.2. Optimal Cutoff of Age, Lymph Nodes, and Tumor Size | Multicollinearity bias between the number of positive lymph nodes and lymph nodes examined was first evaluated by calculating the variance inflation factor (VIF). As is shown in Supplementary | PMC10449593 |
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3.3. Independent Predictors Analysis for CSS of EOC Patients with PE Treatment | REGRESSION | The univariate and multivariate stepwise Cox regression models were performed in the training cohort ( | PMC10449593 |
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3.4. Development of a Nomogram of CSS in Training Cohort | The nomogram was constructed by incorporating the above-identified independent prognostic variables to predict the 3-, and 5-year CSS in EOC patients with PE treatment ( | PMC10449593 |
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3.5. Validation of Nomogram in Training Cohort and Validation Cohort | The discrimination of the nomogram was assessed by time-dependent ROC analysis in both the training cohort and validation cohort (Figures The discrimination of this nomogram was further assessed by the bootstrap validation with 1000 resamplings. The bootstrap-corrected Cindex of the nomogram was 0.72 (95% CI: (0.66, 0.78); 3-year-CSS) and 0.75 (95% CI: (0.70, 0.81); 5-year-CSS) in training cohort and 0.69 (95% CI: (0.60, 0.78); 3-year-CSS) and 0.71 (95% CI: (0.62, 0.80); 5-year-CSS) in validation cohort. The bootstrapped calibration plots for the prediction of 3-year and 5-year CSS in training cohort and validation cohort are shown in | PMC10449593 |
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4. Discussion | ovarian cancer, gynecologic malignancies, gynecological recurrent cancer | OVARIAN CANCER, ADVANCED CANCER | Clinical treatment of gynecological recurrent cancer and advanced cancer is very limited. Recently, with the deepening of collaboration of multidisciplinary technology, PE combined with organ function reconstruction has been gradually applied clinically by some doctors in gynecologic malignancies [It could be summarized that the majority of overall cases in this study are advanced-stage serous OC patients with treatment of PPE and chemotherapy. It is consistent with some reports that PPE was the most common type of PE and chemotherapy was usually recommended to patients after PE treatment regardless of its uncertain effects [Regarding lymph status, LNR and LODDS have been recently proposed as alternative index for assessing lymph node status in ovarian cancer [Subsequently, a prognostic nomogram model was established for EOC patients with PE treatment based on the selected clinical and pathological factors. Nomograms allow wide application in clinical practice by providing a simplified representation of a complicated statistical model utilizing a user-friendly graphical interface. In this constructed nomogram, patients being more than 70 years old, mucinous histologic type, FIGO stage III/IV, ≥9 examined lymph nodes, and 1-12 positive lymph nodes contributed to high scores, which indicate the low survival probability. In accordance with HR results, the FIGO stage and histological type showed the greatest discriminating power when compared with other variables. Based on the results of the ROC curve and Kaplan–Meier curve, it can be concluded that the nomogram exhibited excellent performance of discrimination in both the training and validation cohorts. As such, this new nomogram model can be used to identify high-risk EOC patients after PE treatment. Furthermore, in internal validation, when the nomogram was applied to the training and validation cohorts, the Cindex and calibration curve indicated decent clinical predictive accuracy, reliability, and repeatability. The results of DCA in our study proved that, compared with the FIGO staging, a constructed nomogram was a well-performing model in clinical applicability. Our nomogram is the first nomogram that is specifically applied to OC patients with PE treatment. Meanwhile, compared to reported studies of OC patients, all variables included in our nomograms are objective and not affected by the subjective evaluation of doctors and the individual feelings of patients [ | PMC10449593 |
4.1. Limitations | tumor | TUMOR, COMPLICATIONS | First, the SEER database only provides a collection of patients in the United States, and the nomogram constructed in this study has not been demonstrated to be applicable to other regions. Meanwhile, this nomogram was only validated by dividing the total cases into training group and validation group. Therefore, further external validation of the nomogram in totally different independent clinical cases, especially from different countries, is needed to obtain an unbiased estimation. Second, certain factors that might associate with survival were not incorporated into the study because of insufficient information in the SEER database. For example, many potential tumor biomarkers, including HE4 protein and serum mesothelin, were not included in the analysis. The detailed chemotherapy regimens, information on targeted drugs, complications, and other information with important significance for the prognosis of EOC were also not available in the SEER database. Third, our nomogram was established on retrospective data which has an inevitable inherent bias. Also, this study may have selection bias because only patients with specific clinical information were included. Finally, it should be noted that this study had a relatively small sample size of only 454 patients. This limitation in sample size may account for the moderate predictive power observed in our model. | PMC10449593 |
5. Conclusion | In summary, we found that age, histological type, FIGO stage, number of examined lymph nodes, and number of positive lymph nodes were independent prognostic factors of CSS in EOC patients with PE treatment. We successfully developed a predictive nomogram of 3-year and 5-year CSS which has been demonstrated to present less bias, superior accuracy, and great clinical value. This high-quality nomogram could provide an important reference for individualized therapeutic suggestions and follow-up strategies. | PMC10449593 |
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Acknowledgments | This study was supported by grants from Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (PY2022032), Special Fund project of Laboratory Medicine Research of Jiangsu Medical Association (SYH-3201160-0056), the National Natural Science Foundation of China (No. 82273199), Natural Science Foundation of Jiangsu Province (BK20221417), and Jiangsu Provincial Medical Key Discipline (ZDXK202239). | PMC10449593 |
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Data Availability | The data supporting the findings of this study are available upon request from the corresponding author. | PMC10449593 |
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Ethical Approval | This study was exempted by the Institutional Ethics Committee of the First Affiliated Hospital of Nanjing Medical University since data in the SEER database are anonymous and open access to the public. | PMC10449593 |
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Consent | Written informed patient consent for participation was not needed for SEER database data in accordance with the national legislation and the institutional requirements. | PMC10449593 |
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Disclosure | Xin Fu and Lei Zhang are co-first authors. | PMC10449593 |
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Conflicts of Interest | The authors declare that there are no conflicts of interest. | PMC10449593 |
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Authors' Contributions | Shuna | Ting Wang conceptualized and designed the research, analyzed data, and wrote the manuscript. Xin Fu and Lei Zhang curated data, investigated the study, and developed methodology. Shuna Liu and Ziqi Tao curated data and investigated the study. Fang Wang conceptualized and designed the research, supervised the study, and reviewed and edited the manuscript. Ting Wang, Xin Fu, and Lei Zhang contributed equally to this work. | PMC10449593 |
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Supplementary Materials | tumor | REGRESSION, TUMOR | Supplementary Table 1: Univariate and multivariable Cox regression analyses of CSS (Click here for additional data file.Patient selection flowchart.Optimal cutoff values determination of continuous variables and Kaplan–Meier curves stratified by the values using x-tile software. (a) Ages were split into two groups: ≤70 years old and ≥71 years old; (b) cutoff values of lymph nodes examined were 12 nodes and 25 nodes; (c) cutoff value of lymph nodes positive was 8 nodes; (d) LNR were categorized into three subgroups: (0, 0.03), (0.03, 0.32), and (0.32, 1.00). (e) LODDS were divided into three groups: (−2.25, −1.18), (−1.18, −0.25), and (−0.25, 2.26). (f) Threshold of tumor size was 38 mm.Nomogram to predict 3- and 5-year CSS for EOC patients with PE treatment. The points of each patient could be calculated by adding the assigned points of each characteristic. For example, the red points and dotted line on this graph show the corresponding scores of selected characteristics of each variable. The indicated survival probability of this patient is 71.5% for 3 years and 57.6% for 5 years based on the total point of 232.ROC curves and Kaplan–Meier curves of the nomogram. ROC curves of the constructed nomogram in the training cohort (a) and validation cohort (b) at 3 years (blue line) and 5 years (red line). (c, d) The patients were divided into two groups: ≤ 242 points (low nomoscore group) and >242 points (high nomoscore group). The Kaplan–Meier survival curves of the patients in the training cohort (c) and in the validation cohort (d) were plotted. Calibration plot of constructed nomogram for the prediction of 3-year and 5-year CSS. The bootstrapped calibration plot compared predicted probability (DCA curves of constructed nomogram for the prediction of 3-year and 5-year CSS. The pink line and orange line in DCA curves show the clinical benefit when the clinical strategy was decided by the prediction of the constructed nomogram or FIGO stage in 3-year and 5-year CSS of training cohort (a, b) and validation cohort (c, d), respectively. Demographic and clinical characteristics of EOC patients included in this study.Univariate and stepwise multivariable Cox regression analysis results of CSS in the training cohort ( | PMC10449593 |
Abstract | ALS | Co‐first authors.Organizations within the Pooled Resource Open‐Access ALS Clinical Trials Consortium are listed in the Acknowledgments. | PMC10723227 |
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Objective | death, ALS | AMYOTROPHIC LATERAL SCLEROSIS | Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo‐controlled and open‐label extension phases. On intent‐to‐treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6‐month double‐blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo‐to‐active crossover, we performed a post hoc survival analysis comparing PB and TURSO‐randomized participants from CENTAUR and a propensity score–matched, PB and TURSO‐naïve external control cohort from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) database. | PMC10723227 |
Methods | ALS | Clinical trial control participants from the PRO‐ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO‐randomized CENTAUR participants using prognostically significant covariates in ALS. | PMC10723227 |
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Results | Baseline characteristics including propensity score–matched covariates were generally well balanced between CENTAUR PB and TURSO ( | PMC10723227 |
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Interpretation | ALS | This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo‐to‐active crossover than seen on ITT analysis in CENTAUR. Analyses using well‐matched external controls may provide additional context for evaluating survival effects in future ALS trials. | PMC10723227 |
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Introduction | ALS | The efficacy and safety of an oral, fixed‐dose combination of sodium phenylbutyrate and taurursodiol (PB and TURSO [RELYVRIOOLE phases provide an opportunity for longer‐term assessment of survival outcomes in trials with randomized placebo‐controlled phases of short duration in addition to increasing access to investigational therapies for people living with fatal conditions such as ALS. However, placebo‐to‐active crossover in trials incorporating OLE phases may lead to underestimation of the effect of these therapies on overall survival in ITT analyses.The Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) database is a robust resource of open‐access data relating to clinical outcomes in ALS, | PMC10723227 |
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Methods | PMC10723227 |
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Analysis cohorts | ALS | AMYOTROPHIC LATERAL SCLEROSIS | During the conduct of the CENTAUR trial, eligible participants were in the randomized phase from June 2017 to September 2019 and in the OLE phase from March 2018 to March 2021. CENTAUR trial eligibility criteria allowed for the stable use of riluzole and edaravone before and during the trial. Survival results for the CENTAUR PB and TURSO group in this analysis were obtained from the aforementioned ITT analysis, the methods of which have been previously described.Data from the PRO‐ACT database that were used in the preparation of this article have been volunteered by PRO‐ACT Consortium members. The process for constructing the PRO‐ACT external control group is schematically summarized in Figure Summarized process for constructing the PRO‐ACT external control group. ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; PSM, propensity score matching.To account for potential imbalance in baseline participant characteristics and other variables across trials, | PMC10723227 |
Standard protocol approvals, registrations, and participant consents | The clinical study protocol for CENTAUR was approved by a central institutional review board (the Partners Human Research Committee) for all trial sites, and participants provided written informed consent before entering each trial phase. | PMC10723227 |
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Statistical analysis methods | death | SENSITIVITY | Overall survival analysis was conducted for 1:1 propensity score–matched individuals from the PRO‐ACT external control group and the CENTAUR PB and TURSO group. Overall survival (time to death) was defined as the time from date of randomization to date of death due to any cause. Median overall survival and IQRs were estimated for the two cohorts using the Kaplan–Meier method. The HR between the two groups was estimated from a Cox proportional hazards model. The treatment difference in overall survival between the two groups was declared significant if the two‐sided Sensitivity analyses were performed with different caliper widths for the propensity score matching (0.1, 0.2, and 0.6, in addition to the prespecified caliper width of 0.4), on the full eligible PRO‐ACT analysis set without propensity score matching, and on the full eligible PRO‐ACT analysis set with propensity score inverse probability treatment weighting (IPTW). In addition, change in ALSFRS‐R total score from baseline through 24 weeks was assessed in the propensity score–matched PRO‐ACT external control group with an aim of evaluating the comparability of change in this functional end point to that in the placebo group from the randomized phase of CENTAUR. | PMC10723227 |
Results | SE, ALS | AMYOTROPHIC LATERAL SCLEROSIS, AMYOTROPHIC LATERAL SCLEROSIS | A total of 134 individuals in PRO‐ACT met inclusion criteria for this analysis and had known mortality information (full analysis set; Fig. Baseline characteristics.Data are presented as mean (SD), range unless otherwise noted.ALS, amyotrophic lateral sclerosis; ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; PB and TURSO, sodium phenylbutyrate and taurursodiol; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SD, standard deviation; VC, vital capacity (forced or slow).Denotes covariate used for propensity score matching.At study baseline.This represents the minimum value at baseline. All participants met VC criteria for trial inclusion at screening.Change in ALSFRS‐R total score progression rate from baseline through 24 weeks: CENTAUR trial population versus PRO‐ACT external control group.ALSFRS‐R, Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised; ITT, intent‐to‐treat; PB and TURSO, sodium phenylbutyrate and taurursodiol; PRO‐ACT, Pooled Resource Open‐Access ALS Clinical Trials; SE, standard error.Modified ITT population, which excluded two participants who died soon after randomization.Compared with the observed median (IQR) overall survival of 23.54 (14.56–39.32) months in the CENTAUR PB and TURSO group,Kaplan–Meier analyses: CENTAUR PB and TURSO group and PRO‐ACT external control group. Kaplan–Meier plot for the CENTAUR PB and TURSO group is from the ITT analysis previously conducted at a cutoff date coinciding with the final participant visit in CENTAUR. | PMC10723227 |
Discussion | ALS | To estimate the treatment effect of PB and TURSO on survival in ALS in the absence of the placebo‐to‐active crossover that occurred in the OLE phase of the CENTAUR trial, we compared overall survival in those randomized to PB and TURSO with an external, PB and TURSO‐naïve control group from PRO‐ACT, the largest ALS clinical trials data set. Median overall survival was 10.39 months longer in those originally randomized to PB and TURSO in CENTAUR versus the external control group in this analysis, whereas the ITT analysis of the CENTAUR trial showed that median overall survival for PB and TURSO was 4.8 months longer versus placebo. The results of the current analysis align with a previous analysis using a rank‐preserving structural failure time model (RPSFTM), an advanced statistical method that adjusts overall survival for the effect of treatment crossover in the placebo group within a clinical trial incorporating a crossover design.Though less preferable than a concurrent, randomized control group given the potential for introducing bias, utilization of control data from an external database provides a treatment‐naïve comparator option for active treatment in clinical trials that allow for placebo‐to‐active crossover or completely exclude a concurrent placebo group based on ethical concerns.To minimize bias due to imbalance among nonrandomized cohorts or other trial variables, external controls should be as closely matched to the investigational cohort as possible.Propensity score matching has been proposed by the US Food and Drug Administration as a means of improving the quality of external control dataBecause data from clinical trials are generated in a controlled setting, the use of the PRO‐ACT data set in our analysis provided high‐quality external control data, in contrast to external data obtained from differing sources with varying data quality. Our analysis was also strengthened by the focus on survival, an objective end point that could be consistently and precisely measured in both analysis groups.Our analysis also did not account for potential between‐group differences in the frequency of initiating respiratory support or gastrostomy tube placement, both potentially life‐extending interventions in ALS, as this information is not comprehensively captured in the PRO‐ACT database. Similarly, neurofilament levels are not included in the PRO‐ACT database and could not be used as a covariate for propensity score matching in our analysis. However, the groups were matched based on other baseline covariates that have been previously identified as significant predictors of survival duration in ALS, including time since symptom onset, pre‐baseline ALSFRS‐R, and age and vital capacity at baseline. In addition, the matched cohorts included similar proportions of participants with bulbar‐onset ALS and riluzole use, additional factors that have been shown to predict survival duration.In conclusion, the results of this analysis align with prior analyses using statistical models adjusting for placebo‐to‐active crossover in CENTAUR and suggest a potentially greater survival benefit with PB and TURSO in ALS than seen on ITT analysis. The ongoing global Phase 3 PHOENIX trial ( | PMC10723227 |
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Funding information | ALS | Funding for the CENTAUR trial was provided by Amylyx Pharmaceuticals, Inc., ALS Finding a Cure | PMC10723227 |
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Author Contributions | SP, MQ, AVS, MV, YW, JT, and MC contributed to the drafting and revision of the manuscript for content. All authors provided final approval of the manuscript for submission. SP, AVS, MC, and the PRO‐ACT Consortium played major roles in the acquisition of data. SP, MQ, AVS, MV, YW, JT, and MC analyzed and/or interpreted the data. MQ, MV, and YW conducted all statistical analyses. | PMC10723227 |
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Conflict of Interest | ALS | S. Paganoni reports research grants from the National Institutes of Health, Alector Therapeutics, Biohaven, Cytokinetics, Anelixis Pharmaceuticals, Revalesio Corporation, UCB, Clene, Prilenia, Seelos Therapeutics, Calico, and Denali Therapeutics unrelated to this manuscript; consulting fees from Amylyx Pharmaceuticals, Frequency Therapeutics, SOLA Pharmaceuticals, Stealth BioTherapeutics, Orion, Roche, Janssen, and Arrowhead; honoraria from Medscape; and board membership in the Association of Academic Physiatrists. M. Quintana and M. Vestrucci are employees of Berry Consultants, LLC, report consulting fees from Amylyx Pharmaceuticals for some of the analyses described in the submitted work, and serve as consultants to numerous additional pharmaceutical and device companies. A.V. Sherman reports grants from the National Institutes of Health, US Food and Drug Administration, the ALS Association, and ALS Finding a Cure | PMC10723227 |
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Supporting information |
Table S1
Click here for additional data file. | PMC10723227 |
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Acknowledgments | ALS | AMYOTROPHIC LATERAL SCLEROSIS 1 | The authors wish to thank the individuals who participated in the CENTAUR trial, as well as their caregivers and families; the NEALS site staff and the staff at the Coordination Center at the NCRI, Healey & AMG Center for ALS, Massachusetts General Hospital, and Barrow Neurological Institute; and The ALS Association for providing a grant to the NCRI/Massachusetts General Hospital to support the PRO‐ACT project. Nikhilesh Sanyal, PhD, and Lara Primak, MD, of PRECISIONscientia provided medical writing assistance with the development and revision of the manuscript under the direction of the authors, with financial support from Amylyx and in compliance with international Good Publication Practice guidelines.Data used in the preparation of this article were obtained from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) database. As such, the following organizations within the PRO‐ACT Consortium contributed to the design and implementation of the PRO‐ACT database and/or provided data: ALS Therapy Alliance; Amylyx Pharmaceuticals, Inc.; Cytokinetics, Inc.; Knopp Biosciences; Neuraltus Pharmaceuticals, Inc.; the Neurological Clinical Research Institute at Massachusetts General Hospital; the Northeast Amyotrophic Lateral Sclerosis Consortium; Novartis; Prize4Life; Regeneron Pharmaceuticals, Inc.; Sanofi; Teva Pharmaceutical Industries, Ltd.; and The ALS Association. Of these organizations, only Amylyx participated in the analysis of the data and the writing of the report. | PMC10723227 |
References | PMC10723227 |
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Subject terms | Cognitive Impairment, HAMD, Anxiety, anxiety, cognitive impairment, somatic pain, pain, depressive disorder, MDD, depression, Depression, NRS | CORTEX | This study aims to explore changes in depression and pain for major depressive disorder (MDD) patients with somatic pain after repetitive transcranial magnetic stimulation (rTMS) using the event-related potentials (ERPs) technique. Eighty MDD patients with somatic pain were randomly assigned to drug therapy (DT) and combined therapy (CT) groups. CT group underwent intermittent theta burst stimulation over the left dorsolateral prefrontal cortex (DLPFC) with 800 pulses and 1 Hz over the right DLPFC with 800 pulses, 5 times a week for 3 weeks. All patients were given sertraline at 50–100 mg per day. All subjects were evaluated at baseline and at weeks three and six of therapy using the Hamilton Rating Scale for Depression (HAMD), Hamilton Anxiety Scale (HAMA), and Numerical Rating Scales (NRS), and the latency and amplitude of P300 and mismatch negativity (MMN) were measured. There were no significant differences in all indices between groups at baseline. At 3 weeks, HAMD subscale scores of Cognitive Impairment and NRS scores were significantly lower in the CT group than in the DT group. At 6 weeks, NRS and HAMD total scores in the CT group decreased significantly in the CT group compared with the DT group, especially for anxiety and pain, and the MMN and P300 latencies and P300 amplitude showed greater improvements. Our findings highlight that rTMS in combination with antidepressants is a rapid method of symptom improvement in patients with somatic pain with MDD and is helpful for cognitive impairment and anxiety. | PMC10589316 |
Introduction | cognitive impairment, Pain, pain, depressive disorder, cognitive dysfunction, depressive, MDD, depression | CORTEX | Pain is one of the most common symptoms in patients with major depressive disorder (MDD), being present in 65% of casesCognitive impairment is another common and often persistent symptom of MDD. Patients with pain and cognitive impairment are more challenging to treat and have longer treatment durations. Furthermore, cognitive dysfunction may persist even after the patient's depressive symptoms have significantly resolvedRepetitive transcranial magnetic stimulation (rTMS) is a technique involving noninvasive stimulation of the cerebral cortex. Multiple studies involving rTMS in MDD patients with pain have reported that TMS significantly relieves pain in patients with MDDLately, event-related potentials (ERPs) with a temporal resolution of milliseconds have increasingly been used for cognitive function evaluation. The most frequently reported components of the ERP are P300 and mismatch negativity (MMN). The P300 latency reflects the time spent on cognitive processing of the stimulus and the P300 amplitude is related to the quantity of attentional resources allocated during the task and memory performanceHowever, ERP changes after rTMS treatment in patients with MDD and pain remain unknown. To fill this gap in the literature, the current longitudinal study explored the effects of rTMS-combined antidepressant pharmacotherapy on depression, pain, and cognitive function in MDD patients with pain. Sertraline was chosen for drug therapy for its efficacy and good tolerance.We hypothesized that compared with the drug therapy group (DT), the combination therapy (CT) group (drug therapy combined with rTMS) would show more rapid improvements in depression, pain, and cognitive function. In addition, compared with the DT group, the latency or amplitude of ERP was hypothesized to be significantly enhanced in the CT group. | PMC10589316 |
Results | PMC10589316 |
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Characteristics of participants | HAMD, Anxiety, pain, Depression, NRS | DISEASE | In total, 37 patients in the DT group and 38 in the CT group completed the study with a 92.5% and 95.0% completion rate, respectively. Three cases in the DT group were dropped after 3 weeks for taking other drugs. In the CT group, two cases were lost during the follow-up––one due to work and another who believed that the treatment was ineffective and required cumbersome daily therapy at the hospital. However, the score of the emotion and pain we evaluated is decreasing. The data was only analyzed for the included patients (DT, n = 37; CT, n = 38).At baseline, there were no significant differences in age, gender, the course of disease, Hamilton Rating Scale for Depression (HAMD) score, Hamilton Anxiety Scale (HAMA) score, Numerical Rating Scales (NRS) scores, P300 and MMN latencies of P300, or P300 amplitude between the DT and CT groups (Baseline characteristics of the study population.Results are shown as n (%) for the X | PMC10589316 |
Discussion | cognitive impairment, anxiety, somatic pain, pain, MDD, depression | REMISSION | To our knowledge, this was the first study examining the primary changes in ERPs, improvements and effects of a combination treatment with rTMS and antidepressants on depression, pain and cognitive function in untreated MDD patients with somatic pain. Our findings highlighted that rTMS combined with antidepressants led to rapid symptom improvements in patients suffering from depression and pain.The combined treatment group, which received high-frequency (50 Hz) iTBS stimulation and right 1 Hz low-frequency stimulation, showed greater improvements in pain at 3 weeks than the drug treatment group. Previous studies on pain and depression have shown that rTMS with frequencies greater than 5 Hz can significantly improve depression and pain symptoms in patientsAdditionally, using low-frequency rTMS in the right DLPFC has been shown to increase tolerance to human experimental painOur study also demonstrated that the subscale score of cognitive impairment in the CT group was significantly lower than in the DT group, both at 3 weeks and 6 weeks. MMN and P300 latencies were significantly decreased and P300 amplitude dramatically increased in the CT group compared to the DT group at 6 weeksMore interestingly, the anxiety score and pain relief score showed a significant decrease after 3 weeks. However, there was a significant difference in depression score and ERP evaluation after 6 weeks. These results may indicate that rTMS improves anxiety and pain quickly, but that changes in cognitive function are relatively slow and only have a significant effect at 6 weeks. A multicenter depression study in the United States showed that rTMS can improve depression scores by the second week, and patients' depression scores can significantly improve by the sixth weekAs systematic reviews have reported that active rTMS is significantly more effective than sham rTMS in response and remission rates | PMC10589316 |
Conclusion | MDD, somatic pain, cognitive impairment, anxiety | SECONDARY | Our results highlight that therapy involving rTMS in combination with antidepressants is an effective method for rapid symptom improvement in MDD patients with somatic pain. The combination therapy was helpful for many secondary symptoms such as cognitive impairment, and anxiety. | PMC10589316 |