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['PMC7359576'] | ['32660609'] | ['CR17'] | The primary objective of the study is to evaluate whether the combination of pyrotinib, trastuzumab and AI (Group A) will be superior to trastusumab plus AI (Group B). The primary endpoint is PFS, defined as the time from randomization to the first radiographically documented progression of disease or death from any cause, whichever will occur first. Disease progression will be evaluated according to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [17]. The secondary endpoints are overall survival (OS), objective response rate (ORR), duration of response (DoR), time to response (TTR), clinical benefit response (CBR), quality of life (QoL), safety, and tolerability. The exploratory endpoint is second progression-free survival (PFS2), defined as the time from randomization to second progression or death from any cause. PFS2 will be only recorded in crossover patients. Additional biomarker analyses are planned and regarded as exploratory analyses. Patients will be required to provide additional informed consent for those procedures. This study does not hypothesize about biomarkers or include any adjustment for type I errors. The aim is to highlight biomarkers or combinations of markers that may be predictive for efficacy or AEs. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | [] | To be eligible for inclusion in the trial, patients must provide written informed consent before the commencement of any study-related procedures. All patients must be above 18 years old with an Eastern Cooperative Oncology Group performance status 0–2 and a life expectancy of not less than 12 weeks. Eligible patients should be postmenopausal (fulfilling one or more National Comprehensive Cancer Network guideline criteria) or pre-menopausal with ovarian ablation or suppression. Furthermore, all participants should have pathological confirmed HR+/HER2+ metastatic or inoperable LABC with at least one measurable lesion evaluable according to RECIST 1.1. Also eligible are patients with asymptomatic brain metastases or stable brain metastases after local therapy (provided there is no clinical indication for immediate local re-treatment, as judged by the investigators). Patients should have adequate bone marrow and organ function as defined by the following laboratory values at screening: neutrophil count ≥1.5 × 109/L; platelet count ≥90 × 109/L; hemoglobin ≥90 g/L; total bilirubin ≤1.5 × upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 × ULN (ALT and AST ≤ 5 × ULN for liver metastases); creatinine ≤1.5 × ULN; left ventricular ejection fraction (LVEF) ≥ 50%. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | [] | The exclusion criteria are listed as follows: previous systemic non-hormonal anti-cancer therapy in the metastatic or advanced breast cancer setting; previous treatment with pertuzumab or T-DM1 in neoadjuvant or adjuvant treatment; extensive symptomatic visceral disease, severe organ dysfunction or disease considered by the investigator to be rapidly progressing or life-threatening, with a clinical indication for chemotherapy; the patient received the same AI as advised by the investigator within 7 days before randomization; uncontrolled central nervous system symptoms; disease-free interval from completion of adjuvant/neoadjuvant systemic non-hormonal treatment to recurrence less than 6 months; other malignancies within the last 3 years, except for carcinoma in situ of the cervix or basal cell carcinoma; major surgical procedure or significant traumatic injury within 28 days prior to the study treatment or anticipation of major surgery during the study period; inability to swallow or other factors that affect treatment administration; known hypersensitivity to any of the study drugs; a history of chronic heart failure of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment (with the exception of atrial fibrillation and paroxysmal supraventricular tachycardia); a history of myocardial infarction within 6 months of randomization; a history of LVEF reduction to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy; pregnant or lactating women; QT interval > 470 ms; serious concomitant diseases (including severe hypertension, severe diabetes, active infection, thyroid disease, etc.) that are harmful to the patient’s safety or affect the patient’s completion of the study; the patient is assessed by the investigators to be unable or unwilling to comply with the requirements of the protocol. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | ['MOESM1'] | Eligible patients will be randomized in 2:1 ratio to either Group A or Group B. A stratified randomization will be used to control confounding variables and balance the baseline characteristics between the different treatments. Patients will be stratified by the time since prior ET (< 12 months/≥ 12 months/no prior ET) and location of metastatic lesions (visceral versus non-visceral). Patients randomized to Group A will receive pyrotinib + trastuzumab + AI and patients randomized to Group B will receive trastuzumab + AI. In each group, trastuzumab will be administered every 3 weeks intravenously (8 mg/kg loading doses followed by 6 mg/kg maintenance doses). Pyrotinib will be administered 400 mg orally daily. For ET, all pre- and perimenopausal women will receive ovarian ablation or suppression. The AI is to be determined by investigators before randomization. The available options for AI could be either anastrozole, letrozole, or exemestane (1 mg/2.5 mg/25 mg, once daily, oral). Patients will continue to receive the assigned medication until objective disease progression, symptomatic deterioration, or unacceptable toxicity (at the discretion of the treating physician), death or withdrawal of consent, whichever occurs first. The imaging evaluation will be performed according to the RECIST 1.1. The patients in Group B will be eligible for crossover to Group A in case of disease progression. Patients will be screened at baseline for eligibility. And providing signing informed consent, baseline measurements will be obtained. Survival status will be followed every 12 weeks regardless of treatment discontinuation until death, lost to follow-up, or withdrawal of consent to survival follow-up. Survival information can be obtained via phone, and information will be documented in the relevant case report form. Any post-study cancer treatment will be recorded. All patients will be followed for safety up to 28 days after the last dose of study treatment (pyrotinib/trastuzumab/AIs). For patients who discontinue due to reasons other than progressive disease (PD), death, lost to follow-up or withdrawal of consent to efficacy follow-up, tumor assessments and patient-reported outcomes must continue to be acquired every 6 weeks until PD, death, lost to follow-up, or withdrawal of consent to efficacy follow-up. Group B patients who choose to cross over after first objective progression will have their progression status recorded every 6 weeks to assess time to the second PD. Schedule of enrollment, interventions, and assessments are shown in thesupplementary material. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | [] | The primary objective of this study is to compare the PFS between the two groups. The hypothesis is based on hazard ratio (HR): H0: HR = 1; Ha: HR ≠ 1. In the case of 2:1 allocation, a sample of 180 evaluable patients with 144 events is expected to provide 80% power (significance level 0.05) to detect an improvement in median PFS, from 8.0 months with trastuzumab plus an AI to 13.0 months when adding pyrotinib [PASS 15]. Taking the withdrawal rate as approximately 10%, the sample size will be 198 patients. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | [] | The difference in PFS (primary endpoint) will be estimated using the full analysis set (FAS) in a stratified log-rank test accounting for all stratification factors and a Cox proportional hazards model to explore baseline factors that may affect PFS. Secondary objectives include comparisons of OS, ORR, TTR, DoR, CBR, QoL, and safety. A stratified log-rank test (using the same stratification factors as for the PFS analysis) will be used to compare OS, TTR and DoR between the two groups. Kaplan-Meier curves, median PFS/OS, TTR, and DoR HR with appropriate confidence intervals will be reported. Exploratory analyses will be conducted for PFS2. A 95% CI for ORR/CBR will be provided. The comparison for response rates between the two groups will be assessed using the Cochran-Mantel-Haenszel test with the same stratification factors as for the PFS analyses. Analyses of ORR/CBR will be performed on the FAS population. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | [] | The type, grade and frequency of AEs will be recorded. AEs and abnormal findings in laboratory tests will be listed with the relationship to the study treatments. The AE summary tables for crossover patients will include all AEs that occurred after the start of crossover treatment until the end of the 30-day follow-up period. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7359576'] | ['32660609'] | ['CR11', 'CR12'] | This study aims to verify that the addition of pyrotinib to trastuzumab plus AI may convey survival benefits to HR+/HER2+ MBC or LABC patients. Since there is a scarcity of existing trials on AI with dual HER2 blockade, this study aims to generate evidence that pyrotinib combined with trastusumab and AI could be used as a de-escalating treatment with less toxicity and comparable efficacy for patients. As a substantial number of patients in the ALTERNATIVE [11] and PERTAIN [12] trials received chemotherapy, the effect of AI and anti-HER2 agents is likely to have been masked in these two trials. Subgroup analysis of the PERTAIN trial indicated that patients who refused the induction chemotherapy showed significant survival benefit with an additional anti-HER2 agent, while patients who had chemotherapy did not benefit from dual anti-HER2 blockage. Additionally, chemotherapy may have severe AE outcomes, which have the potential to compromise therapeutic compliance. Therefore, it is important to further evaluate the effect of ET as an alternative to chemotherapy for HER2+ MBC in order to deliver efficacious treatments with a favorable safety profile. The present study was designed to conduct a thorough comparison in low-risk patients without the administration of chemotherapy to validate the efficacy of dual HER2 blockade with endocrine therapy. If the present study complies with this hypothesis, phase III trials would focus on the following issues: 1) whether AI + trastuzumab + pyrotinib is superior to AI + trastuzumab + pertuzumab; 2) high-risk patients could be included and treated with chemotherapy plus dual-HER2 blockade as induction therapy. If the participants respond well, further studies would evaluate whether AI plus trastuzumab and pyrotinib would be effective as maintenance treatment. The reason for excluding patients with previous exposure to pertuzumab and T-DM1 is that patients pre-treated by pertuzumab and T-DM1 experienced relapse, which indicated that the cancer was likely to have had an aggressive biological behavior and more intensive treatment may be needed. Therefore, this subgroup of patients may not be suitable for this de-escalating strategy with only ET and anti-HER2 therapy. Furthermore, since T-DM1 is not available in China and pertuzumab was only obtainable last year and was covered by insurance for the neoadjuvant and adjuvant setting only, it could be speculated that in the accrual period of the present project, patients who were previously exposed to pertuzumab and T-DM1 may only account for a very small proportion of patients with HER2+ MBC. Including this patient subgroup may potentially increase the heterogeneity of participants and undermine the strength of the final conclusion. Therefore, the study design excluded patients that were previously treated with pertuzumab or T-DM1 and defined a low-risk MBC subgroup that may benefit from AI and anti-HER2 therapy with the omission of chemotherapy. The study design could also potentially increase the homogeneity of study participants, which could provide more robust evidence for future studies. In addition, prespecified biomarker and subgroup analyses are also included in this protocol. These may extend current knowledge on the prognostic and predictive value of available clinicopathological parameters and may also help to define a suitable MBC patient subgroup with potential survival benefit with the addition of pyrotinib. Of note: the present study focuses on a low-risk patient subgroup to implement a de-escalating strategy for HER2+ MBC. The generalization of results to patients with heavy disease burden or rapidly progressive disease should be made with great caution. | PMC7359576 | Study Protocol | null | 32,660,609 | Pyrotinib with trastuzumab and aromatase inhibitors as first-line treatment for HER2 positive and hormone receptor positive metastatic or locally advanced breast cancer: study protocol of a randomized controlled trial | Wang C, Lin Y, Zhou Y, Mao F, Zhu H, Guan J, Zhang X, Shen S, Huang X, Chen C, Yao R, Zhao J, Sun Q. | BMC Cancer. 2020 Jul 13;20(1):653. doi: 10.1186/s12885-020-07143-2. | Wang C | BMC Cancer | 2,020 | 2020/07/15 | PMC7359576 | null | 10.1186/s12885-020-07143-2 | oa_comm/txt/all/PMC7359576.txt | 509144d7d25c91edabdf727bcf33b544 | BMC Cancer. 2020 Jul 13; 20:653 | 2021-06-19 05:50:23 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | The reliable quantification of individuals’ physiological response to acute exercise bouts are of major importance for monitoring training. Both, subjective as well as objective markers are used to control athletes’ training in accordance with individual abilities. When training stimuli are wrongly applied due to a lack in load management, it results in an imbalance in the exercise load-recovery cycle with the well-known consequence of overtraining, increased risk of injury, and the inhibition of fundamental adaptation processes1–3. Therefore, it seems desirable to further explore the reliability of subjective and objective markers in order to understand how individual athletes deal with physical strains, and thus optimize exercise load-recovery balance. The need of accurate and reproducibly biomarkers in clinical practice, which reflect objective, quantifiable medical signs or effects of treatments and interventions in physiology of biochemical processes, has become a commonplace character4. In order to evaluate and establish suitable markers for monitoring training, and recovery, it is important to investigate subjective and objective process-based changes with high levels of accuracy and precision5. However, these requirements are questionable for various parameters, since many biomarkers have crucial limitations and an immense fluctuation width1–3. Previous studies concluded that it is important to assess the reliability and specificity of markers in controlled interventional trials6.
Particularly in the context of sport, there are only limited data in consideration of reliable markers which reflect the physiological exercise response and recovery processes7. Actually, there is still insufficient knowledge available as to which specific parameters are most suitable to monitor exercise load-recovery status1. Some metabolic, immunological and haematological markers are commonly used as objective physiological exercise response indicators8. However, markers such as creatine kinase (CK), which is released in response to muscle fiber damage, are known to have a large intraindividual and interindividual variability9,10. Though, the detailed evaluation of selected haematological parameters, inflammatory markers, enzymes, and metabolic markers such as haemoglobin (HGB)8, interleukin (IL-)-1 receptor antagonist (IL-1RA)11, lactate dehydrogenase (LDH)12or thiobarbituric acids (TBARS)13are still pending. These markers were chosen due to their use in exercise context analyzing immune activation, metabolic demands, or oxidative stress14. Besides, regarding a comprehensive and serious assessment of athletes’ load state, the use of combinations of suitable parameters including functional testing, subjective testing and biochemical analyses should be considered15,16. In this regard, suitability is defined by a certain exercise sensitivity and correlation to muscle force parameters, such as maximum voluntary contraction (MVC)17. Some studies proved the suitability of muscle force and subjective parameters such as the rating of perceived exertion (RPE) or the multidimensional mood state as subjective tools for physical performance assessments18–20. Accordingly, the discovery of additional markers might contribute to creating a panel of parameters which might offer the possibility of analyzing multiple aspects of human performance and health status. The aim of the current study was to examine the different exercise response, changes during recovery, and the test–retest reliability of various subjective parameters, muscle force values and blood biomarkers after strenuous bouts of endurance exercise; thereby evaluating their suitability for monitoring exercise load and recovery. We hypothesized that some of the analyzed parameters are suitable and reliable as markers which reflect the physiological exercise response and recovery processes and can be used for sports practice. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | ['Fig1', 'Fig1', 'Fig1', 'Fig1', 'Fig2', 'Fig2', 'Fig2', 'Fig2', 'Fig2', 'Fig2', 'Fig3', 'Fig3'] | Results indicated that TBARS (F3= 79.43;p< 0.001), LDH (F3= 208.72;p< 0.001), CK (F1.44= 153.09;p< 0.001) and cortisol (F2.33= 99.89;p< 0.001) showed significant main effects over the measuring time points (MTPs). Both exercise trials induced an increase of TBARS (Fig.1a), LDH (Fig.1b) and CK (Fig.1d) immediately after the tests (p< 0.001), whereas no changes were found for cortisol (Fig.1c). While the concentrations of TBARS, LDH and cortisol decreased three hours after the running field tests (RFTs) (p< 0.001), CK further increased (p< 0.001). Nevertheless, all four biomarkers showed significant differences 3 h (3 h) after the exercise tests compared to pre-exercise levels (p< 0.001). 24 h (24 h) after, levels of TBARS decreased back to baseline (3–24 h,p= 0.018). In contrast, concentrations of CK further increased (3–24 h,p< 0.001), while cortisol concentration turned again into a rise (3–24 h,p< 0.001). LDH, CK and cortisol were still increased after 24 h compared with pre-exercise levels (p< 0.001). Analysis of reliability exhibited good to moderate intraclass correlation coefficients (ICCs) for TBARS (ICC = 0.79), LDH (ICC = 0.73), cortisol (ICC = 0.7) and CK (ICC = 0.64).Figure 1Changes of metabolites (a), enzymes (b,d), and hormones (c) after, 3 h after and 24 h after two identical endurance running field tests (Test 1 and Test 2). Data are presented as mean ± standard deviation. *Significantly different from previous measuring time point of both tests. #Difference against pre-exercise (before) in both tests (p< 0.05). Significant main effects were found for the cytokines IL-1RA (F2.36= 210.85;p< 0.001), IL-8 (F3= 30.09;p< 0.001) and C-reactive protein (CRP) (F1.39= 63.52;p< 0.001) over the measuring time points. The RFTs induced an increase in IL-1RA, IL-6, IL-8, IL-10, and IL-15 immediately after exercise (p< 0.0001). In contrast, no immediate changes of CRP levels (Fig.2b) were found. Peaking immediately after, concentrations of IL-8 (Fig.2c), IL-6 (Fig.2d), IL-15 (Fig.2e), and IL-10 (Fig.2f) decreased 3 h after the RFTs (p< 0.001), while IL-6 and IL-15 were still increased compared to pre-exercise values (IL-6:p< 0.001; IL-15:p= 0.004). Similarly, IL-1RA (Fig.2a) peaked 3 h after the RFTs (p< 0.001). Levels of both, IL-6 and IL-1RA, returned to baseline at 24 h after the running trials (p< 0.001). CRP showed a delayed peak at 24 h after the RFTs. For IL-15 a further increase was found between 3 and 24 h after the RFTs (p< 0.0001). The best test–retest reliability was measured for IL-1RA (ICC = 0.72). Moderate ICC values were calculated for CRP (ICC = 0.71), IL-8 (ICC = 0.67), IL-6 (ICC = 0.64) and IL-15 (ICC = 0.55), while the ICC of IL-10 was below 0.5 (ICC = 0.24).Figure 2Concentrations of various cytokines (a,c,d,e,f) and plasma proteins (b) before, after, 3 h after and 24 h after two identical endurance running field tests (Test 1 and Test 2). Data are presented as mean ± standard deviation. *Significantly different from previous measuring time point of both tests. #Difference against pre-exercise (before) in both tests (p< 0.05). For all blood cell related markers, the two-way ANOVA revealed significant differences over the MTPs, such as mean corpuscular volume (MCV) (F3= 56,15;p< 0.001) and platelets (PLT) (F2.48= 342.75;p< 0.001). Post hoc analysis of blood cell related markers showed an increase in MCV, haemoglobin (HGB), PLT, erythrocytes (RBC) and haematocrit (HCT) (Fig.3a–e) immediately after exercise (p< 0.001). In contrast, exercise trials were followed by a decrease of mean corpuscular haemoglobin concentration (MCHC) (Fig.3f) immediately after the RFTs (p= 0.005). While MCV, PLT, HGB, RBC and HCT decreased 3 h after (p< 0.001), the MCHC values turned into a significant increase (p< 0.001). The concentration of MCV increased (p< 0.001) 24 h after both RFTs, again. For HGB, PLT, RBC, and HCT significant differences between pre-exercise and 3 h (p< 0.001) and 24 h (HGB:p< 0.001; HCT:p< 0.002; PLT:p< 0.046; RBC:p< 0.001) were shown. With regard to the test–retest reliability, excellent to good ICC levels were found for MCV (ICC = 0.96), HGB (ICC = 0.86), PLT (ICC = 0.86), RBC (ICC = 0.84), HCT (ICC = 0.78) and MCHC (ICC = 0.75). However, for other blood markers such as mean corpuscular haemoglobin (MCH), lymphocytes (LYM), platelets-lymphocyte ratio (PLR), neutrophils (NEU), neutrophils-lymphocytes ratio (NLR), systemic immune-inflammation index (SII) and leukocytes (WBC), no significant changes over the MTPs or only moderate ICC values between 0.51 – 0.74 were found (data not shown).Figure 3Effects of both running field tests (Test 1 and Test 2) on various haematological markers after, 3 h after and 24 h after. Data are presented as mean ± standard deviation. *Significantly different from previous measuring time point of both tests. #Difference against pre-exercise (before) in both tests (p< 0.05). Venous blood samples were collected in vacutainers. Plasma vacutainers were anticoagulated with EDTA. It was centrifuged at 2,500 × g for 10 min at 4 °C immediately after sampling, while serum samples had clotted for 30 min before centrifugation. Samples were separated into aliquots and stored in Eppendorf tubes at −80 °C until analysis. IL-1RA, IL-8, IL-15 and IL-10 were determined by high-sensitivity ELISA (Quantikine ELISA Kits: R&D Systems, analytical sensitivity: IL-1RA: 18.3 pg/mL, IL-8: 0.4 pg/mL, IL-10: 0.17 pg/mL, IL-15: 2 pg/mL; MVZ, Koblenz, Germany). Enzymes, CK and LDH, as well as the plasma protein CRP were analyzed by ELISA using a Cobas 8,000 Immunoassay System (Roche Diagnostics, analytical sensitivity: CK: 7 U/L, LDH: 10 U/L, CRP: 0.3 mg/L; MVZ, Koblenz, Germany). Levels of cortisol and IL-6 were measured by Advia Centaur XPT immunoassay system (Siemens, analytical sensitivity: cortisol: 3 ng/mL, IL-6: 2.7 pg/mL; MVZ, Koblenz, Germany). Plasma concentration of TBARS, a metabolite of lipid peroxidation, was determined spectrofluorimetrically. Briefly, plasma samples were heated with thiobarbituric acid reagent at 100 °C for 60 min. After cooling, it was neutralized with alkaline methanol. Finally, samples were centrifuged at 3,000 × g and TBARS levels were measured by fluorescence signals (excitation wavelength 532 nm; emission wavelength 553 nm; Fluorescence Spectrometer LS55, PerkinElmer, Rodgau, Germany). Numbers of WBC, RBC, LYM, PLT, and NEU were determined using an automated haematology analyzer (Sysmex KX-21 N Autoanalyzer, TOA Electronics, Japan). Furthermore, levels of HGB, HCT, MCH, MCV and MCHC were evaluated. SII, PLR as well as NLR were calculated as previously described39. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | ['Fig4', 'Fig4', 'Fig4'] | No changes over time were found for the 5-bound distance (Fig.4a). However, for this test an excellent ICC of 0.96 was calculated. The two-way ANOVA revealed significant differences in both MVCs (knee flexion:F2.61= 14.18,p< 0.001; knee extension:F2.49= 25.01,p< 0.001) parameters over the MTPs. MVCs of the knee extensors (Fig.4b) and the knee flexors (Fig.4c) decreased immediately after the RFTs (p< 0.001). Both parameters returned to pre-exercise values at 3 h after exercise. Excellent ICC values for the MVC of knee extensors (ICC = 0.93), as well as knee flexors (ICC = 0.92) were calculated.Figure 4Five-bound test for jump distance (a), MVC in knee extensors (b), and knee flexors (c) for muscle force before, after, 3 h after and 24 h after two identical endurance running field tests (Test 1 and Test 2). Data are presented as mean ± standard deviation. *Significantly different from previous measuring time point of both tests. #Difference against pre-exercise (before) in both tests (p< 0.05). To investigate the muscle force performance of the lower limbs, a 5-bound test (5BT) for measuring jump distance and an isometric strength test for measuring maximum voluntary contraction of knee flexion and extension were used. The 5BT was carried out as previously described40. Briefly, subjects were required to stand with their preferred foot forward at a marked starting point and bound five consecutive bounds with alternating left and right foot. Three trials were performed and the jump with the largest horizontal distance (m) was documented. The jump distance was measured from the marked starting position to the heel of the rear foot after the fifth jump. MVC of knee extensors and knee flexors were analyzed using isometric strength dynamometer m3diagnos (Schnell, Peutenhausen, Germany). First, subjects were seated and fixed in a standardized position with a defined device angle of 60° to measure the MVC of the knee extensors. An abdomen belt and crossed arms in front of the chest limited any extraneous movements of the upper body. Secondly, the MVC of knee flexors was examined in a lying position with a defined device angle of 150°. For each test, the best value of two trials was recorded. MVCs were calculated by analysis software (Diagnos Professional V1.0, Schnell). | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | ['Fig5', 'Fig5'] | The two-way ANOVA revealed significant changes over time for RPE values (Fig.5a) (F3= 345.19;p< 0.001). For the test–retest reliability, a poor ICC of 0.49 was found. Data from the acute multidimensional mood state showed lower scores immediately after the RFTs as well as three hours after exercise. We compared this to pre-exercise levels (F2.62= 13.94;p< 0.001) (Fig.5b). Values increased back to baseline between three hours and 24 h after (p= 0.001). In view of the results between both MTPs, an ICC of 0.70 was found.Figure 5Rating of perceived exertion (a) requested using BS and multidimensional mood state (b) scaling by using the MDMQ before, after, 3 h after and 24 h after two identical endurance running field tests (Test 1 and Test 2). Data are presented as mean ± standard deviation. *Significantly different from previous measuring time point of both tests. #Difference against pre-exercise (before) in both tests (p< 0.05). The subjective RPE were requested using the BS41. Furthermore, each subject had to complete a German version of the MDMQ42. It contains twelve items rated on a five-point Likert scale and measures three subscales (good-bad mood, alertness-tiredness and calmness-restlessness). These subscales are summed up, yielding a score between four and 20, with higher scores indicating better mood, higher alertness and calmness. From all three subscales, an index between twelve and 60 was calculated, which reflects the acute multidimensional mood state. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | A correlation was found between MVC in knee extension and TBARS immediately after (r= 0.26,p= 0.044), 3 h after (r= 0.34,p= 0.009) and 24 h after (r= 0.30,p= 0.020) the RFT at testing day 1 (TD1). Interestingly, there were also correlations in the changes between the pre-exercise value and 3 h after (r= -0.30,p= 0.021). In addition, the MVC in knee flexion correlated with the TBARS three hours after (r= 0.31,p= 0.031) and 24 h after (r= 0.28,p= 0.030). In confirmation with these results, the differences in measuring times pre-exercise to 24 h after could also correlate between knee flexion and TBARS (r= −0.26,p= 0.048) An association between CK and MVC knee extension over all MTPs (r= 0.40,p= 0.002;r= 0.38,p= 0.004;r= 0.28,p= 0.034;r= 0.36,p= 0.006) was detected. Furthermore, correlations between the MVC values in knee flexion and CK was determined based on the calculations between the changes from pre- to post-exercise (r= 0.27,p= 0.039) as well as to 3 h after (r= -0.36.p= 0.005). Interestingly, correlation analysis revealed an association between both MVC parameters and IL-1RA immediately after exercise at TD1 (MVC knee flexors—IL-1RA:r= 0.31,p= 0.017; MVC knee extensors—IL-1RA:r= 0.31,p= 0.019). Finally, a significant correlation of the changes between IL-1RA and MVCs pre- and post-exercise was found (r= 0.27,p< 0.044). The trend of the MVC values was similar to the trend of all correlated biomarkers. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | No differences between trained and untrained participants were found for the changes of any parameter over time. With regard to the reliability, CK revealed a poor reliability in the subgroup of trained individuals (ICC = 0.49), while reliability was categorized as good (ICC = 0.84) for the untrained group. The opposite was true for CRP. In the subgroup of trained participants a good reliability was found (ICC = 0.80), while the reliability in the untrained subgroup was calculated as poor (ICC = 0.48). | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | The novel findings of the present study are the high reliability of TBARS, LDH, IL-1RA, MCV, HGB, PLT, RBC, HCT, and MCHC after two identical controlled bouts of endurance exercise, suggesting their suitability as blood-based biomarkers for monitoring physiological exercise response and recovery status in endurance athletes. Based on the high associations to MVC, CK seems to be a suitable biomarker. However, the reliability of CK was only moderate, questions its use as a marker in sports practice. MVCs and the MDMQ seem to represent appropriate complementary monitoring tools to the blood markers. Regarding blood-based biomarkers, the highest reliability was found for TBARS, followed by LDH and IL-1RA values. A similar physiological exercise response-recovery curve for the TBARS concentrations was shown in a recent study by Krüger et al. (2016) after a 30 min continuous bicycle test21. Other findings confirm a high responsiveness of TBARS after exercise, which physiologically reflects an increased oxidative stress and subsequently an enhanced lipid peroxidation after acute exercise22. The observed correlations between TBARS and MVCs after the endurance exercise support an association between levels of oxidative stress and muscle force, and also proved the potential suitability of TBARS as a diagnostic parameter in endurance sports2,10. Despite the observed high reliability of TBARS as a parameter for evaluating physiological exercise response and recovery processes, the method of TBARS analysis has been generally considering critically in the literature due to several limitations. As discussed by Cobley et al. (2017), a major flaw of TBARS measurement is the low specificity of TBARS which react with various substrates to form malondialdehyde (MDA) such that most MDA is generated by the assay itself23. In addition, the heating step during TBARS analysis causes partial lipid decomposition leading to the formation of extraneous MDA. However, current data proved that standardized procedures might compensate for some methodological flaws. LDH values showed similar kinetics like TBARS over time. With regard to high reliability of blood LDH values and results of previous studies, this marker might represent another suitable biomarker for exercise load and recovery24. Within the cytokines, IL-1RA showed the highest reliability and, in parallel, seems to be associated with physiological exercise response and progressive recovery. IL-1RA is secreted by various types including immune cells, and inhibits pro-inflammatory activities of various cytokines. The observed changes in IL-1RA concentration correspond with earlier observations which showed a peak at one and a half to two hours after exercise and a decrease back to baseline levels 24 h after treadmill running25. However, the reliability of IL-1RA has not been established so far. Interestingly, we found an association to MVC, suggesting a link to muscular fatigue. Thus, the anti-inflammatory cytokine, IL-1RA, seems to be a reliable and suitable marker which reflect the physiological exercise response and recovery processes in athletes’ during endurance exercises. IL-10 is primarily expressed by monocytes and represents an anti-inflammatory cytokine, while IL-15 is a regulator of the activity of T cells and natural killer cells26. Limitations in the methodological analysis of IL-10 and IL-15 are suggested to be the reason for the weak reliabilities within these cytokines. The results of both markers are below the limit of detection of all commercially available enzyme-linked immunosorbent assay (ELISA) kits. Thus, IL-10 and IL-15 are not seriously quantifiable by this method. CK is a frequently used diagnostic marker for detecting exercise-induced muscle disruption or increased cell permeability. With regard to the assessment of suitability, CK is exercise sensitive and CK blood concentrations highly correlated to MVC values at different time points. Contrary to our expectations, for CK, only a moderate reliability was found. Due to the high interindividual variability in serum CK, the assignment of reliable reference values for athletes is complicated10. In accordance with these results, a study of Roe et al. (2016) found only a low reliability with a high coefficient of variation and a poor sensitivity measured in rugby players27. It is suggested that variabilities in CK release after exercise is caused by the existence of high and low responders due to the availability of different gene polymorphisms. However, other factors, such as training status or gender, might affect the reliability of CK9. In addition, the peak of CK values was somewhat delayed at 24 h after the RFTs, making it difficult to associate this parameter to muscular fatigue and to represent possible muscular recovery processes. This finding is consistent with other data that proved a poor correlation of CK values with other objective physiological markers25. However, it should be evaluated if CK is a more eligible marker for determination of muscular damage after eccentric or unaccustomed exercise over days. For the majority of the haematological markers, a high reliability was found. These parameters include MCV, HGB, PLT, RBC, HCT, and MCHC. Excellent reliability was calculated for MCV. MCV is a predictive indicator for haematological diseases and according to findings of the resulting data, also a suitable marker to represent the physiological exercise response and recovery processes. A review of seasonal variations of haematological parameters in athletes summarizes concordant characteristics within the same sport discipline28. It could conceivably be hypothesized that the methodological analyses of haematological markers have a higher stability compared to the cytokine or enzyme measurements. It is assumed that the immediate processing and the lack of any centrifugation or freezing procedures result in a higher reliability. However, a previous study has proven a potential negative impact on the stability of cytokine measurements in plasma29. While haematological markers might be affected by an increased mechanotransduction and plasma volume contraction during strenuous endurance exercise bouts30, most cytokines are released by different cell types and are involved in multiple physiological processes. However, data about the reliability of haematological markers are rare, although many studies have called for follow-up studies to review the quality criteria31. Interestingly, MVCs can be classified as highly reliable. In line with previous studies, a decreased MVC of knee extension, as well as a reduction in MVC of knee flexion, were found after endurance exercise trials18. Similarly, an excellent reliability of MVC was previously confirmed32. Previous studies which quantify the load condition after endurance exercise use the MVCs of the lower limbs to examine muscular fatigue directly by functional testing18. Thus, MVC analysis of knee flexion and knee extension might be useful functional tests to analyze exercise load and recovery in endurance exercise. It is somewhat surprising that the MDMQ data quoted higher reliabilities compared to Borg scale (BS) values. RPE is regularly used in sports science research and a valid parameter of internal training load33. However, not much is known about its reliability in the context of endurance exercise. In contrast, the score of multidimensional mood state is rarely used in sports science. Nevertheless, a reliability of ICC = 0.70 was found, indicating that the questionnaire might be a suitable complementary diagnostic tool for the assessment of exercise load and recovery processes in endurance sports. Interestingly, the training status had negligible effects on the physiological exercise response. Accordingly, the suitability of the exercise response and recovery markers was not significantly different between the subgroups of trained and untrained individuals. However, the reason might be that we did not recruit highly trained endurance athletes for this study. Surprisingly, we found a difference in the reliability of CK and CRP. Here, CK showed a lower reliability for trained compared to untrained subjects, while for CRP higher reliability was found in the trained subgroup. Finally, a number of important limitations need to be considered. The preliminary testing, as well as further exercise trials in the study, were performed in the field rather than under laboratory conditions. In addition, we did not use the maximum oxygen consumption (VO2max) as a gold standard to control exercise intensities34. Therein, we see greater benefits from our method, particularly regarding the transferability in sports practice. Due to the limited space, we could not analyze the differences between gender, menstruation cycle and training status. This study focused exclusively on research of suitable and reliable physiological exercise response and recovery markers with a high number of random participants. In conclusion, the best reliability and suitability were found for TBARS and IL-1RA suggesting their eligibility as markers for the monitoring of exercise response and recovery processes in endurance sports. Also, a good reliability was found for LDH, while CK showed good suitability but only moderate reliability. Accordingly, data indicate to expand the panel of blood biomarkers to monitor the athletes’ load-recovery status in a reliable way. Perhaps, the use of a combination of selected blood markers, MVC measurements, and subjective assessment tools such as MDMQ, should be discussed. Further research in this field is needed to evaluate the suitability of marker combinations, which comprehensively assess physiological exercise response and recovery processes in athletes. These findings should be combined with the development of innovative analyzing tools, that can be applied by athletes and trainers. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | ['Tab1'] | For a test–retest study design, 106 trained and untrained male and female subjects, aged 19–43 years, were recruited randomly and voluntarily to participate. 62 (31 male and 31 female) of them completed all examinations and were included in statistical analysis. According to the American College of Sports Medicine guidelines for exercise testing and prescription, the participants were differentiated based on their endurance capacity in subgroups of trained (T) (N = 37) and untrained (UT) (N = 25) individuals35. The T group consisted mainly of runners, strength athletes, and semi-professional team sports players such as soccer, handball, and volleyball players. All other subjects were defined as either recreational active or inactive individuals. Their personal characteristics and anthropometric data are collectively shown in Table1. All subjects were informed about the nature, purpose, and potential risks of the study and signed an informed consent statement prior to study participation. The local Ethical Committee of the Justus-Liebig-University Giessen (Germany) reviewed the study and approved ethical clearance, which was obtained according to the Declaration of Helsinki. In order to ensure that all subjects were physically healthy and fit enough to participate in sporting activities, they were medically screened. Exclusion criteria consisted of smoking, pregnancy, mothers in the lactation period, cardiovascular diseases, acute infections, musculoskeletal injuries, acute symptomatic respiratory deficits, and chronic diseases.Table 1Subject characteristics and anthropometric data (n = 62).VariablesOverallTrained (T)Untrained (UT)Age (years)25.3 ± 4.6 (19–43)25.62 ± 5.3 (19–43)24.8 ± 3.4 (19–35)Height (cm)175.8 ± 10.1 (155–201)172.2 ± 8.8 (155–191.5)181.2 ± 9.5 (158–201)Weight (kg)72.9 ± 13.8 (50–109)67.8 ± 10.7 (50–99)80.6 ± 14.6 (52.5–109)BMI* (kg/m2)23.4 ± 2.8 (18.8–30.2)22.8 ± 2.5 (18.8–28.8)24.4 ± 3.1 (19.9–30.2)Data are presented as Mean ± SD (Min.–Max.).*BMIbody mass index. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | The first step of the experimental approach contains testing of endurance capacity parameters to monitor the kinetics of various markers during further two identical strenuous exercise trials under controlled conditions. Subjects were tested for their endurance capacity during a continuous progressive exercise field test using lactate diagnostic, as previously described36. Briefly, subjects started on a 200 m running track at 6 km/h and increased their running speed by 2 km/h every three minutes until subjective exhaustion. Prior to the field test, between the three-minute stages with a break of 30 s and immediately after exhaustion, 20 µL of capillary blood was taken from the earlobe with an end-to-end glass capillary. Heart rate (HR) was continuously tracked using HR monitors (Polar FT1, Polar Electro Oy, Finland). Blood lactate values were analyzed using enzymatic-amperometrical detection (Bosen S-Line Plus, EKF-Diagnostics Sales GmbH, Magdeburg, Germany). HR and blood lactate values were used to evaluate the individual anaerobic threshold (IAT) using the Ergonizer Software for medical application (Ergonizer Software 4.9.4, Freiburg, Germany). The IAT was used to determine the individual running intensity during the following strenuous exercise trials. Calculation of IAT was performed by adding the constant value of 1.5 mmol/L to lactate concentration at the individual's lactate threshold37. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | Approximately one week after the preliminary test, first testing day TD1 of strenuous exercise trial took place. Both testing days (TDs) started between 8:00 and 9:00 am for each subject. Prior to the TDs, subjects were instructed on several standardized conditions to which they had to comply. From four days before the particular TDs, subjects were not allowed to take part in any exhausting physical activity, only regenerative training was acceptable. Furthermore, it was forbidden to consume alcohol the day before. A nutrition protocol had to be drawn up, which included all consumed drinks and meals one day prior TD1 as well as breakfast on the testing day. The protocol served as a guideline for the food intake prior to the second testing day (TD2) to ensure standardized conditions. At the respective testing day, subjects had to fill out a questionnaire concerning their regular physical activity and their usual nutrition. All participants did not change their regularities in nutrition as well as in physical activity in between the exercise trials. In female subjects, the menstrual cycle was documented as well. These questionnaires were issued to document large deviations in these habits and to exclude possible changes in physical performance between TD1 and TD2. The testing procedure contains two identical 60-min continuous endurance running field tests RFTs, intermitted by a recovery period of approximately four weeks. In order to examine the test–retest reliability of measured parameters, the previously described standardized conditions during both TDs were given high significance. The exercise protocol consisted of 40 min running at an intensity corresponding to 95% of HR at IAT, followed by 20 min at 110% in order to ensure exhaustion. The participants completed both RFTs at the same duration at the respective HR. Specific duration and intensity were chosen after the evaluation of a pilot study as well as in previous studies38. The outcome measures were collected before, immediately after, 3 and 24 h after each exercise test by double analysis. MTPs were chosen to make data comparable to previous studies11,21. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC7368084'] | ['32681124'] | [] | Data of all subjects are presented as means ± standard deviation of the mean and the minimum and maximum values. In cases of normal or log-normal distribution (Kolmogorov–Smirnov test), data were analyzed using the two-way ANOVA to observe mean differences between the MTPs depending on the TDs. If analysis revealed any significant main effects between the MTPs (p< 0.05), post hoc analysis was conducted by using the Bonferroni test. To consider training status, we separated the participants into subgroups of trained and untrained individuals and added these as between-subjects factor into the ANOVA analysis. Furthermore, analysis of the test–retest reliability between the MTPs of TD1 and TD2 was carried out with the ICC (model: two-way mixed effects; type: single measurement; definition: absolute agreement). In all cases, ICC > 0.5 was accepted as a minimal test–retest reliability. Values between 0.5 and 0.75, 0.75 and 0.9, and greater than 0.9 are indicative of moderate, good, and excellent reliability43. Pearson’s correlation analysis was used to analyze the suitability of the parameters. In all cases,p< 0.05 was accepted as being significant. Statistical power analysis was performed according Cohen et al. (1988)44. All statistical analyses were carried out using SPSS version 25 (IBM SPSS Statistics 25, IBM GmbH, Munich, Germany). Figures were created with GraphPad Prism 5.01. | PMC7368084 | Article | null | 32,681,124 | Reliability and suitability of physiological exercise response and recovery markers | Reichel T, Boßlau TK, Palmowski J, Eder K, Ringseis R, Mooren FC, Walscheid R, Bothur E, Samel S, Frech T, Philippe M, Krüger K. | Sci Rep. 2020 Jul 17;10(1):11924. doi: 10.1038/s41598-020-69280-9. | Reichel T | Sci Rep | 2,020 | 2020/07/19 | PMC7368084 | null | 10.1038/s41598-020-69280-9 | oa_comm/txt/all/PMC7368084.txt | 60dc8c9047a47c5b674faee05945d073 | Sci Rep. 2020 Jul 17; 10:11924 | 2021-06-19 05:51:30 | CC BY | no |
['PMC6001778'] | ['29578260'] | ['nbm3905-bib-0001', 'nbm3905-bib-0002', 'nbm3905-bib-0003', 'nbm3905-bib-0004', 'nbm3905-bib-0005', 'nbm3905-bib-0006', 'nbm3905-bib-0007', 'nbm3905-bib-0008', 'nbm3905-bib-0009', 'nbm3905-bib-0010', 'nbm3905-bib-0011', 'nbm3905-bib-0012', 'nbm3905-bib-0013', 'nbm3905-bib-0014', 'nbm3905-bib-0015', 'nbm3905-bib-0016', 'nbm3905-bib-0017', 'nbm3905-bib-0018', 'nbm3905-bib-0019', 'nbm3905-bib-0016', 'nbm3905-bib-0020', 'nbm3905-bib-0021', 'nbm3905-bib-0022', 'nbm3905-bib-0023', 'nbm3905-bib-0009'] | Exercising muscle tissue has been studied for several decades using magnetic resonance spectroscopy (MRS).(1,2) In particular, time‐resolved31P MRS is a valuable non‐invasive tool to investigate the metabolic response of exercising muscle in humans. Physiologically relevant parameters such as pH, PCr recovery time constantτPCrand maximum oxidative capacityQmax(3,4) can be calculated from time courses of phosphocreatine and inorganic phosphate.5 A challenge with dynamic studies of muscle tissue is to achieve the temporal resolution to follow the course of the target metabolites, while localizing the origin of the signal to active muscle only and maintaining sufficient signal‐to‐noise ratio (SNR). Several exercise‐recovery studies differentiating signals from gastrocnemius and soleus, which are the main contributors to force in plantar flexion, have been published using either localized MRS(6,7,8,9) or MRI.(10,11,12,13,14) Both muscles act on the Achilles tendon and are attached to different positions on the proximal end. Soleus is connected to the tibia and gastrocnemius lateralis and medialis originate at the femur; therefore changes of the knee angle affect these muscles to a different extent.(15,16) Additionally, the fibre‐type composition differs between these calf muscles: soleus is predominantly composed of slow twitch fibres (80 %), while a more even distribution of slow and fast twitch fibres has been reported in gastrocnemius.(17,18) Because of these biomechanical and anatomical differences, the knee angle is a crucial parameter determining the distribution of workload between calf muscles during plantar flexion exercise.19Previous studies have shown that soleus is more activated with a flexed knee, while gastrocnemius contributes more with an extended knee. Price et al16used MRI and surface electromyography to study the pre‐ versus post‐exercise changes ofT2and electromyography activity in two groups of 12 subjects exercising at three different knee angles. Valkovic et al20acquired dynamic spiral spectroscopic31P magnetic resonance (MR) images in five volunteers performing plantar flexion with two different knee angles. To our knowledge, measurements of dynamic31P MR spectra of exercising calf muscle with a variation of knee angle have not been made so far in more than two positions. However, this allows a more detailed quantification of the influence of knee angle on the distribution of the workload between calf muscles contributing to plantar flexion in a natural movement pattern. Recently, a semi‐localization by adiabatic selective refocusing (LASER) sequence(21,22) has been developed, which is capable of acquiring spectra from multiple independent volumes in an interleaved fashion.23This technique provides the same temporal resolution as the original single‐voxel spectroscopy (SVS) sequence, but acquires data from two voxels. It is therefore a suitable technique to measure the metabolic response of two different muscles dynamically during a single exercise‐recovery experiment. This work investigates the impact of the knee angle on the distribution of workload between gastrocnemius and soleus during plantar flexion9by executing this exercise at four different knee angles and acquiring time‐resolved31P spectra at 7 T, using a multivoxel semi‐LASER sequence. | PMC6001778 | Research Article; Research Articles | null | 29,578,260 | Dynamic multivoxel-localized (31) P MRS during plantar flexion exercise with variable knee angle | Niess F, Fiedler GB, Schmid AI, Laistler E, Frass-Kriegl R, Wolzt M, Moser E, Meyerspeer M. | NMR Biomed. 2018 Jun;31(6):e3905. doi: 10.1002/nbm.3905. Epub 2018 Mar 26. | Niess F | NMR Biomed | 2,018 | 2018/03/27 | PMC6001778 | null | 10.1002/nbm.3905 | oa_comm/txt/all/PMC6001778.txt | 4a52d80b931f0743e72c7485bfb79cf6 | NMR Biomed. 2018 Jun 26; 31(6):e3905 | 2021-06-18 17:20:58 | CC BY | no |
['PMC6001778'] | ['29578260'] | ['nbm3905-bib-0024', 'nbm3905-bib-0025', 'nbm3905-bib-0023', 'nbm3905-bib-0023', 'nbm3905-bib-0023', 'nbm3905-bib-0023', 'nbm3905-bib-0026', 'nbm3905-bib-0027', 'nbm3905-bib-0028', 'nbm3905-bib-0003', 'nbm3905-bib-0004', 'nbm3905-bib-0005'] | Magnetic resonance spectroscopy data from gastrocnemius medialis and soleus of healthy volunteers were acquired simultaneously during rest, exercise and recovery, repeatedly for each knee angle. 12 subjects (8 males and 4 females, age 26.4 ± 4.9 years, body mass index 22.1 ± 1.7 kg/m2) participated in the study after having declared written informed consent to the protocol, which is in accordance with the guidelines of the local ethics committee and the latest version of the declaration of Helsinki. All subjects were recreationally physically active. The measurement protocol consisted of 1 min rest, 3 min exercise and 5 min recovery using a custom‐built pneumatic pedal ergometer (similar to that described in Meyerspeer et al24) for plantar flexion during the MR measurements. The exercise intensity was standardized for all measurements by inflating the pneumatic system to 0.4 bar, using a manual pump. The subjects were instructed to time the plantar flexion exercise so that tissue motion during data acquisition was minimized, with a single pedal push between the MRS acquisitions, every 3 s. The force was measured continuously during exercise, using sensors on the ergometer and recorded by an external computer in the control room. A multichannel (two channels1H, three channels31P) surface coil array, which was shaped to a half cylinder (d=14 cm,l=10 cm) to match the anatomy of a human calf,25was used for RF transmit and receive in a 7 T Magnetom whole‐body MR system (Siemens Healthcare, Erlangen, Germany). The coil was placed on a support with adjustable angle (in steps of 5°), which was positioned on plastic spacers to adapt the height. Each subject performed a total of four exercise‐recovery bouts, each with a different angle of the support (0° , 5° , 10° , 15°), designed to flex the knee by angles between 10° and 40°. The order of the measured knee angles was randomized between subjects, to rule out the possible effects of insufficient recovery from exercise. With this range of inclinations, the space available with the configuration used in the magnet bore was exploited to its maximum. The corresponding knee angle was measured with a protractor, using the lines from the knee to the hip (with the greater trochanter as a marker) and from the knee to the ankle as reference. This measurement was done repeatedly (five measurements per angle) in five representative subjects. The angle of the pedal was adapted to the posture of the leg, to always achieve a 90° angle between the foot and the lower leg in the neutral position. The acquisition time of31P MRS data for each knee angle was 9 min, followed by a minimum pause of 15 min for angle adjustment, which required retraction of the patient bed from the scanner and repositioning of the subject. Consequently, the time between the end of an exercise bout and the start of the subsequent exercise was at least 21 min. During this period the muscle was at rest and PCr, Pi and the pH were allowed to recover to basal levels. Ten subjects were scanned in two sessions on different days, studying two knee angles per session, while it was possible to measure two subjects in a minimum total measurement time of 90 min, each, consisting of less than 10 min for initial preparation in the scanner room, 4 x 9 min acquisition time and 3 x 15 min for subject repositioning and angle adjustments. A dynamic localized multivoxel31P MRS sequence with adiabatic refocusing pulses (semi‐LASER)23was used to select anatomy‐matched voxels in the muscles of interest, gastrocnemius medialis and soleus. The voxels were carefully positioned, taking into account the angle of the calf, with the help of a localizer image and 25 transversal gradient‐echo MRI slices, which were acquired at each angle. The average31P MRS voxel sizes were VOIgastroc.=55 ± 12 cm3and VOIsoleus=51 ± 9 cm3, respectively. The voxels in gastrocnemius medialis and soleus were measured interleaved with a delay of 3 s (i.e. with a total repetition time of 6 s, corresponding to the effective recovery time forT1relaxation with this acquisition scheme23) and an echo time ofTE=29 ms for each voxel. Calibration scans were performed in each subject before the exercise‐recovery experiments to adjust the RF transmit voltages, using the multivoxel31P MR sequence. The excitation pulse duration for both voxels was 2.6 ms and the adiabatic refocusing pulse duration was 4.6 ms. It is important to ensure that excitation slices of the voxels do not overlap, to avoid unwanted mutual saturation. In contrast, an overlap of the refocusing slices is acceptable, as the corresponding saturation is negligible with the set‐up used.23The voxel in gastrocnemius is always located closer to a surface coil placed below the calf than the one in soleus and therefore a lowerB1amplitude is required for refocusing. However, since refocusing planes mutually overlap between voxels in gastrocnemius and soleus,B1amplitudes of both voxels need to be equal, to ensure full refocusing in soleus, as described by Niess et al.23The shim volume was set up as small as possible, but sufficiently large to contain both voxels at once. NMR raw data were extracted and processed using in‐house developed Python scripts. Phosphocreatine (PCr) and inorganic phosphate (Pi) resonances were quantified using the fitting routine AMARES26in jMRUI.27The pH value was calculated from the chemical shift of PCr and inorganic phosphate for each pair of effective averaged acquisitions using jMRUI.28PCr depletions (dPCr) were calculated by normalizing every acquisition to the median of the last minute of recovery of the data set. Values for end‐exercisedPCrare given as the mean and standard deviation (SD) of the last five acquisitions during exercise. Recovery time constantsτPCrwere fitted mono‐exponentially to the PCr recovery time course. Maximum oxidative capacity (Qmax) was calculated fromdPCr,τPCrand pH using an ADP‐control model, as described in Kemp et al3and Fiedler et al4and using common assumptions mentioned by Kemp et al.5The SNR was calculated from the fully relaxed first spectrum acquired at the beginning of each time series, using the amplitude of the PCr signal and the SD of noise measured 12 ppm off‐center across one eighth of the total bandwidth. Statistical tests were performed on the results ofdPCr, end‐exercise pH (pHee),τPCrandQmaxacquired for all knee angles. One‐way analysis of variance (ANOVA) with a post‐hoc analysis using Tukey's honestly significant difference (HSD) was used where applicable, i.e. when data followed a normal distribution; otherwise Friedman's test combined with Nemenyi's post‐hoc test was used. | PMC6001778 | Research Article; Research Articles | null | 29,578,260 | Dynamic multivoxel-localized (31) P MRS during plantar flexion exercise with variable knee angle | Niess F, Fiedler GB, Schmid AI, Laistler E, Frass-Kriegl R, Wolzt M, Moser E, Meyerspeer M. | NMR Biomed. 2018 Jun;31(6):e3905. doi: 10.1002/nbm.3905. Epub 2018 Mar 26. | Niess F | NMR Biomed | 2,018 | 2018/03/27 | PMC6001778 | null | 10.1002/nbm.3905 | oa_comm/txt/all/PMC6001778.txt | 4a52d80b931f0743e72c7485bfb79cf6 | NMR Biomed. 2018 Jun 26; 31(6):e3905 | 2021-06-18 17:20:58 | CC BY | no |
['PMC6001778'] | ['29578260'] | ['nbm3905-bib-0023', 'nbm3905-tbl-0001', 'nbm3905-fig-0001', 'nbm3905-fig-0001', 'nbm3905-fig-0001', 'nbm3905-fig-0002', 'nbm3905-fig-0002', 'nbm3905-fig-0002', 'nbm3905-tbl-0001', 'nbm3905-tbl-0002', 'nbm3905-tbl-0001', 'nbm3905-fig-0003', 'nbm3905-tbl-0001', 'nbm3905-fig-0003', 'nbm3905-tbl-0001', 'nbm3905-fig-0003', 'nbm3905-fig-0004', 'nbm3905-bib-0004', 'nbm3905-fig-0004', 'nbm3905-fig-0004'] | The SNR of PCr at rest did not change significantly between knee angles and was 120 ± 24 in gastrocnemius medialis and 42 ± 12 in soleus on average across all subjects (mean ± SD). The linewidths, quantified throughout the experiment, were 7.8 ± 1.2 Hz in gastrocnemius medialis and 8.3 ± 1.5 Hz in soleus, which is consistent with previously published data.23The average knee angles measured in each position were 14°, 20°, 33° and 38°; the reproducibility across five repeated measurements was within 2°(SD). The average force that was applied on the pedal during exercise was 249 ± 60 N. The intrasubject variability between knee angles was 8 % (SD) on average. The corresponding power output was 6.2 ± 3.4 W, with a variation of 14 %. In Table1, the group averages of end‐exercise PCr depletion, end‐exercise pH, PCr recovery time constant, linewidths and SNR are reported for each knee angle and muscle (gastrocnemius medialis and soleus). To illustrate the placement of31P semi‐LASER volumes of interest (VOIs) in the calf muscles at different knee angles, gradient‐echo images of one representative subject are shown in Figure1A and B. Spectra acquired with a time resolution of 6 s during rest, exercise and recovery with 14° and 38° knee angles are shown as time series in Figure1C and D. Corresponding averaged spectra (n=5) of the last 30 seconds of rest and end‐exercise are shown in Figure1E and F. End‐exercise PCr depletion is plotted versus knee angle for gastrocnemius medialis in Figure2A and for soleus in Figure2B, for individual subjects (colored symbols) and as a group average (black). Linear regression was calculated for end‐exercise PCr depletion averaged across subjects at each knee angle (black line) and additionally for each subject separately (colored lines); see Figure2C and D. In gastrocnemius medialis,dPCrcorrelated negatively with the knee angle and values showed significant differences (p<0.05); see Table1. In contrast, the correlation found in soleus was positive and end‐exercise PCr depletion changed significantly with the angle of the knee. In both calf muscles studied, a linear relationship was found between the knee angle anddPCr. The coefficient of determination of the linear regression wasR2=0.80 ± 0.16 in gastrocnemius andR2=0.53 ± 0.24 in soleus, given as mean ± standard deviation (SD) across all subjects. Individual and averaged results (R2and slopes) of all subjects are shown in Table2. The slopes of all linear regression lines for individual subjects were negative in gastrocnemius and the majority of the slopes were positive in soleus. Only two subjects showed negative but very small slopes in soleus (−0.02 and −0.08), while one of these subjects showed very high (74 ± 15%) and very low (9.5 ± 1.5%) end‐exercise PCr depletion on average over all knee angles. Calculated end‐exercise pH in gastrocnemius medialis increased significantly with the angle of the knee (p<0.05), from 6.77 ± 0.12 to 6.99 ± 0.12, as shown in Table1. In soleus, pHeewas independent of the knee angle when regarding group averages, as shown in Figure3and Table1. The PCr recovery time constantsτPCrincreased significantly along with the acidification in gastrocnemius medialis (p<0.05; see Figure3C and Table1). The increase found in soleus (see Figure3D) did not reach statistical significance. Data points forτPCrwere excluded from the analysis if the standard deviation exceeded 30 s (presumably indicating impaired reliability of the PCr recovery fit, related to insufficient PCr depletion). Data points of gastrocnemius were not affected, but 13 out of 48 data points from soleus were excluded. Maximum oxidative capacityQmaxwas 0.53 ± 0.13 mM/s on average in gastrocnemius medialis and 0.49 ± 0.36 mM/s in soleus (0.45 ± 0.25 mM/s when averaging data were acquired with 33° and 38° knee angle only). IndividualQmaxdata points, together with a box and whiskers plot, are shown for all knee angles in Figure4A and B. A one‐way ANOVA test in both calf muscles studied showed thatQmaxdid not change significantly with different knee angles. A significant pH drop was observed above a threshold of approximately 60%PCr depletion in gastrocnemius medialis, as previously reported by Fiedler et al.4Figure4C shows the relationship between end‐exercise PCr depletion and end‐exercise pH for both muscle groups. Only a few data points from soleus showed depletions above 60%(n=6), which was associated with an average pH of 6.93 ± 0.03. When comparing these data points with data from gastrocnemius falling in the same range of PCr depletion, i.e. between 60%and 87%(n=15), a significantly lower end‐exercise pH 6.85 ± 0.07 was found for gastrocnemius (p<0.05, Wilcoxon rank‐sum test). The corresponding maximum oxidative capacities were not significantly different withQmax=0.47 ± 0.12 mM/s (gastrocnemius) andQmax=0.60 ± 0.22 mM/s(soleus). The correlation betweenQmaxvalues and end‐exercise pH of gastrocnemius medialis and soleus is shown in Figure4D. | PMC6001778 | Research Article; Research Articles | null | 29,578,260 | Dynamic multivoxel-localized (31) P MRS during plantar flexion exercise with variable knee angle | Niess F, Fiedler GB, Schmid AI, Laistler E, Frass-Kriegl R, Wolzt M, Moser E, Meyerspeer M. | NMR Biomed. 2018 Jun;31(6):e3905. doi: 10.1002/nbm.3905. Epub 2018 Mar 26. | Niess F | NMR Biomed | 2,018 | 2018/03/27 | PMC6001778 | null | 10.1002/nbm.3905 | oa_comm/txt/all/PMC6001778.txt | 4a52d80b931f0743e72c7485bfb79cf6 | NMR Biomed. 2018 Jun 26; 31(6):e3905 | 2021-06-18 17:20:58 | CC BY | no |
['PMC6001778'] | ['29578260'] | ['nbm3905-bib-0016', 'nbm3905-bib-0020', 'nbm3905-bib-0004', 'nbm3905-bib-0022', 'nbm3905-bib-0029', 'nbm3905-bib-0030', 'nbm3905-bib-0004', 'nbm3905-bib-0011', 'nbm3905-bib-0003', 'nbm3905-bib-0004', 'nbm3905-bib-0014', 'nbm3905-fig-0004', 'nbm3905-fig-0004', 'nbm3905-bib-0004', 'nbm3905-fig-0004', 'nbm3905-bib-0016', 'nbm3905-bib-0015', 'nbm3905-bib-0016', 'nbm3905-bib-0019', 'nbm3905-bib-0031', 'nbm3905-bib-0032', 'nbm3905-bib-0031', 'nbm3905-bib-0017', 'nbm3905-bib-0020', 'nbm3905-bib-0004'] | A relation between knee angle and the recruitment pattern of gastrocnemius and soleus is expected according to anatomy and has been explored with1H MRI16and31P MRS.20The purpose of this study was to investigate the effect of knee angle on metabolic changes in those muscles in further detail, in order to establish a more comprehensive model by acquiring localized31P MRS data in exercising calf muscles with a simple and time‐efficient method with four different knee angles. The metabolic parameters measured with localized dynamic31P MRS, which are linked to muscle activation (i.e. PCr depletion, pHeeandτPCr), showed a strong dependence on the angle of the knee during plantar flexion. In gastrocnemius, a strong correlation was found between the knee angle and the end‐exercise PCr depletion. Results showed a linear behaviour, with a decreasing metabolic response with increasing knee angle. PCr depletion, end‐exercise pH and PCr recovery time were significantly different between measurements. The observed relationship between strong muscle activation, evidenced by PCr depletion, acidification and a concurrent increase ofτPCr, is consistent with previous results.(4,22,29,30) In soleus, moderate to strong linear correlations between knee angle and PCr depletion were observed, with the opposite sign to those in gastrocnemius, i.e. an increasing knee angle was associated with increasing PCr depletion in most subjects. The effect of the knee angle on the derived parameters was, however, less pronounced in soleus than in gastrocnemius, i.e. PCr depletion in soleus was significant, but did not reach the levels of depletion in gastrocnemius, and pHeeremained neutral or indicated only mild acidification. The variability of PCr depletion was more pronounced in soleus than in gastrocnemius, especially in two subjects who recruited soleus to the same extent for all knee angles, resulting in similar slopes close to zero (−0.02 and −0.08), but, interestingly, showed significantly different PCr depletion (74 ± 15%) and (9.5 ± 1.5%). It is very unlikely that this observation is due to a motion artifact; it may reflect apparent differences in types of training and individual natural movement patterns between subjects, which could impact the recruitment of soleus during plantar flexion exercise. Furthermore, this might be a consequence of using the same workload for all volunteers, although the majority of subjects showed comparable changes of muscle recruitment between different knee angles. However, the intrasubject variability of the measured force between knee angles was 8 %, which allows for investigation of muscle groups contributing differently with a variable knee angle at a constant force output. Despite the inter‐subject variability of end‐exercise PCr depletion (in both muscles), the coefficients of determination of the linear fits and the slopes were consistent and similar within each muscle, which supports the hypothesis that the knee angle has a strong role in determining the distribution of workload between the two calf muscles studied. The PCr recovery time constantsτPCrquantified in both muscles were in good agreement with the literature.(4,11) When using localized spectroscopy, only tissue from a single muscle contributes to the signal and therefore a mono‐exponential fitting routine during PCr recovery was used. Fitting a bioexponential model to our data was tested and resulted in equivalent results, i.e. the PCr recovery times of both compartments were identical (differences smaller than 1 %). When PCr depletion was low, biexponential fit results were not reliable. Knee angulation modulates the level of muscle activation, but did not influence the calculated mitochondrial capacityQmaxderived from the ADP model3of both muscle groups. This demonstrates the robustness of the applied method. CalculatedQmaxvalues presented here are in excellent agreement with the publication of Fiedler et al4which contains results from gastrocnemius medialis and soleus measured in another cohort of subjects, and also with the work of Schmid et al14reporting results from gastrocnemius medialis only. Values ofQmaxfrom gastrocnemius were reliable for all knee angles, as the PCr depletion was sufficient in most of the subjects shown in Figure4A.Qmaxresults from soleus showed a higher variability, especially with the knee flexed by 14° or 20°, since end‐exercise PCr depletion in the majority of subjects was too low in soleus to obtain highly accurate results with these knee angles. For 33° and 38°, theQmaxobtained was more robust and more similar to results of gastrocnemius medialis on average; see Figure4B. In contrast to the publication of Fiedler et al4neither gastrocnemius nor soleus showed a correlation betweenQmaxand end‐exercise pH; see Figure4D. This could be explained by the fact that we acquired three times more data points in total, with four acquisitions per subject, over a wider range of stimulation intensities per muscle. Significant differences of muscle activation between knee angles were found, whileQmaxvalues did not change significantly. This is consistent with the notion that maximum oxidative capacity is an intrinsic parameter to the muscle tissue and should be independent of the degree of stimulation, provided there is sufficient oxygen supply. The results of all four knee angles did not show any sign that the time for the muscles to return to the basal state would have been too short and that possible residual effects on enzymatic activity, glycogen repletion, water content or vasoreactivity were not taken into account in this study. To maintain a coherent exercise protocol, the same force was chosen for all knee angles (similar to Price et al16). This resulted in an exercise response for gastrocnemius that can be explained consistently as decreasing recruitment with a bent knee. Gastrocnemius is a bi‐articular muscle, i.e. it crosses two joints in series and is therefore shortened in length with a flexed knee, while soleus is attached to the tibia and does not change in length by knee angulation.(15,16) Muscle shortening has been linked to a decrease in the number of available sites for cross‐bridge formation,19which influences a muscle's force output31and hence energy cost.32Furthermore, the relation between sarcomere length and force output depends on the type of muscle.31This may contribute to the explanation of why PCr depletion in soleus did not increase to the same extent as the corresponding decrease in gastrocnemius. The slope of the linear regression of depletion versus angle was smaller in soleus and, consequently, maximum depletions typically reached in soleus were smaller than the strong depletions found in gastrocnemius medialis. A further possible explanation for these findings is that soleus differs from gastrocnemius in fibre‐type composition17and cross‐section area, therefore it could be capable of producing higher maximum force output or it might show a different metabolic reaction to an equivalent workload. However, changing the ergometer pedal's recoil force with angle would render the protocol inconsistent (particularly for the measurement in gastrocnemius). Moreover, additional measurements with increased force and a flexed knee were attempted, but did not generate similar depletion to that in gastrocnemius medialis or were not well tolerated by the subject. The observation that the PCr depletion in soleus was stronger with a flexed knee than with a straight leg, but without depletion reaching the maximum depletion levels of gastrocnemius, has also been reported by Valkovic et al.20 Despite the finding thatQmaxwas not significantly different between gastrocnemius and soleus, the notion of a metabolic difference between the muscle tissues is supported by the trend towards different pH reached at similarly elevated PCr depletions: PCr depletions above 60%were associated with a pronounced fall in pH for gastrocnemius medialis, which is associated with the lactate threshold and was previously observed with a similar protocol.4Interestingly, however, the pH fall was less pronounced when comparable PCr depletions were reached in soleus. Such a difference could be linked to intrinsic metabolic differences between the muscle tissue of gastrocnemius and soleus. This might reflect the fact that soleus consists of less glycolytic muscle fibres and could be the focus of a future study. | PMC6001778 | Research Article; Research Articles | null | 29,578,260 | Dynamic multivoxel-localized (31) P MRS during plantar flexion exercise with variable knee angle | Niess F, Fiedler GB, Schmid AI, Laistler E, Frass-Kriegl R, Wolzt M, Moser E, Meyerspeer M. | NMR Biomed. 2018 Jun;31(6):e3905. doi: 10.1002/nbm.3905. Epub 2018 Mar 26. | Niess F | NMR Biomed | 2,018 | 2018/03/27 | PMC6001778 | null | 10.1002/nbm.3905 | oa_comm/txt/all/PMC6001778.txt | 4a52d80b931f0743e72c7485bfb79cf6 | NMR Biomed. 2018 Jun 26; 31(6):e3905 | 2021-06-18 17:20:58 | CC BY | no |
['PMC6001778'] | ['29578260'] | [] | The knee angle influences the distribution of workload between gastrocnemius and soleus muscles during plantar flexion. Consequently, it affects metabolic parameters measured with31P MRS during exercise and recovery. The recruitment of gastrocnemius decreased significantly when increasing the knee angle, which was reflected by a negative linear correlation between knee angle and PCr depletion and by significant changes of end‐exercise pH values and PCr recovery time. The effect in soleus was opposite and less pronounced. The results of this study, based on time‐resolved multivoxel31P MRS during calf muscle exercise, suggest that the knee angle should be considered in the widely used study designs employing localized or unlocalized data acquisition for the investigation of human exercise physiology. | PMC6001778 | Research Article; Research Articles | null | 29,578,260 | Dynamic multivoxel-localized (31) P MRS during plantar flexion exercise with variable knee angle | Niess F, Fiedler GB, Schmid AI, Laistler E, Frass-Kriegl R, Wolzt M, Moser E, Meyerspeer M. | NMR Biomed. 2018 Jun;31(6):e3905. doi: 10.1002/nbm.3905. Epub 2018 Mar 26. | Niess F | NMR Biomed | 2,018 | 2018/03/27 | PMC6001778 | null | 10.1002/nbm.3905 | oa_comm/txt/all/PMC6001778.txt | 4a52d80b931f0743e72c7485bfb79cf6 | NMR Biomed. 2018 Jun 26; 31(6):e3905 | 2021-06-18 17:20:58 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-bib-0001', 'jde15950-bib-0001', 'jde15950-bib-0002', 'jde15950-bib-0003', 'jde15950-bib-0004', 'jde15950-bib-0005', 'jde15950-bib-0006', 'jde15950-bib-0007', 'jde15950-bib-0008', 'jde15950-bib-0009', 'jde15950-bib-0010', 'jde15950-bib-0011', 'jde15950-bib-0012', 'jde15950-bib-0013'] | Dry skin is observed in 50%–90% of patients with end‐stage renal disease and persists or even worsens despite dialysis.1Pruritus is also reported in 12%–90% of patients with end‐stage renal disease.1Suggested causes of pruritus in patients with end‐stage renal disease undergoing dialysis include dry skin, the influence of dialysis membranes, and the effect of increased circulating pruritic cytokines.2,3A descriptive study of the risk factors for pruritus in patients undergoing dialysis revealed more intense pruritus in patients with dry skin than in those with normal skin.4Additionally, a greater number of dermatoses and longer duration of dialysis are reportedly associated with poorer scores on the Dermatology Life Quality Index (DLQI),5a tool used to measure the quality of life (QOL) related to skin disease.6For pruritus in particular, greater severity is reportedly associated with poorer QOL7and higher mortality.8 Dry skin in patients undergoing dialysis is regarded as a type of xerosis,9for which treatment with a moisturizer is recommended. In Japan, heparinoid‐containing products have been approved as prescription moisturizers and are used to treat xerosis associated with skin diseases such as atopic dermatitis, senile xeroderma, and dry skin in patients undergoing dialysis. Pruritus is typically treated with antihistamines,10but there is reportedly no correlation between the severity of pruritus and blood histamine levels in patients undergoing dialysis.11In fact, antihistamines are ineffective in many cases of pruritus. Specialized medicines for the treatment of pruritus in dialysis patients, such as kappa opioid receptor agonists, have recently also been used, but the symptoms are not completely suppressed. Given that moisturizers have been reported to be effective in patients with pruritus according to the 2020 clinical practice guidelines for the management of pruritus12in Japan, and that xerosis may cause pruritus in patients undergoing dialysis, the application of moisturizers has been found to be effective for both xerosis and pruritus. However, evidence to support this effectiveness is limited to the results of a few observational or experimental studies, therefore stronger evidence on this topic is needed. We previously conducted an exploratory study of 12 patients with chronic kidney disease and xerosis undergoing hemodialysis, and the results suggested the effectiveness of a moisturizer for xerosis and associated pruritus in these patients.13In that study, we evaluated 2‐week (group A) versus 4‐week (group B) application of a heparinoid‐containing product with weekly measurement of the water content of the stratum corneum (WCSC). The WCSC increased in both groups up to week 2 and was then maintained in group B up to week 4, but decreased in group A after week 2. However, a significant difference in the WCSC at week 4 (the primary endpoint of the study) was not observed between the two groups, possibly because of an insufficient sample size. Pruritus also improved during treatment with the study product and deteriorated after the end of the moisturizer application in group A, with a significant difference between the two groups at week 4 (P= 0.01, pairedt‐test). The present confirmatory study was designed with an adequate sample size based on the preceding study results. The DLQI was used as an additional endpoint to investigate the influence of a heparinoid‐containing product on QOL. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | This study was approved by the ethics review committees of Nippon Medical School (16 June 2017; Approval No. 229006) and Adachi Kyosai Hospital (24 August 2017), and was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (No. UMIN000029360). The study was conducted in compliance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects and the ethical principles of the Declaration of Helsinki. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | This study was conducted at the Kidney Disease Clinic of Nippon Medical School, Koyama Memorial Hospital, and Moka Hospital from October 2018 to May 2019. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-fig-0001', 'jde15950-fig-0001', 'jde15950-bib-0014', 'jde15950-bib-0015'] | This was a multicenter, open‐label, randomized, before–after, parallel‐group comparative study. The study schedule is shown in Figure1. Participants were randomized in a 1:1 ratio to groups A and B. In group A, the study product was applied for 2 weeks (period I), while in group B, the study product was applied for 8 weeks (2 weeks in period I plus 6 weeks in period II). Randomization of the participants was conducted before initiation of treatment. Study assessments were performed at weeks 0, 1, 2, 3, 4, 6, and 8. The study product was a heparinoid moisturizer containing glycerin, petrolatum, and squalene as the major additives (Hirudoid Lotion 0.3%; Maruho Co., Ltd., Osaka, Japan). The study product was applied to dry and itchy areas, including the hypochondriac region (the site at which the WCSC was measured), in principle twice daily in the morning and after taking a bath (or at bedtime on a day without bathing), but once daily after dialysis on the days of assessments, according to the study schedule in Figure1. The amount to be applied was based on the fingertip unit,14with 0.5 g regarded as the amount required to cover the area of two palms. This was originally the standard amount of topical steroid application, and its applicability for moisturizers has been reported previously.15Video‐assisted education was provided to all participants to demonstrate appropriate application methods. Any oral, injectable, or topical medication, including antipruritic medications, that was being used at the start of study treatment (week 0) and required continuation during the study period was continued with no change to the dosage regimen. Additionally, throughout the study period, no change was allowed in the dialysis conditions (type of dialysis, frequency per week), and concomitant use of any other heparinoid‐containing products, urea preparations, or petrolatum was prohibited. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-bib-0013'] | The study participants were clinically stable patients with chronic kidney disease undergoing hemodialysis. Their age ranged from 20 to 80 years on the day on which they gave informed consent, and all had been diagnosed with xerosis in the hypochondriac region and had dialysis‐associated pruritus at the start of the study treatment. Fully informed written consent was obtained from all participants before enrollment. Patients were excluded if they had used any moisturizer (heparinoid‐containing products, urea preparations, or petrolatum) within 3 weeks before the scheduled start day of the study treatment, had a history of allergy to any heparinoid‐containing product, or were otherwise ineligible for this study in the opinion of the investigator. The target sample size was set to 38 participants per group based on the results of our preceding exploratory study,13assuming an intergroup difference of 7.61 in the mean WCSC at week 4 (the primary endpoint of this study) with a standard deviation of 9 for both groups, a 1:1 randomization ratio, a 5% two‐sided significance level, 90% power, and allowance for a 20% dropout rate. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-fig-0002', 'jde15950-tbl-0001'] | Sex, age, height, and body weight were recorded on the day on which participants gave informed consent. Although the target sample size was 76, enrollment was stopped after 71 patients were enrolled because almost no participants dropped out and the required number for analysis was reached early. Of the 71 enrolled patients, one was withdrawn from the study because of adverse events and the remaining 70 participants completed the study (Figure2). All enrolled participants were included in the efficacy and safety analysis sets. Patient demographics are shown in Table1. In both groups, men were predominant (26 men and 10 women in group A, 22 men and 13 women in group B). The mean age was 64.1 ± 10.2 years in group A and 61.6 ± 12.6 years in group B. Ten (27.8%) of 36 patients in group A and seven (20.0%) of 35 patients in group B used drugs that may affect pruritus (topical steroids, oral antihistamines, and oral nalfurafine hydrochloride) at the start of the study treatment. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-tbl-0002'] | Adherence to study treatment was assessed at weeks 1, 2, 3, 4, 6, and 8 based on the patient's self‐completed diary and an interview with the participant. The following five categories were used to assess adherence: “completely or nearly as directed (applied on ≥90% of occasions),” “fairly as directed (applied on 75% to <90% of occasions),” “at least half as directed (applied on 50% to <75% of occasions),” “less than half as directed (applied on <50% of occasions),” and “never applied.” Adherence to study treatment is summarized in Table2. During the treatment period (period I for group A, periods I and II for group B) the study product was applied “Completely or nearly as prescribed” in 77.8%–91.4% of participants. Outside the treatment period (period II for group A), the study product was “Never applied” in 94.4%–100.0% of participants. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-bib-0013'] | The WCSC was measured on each day of evaluation 1 to 2 hours after the start of a dialysis session. One site in either the left or right hypochondriac region was designated as the measurement site for each participant. The measurement was conducted using the same instrument as in the previous study13(Corneometer and Multi Display Devices MDD4; Courage + Khazaka Electronic GmbH, Köln, Germany). Measurement of the WCSC by the corneometer is based on the electrical capacitance of the skin surface (at approximately 15 µm depth) and values ranging from 0 to 120 arbitrary units (AU) were delivered. On each day of evaluation, the WCSC was measured five times and the average of the five measurements was recorded. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | A board‐certified dermatologist centrally rated the severity of skin dryness on a five‐point scale according to the criteria shown in Supporting Information Table S1, based on photographs of the hypochondriac region (at the measurement site for WCSC) taken on each day of evaluation. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | Participants rated skin pruritus at the study product application site on a 100‐mm visual analog scale (VAS; 0 mm indicating no pruritus and 100 mm indicating the worst possible pruritus) before the start of dialysis on each day of evaluation. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-bib-0005'] | The participants assessed skin disease‐specific QOL at weeks 0, 2, 4, and 8 by completing the DLQI questionnaire,5which comprises six domains: “Symptoms and feelings” (questions 1 and 2), “Daily activities” (questions 3 and 4), “Leisure activities” (questions 5 and 6), “Work and school” (question 7), “Personal relationships” (questions 8 and 9), and “Treatment” (question 10). | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | Adverse events that occurred during weeks 0–8 were investigated. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | The efficacy analysis set comprised participants who used the study product during weeks 0 to 8 and for whom any efficacy data were available. The safety analysis set comprised participants for whom any safety data were available after using the study product. The analysis of patient demographics included all patients enrolled in the study, with calculation of the summary statistics by group. The primary efficacy endpoint was analyzed with calculation of summary statistics by group, and intergroup comparison was performed with the unpairedt‐test. The secondary efficacy endpoints were summarized for each day of evaluation, with calculation of summary statistics by group. The skin dryness score and the pruritus VAS score were compared between the groups using Wilcoxon's rank‐sum test or within groups using Wilcoxon's signed‐rank test (period I [weeks 1 and 2] vs week 0, and period II [weeks 3, 4, 6, and 8] vs week 2). Other variables were compared between the groups by the unpairedt‐test or within a group by the pairedt‐test (period I vs week 0 and period II vs week 2). In the intergroup comparison, the estimated difference and its 95% confidence interval were calculated. A two‐sided test was used for all statistical analysis. The significance level was set at 5% for intergroup comparisons and 2.5% or 1.25% for intragroup comparisons, adjusted for multiplicity using the Bonferroni method. In the safety evaluation, the number of participants who had adverse events, the numbers of adverse events, and the incidence of adverse events in periods I and II were calculated by group and overall. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-fig-0003'] | The WCSC over time is shown in Figure3and Table S2. The mean WCSC at week 4 (primary endpoint) was 28.8 ± 10.4 AU in group A and 36.4 ± 12.2 AU in group B (P= 0.0068, estimated difference −7.6, 95% confidence interval −13.0 to −2.17). Compared with the value at week 0 (26.0 ± 9.0 AU in group A, 25.2 ± 10.0 AU in group B), the WCSC was significantly increased by the end of period I (week 2) in both groups (39.0 ± 12.5 AU in group A, 38.5 ± 11.0 AU in group B;P< 0.00001 for both vs week 0). After week 2, the value in group B was maintained until the end of period II (week 8) (36.8 ± 11.5 AU;P= 0.9532 vs week 2), while the value in group A began decreasing and finally reached 25.1 ± 8.6 AU at week 8 (P< 0.00001 vs week 2). The room temperature and relative humidity (RH) at the start of the measurement of WCSC were 18.2–28.5°C and 18.7–61.3%RH, respectively. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-fig-0004'] | The skin dryness score over time is shown in Figure4and Table S3. At week 2, the score significantly decreased in both groups (group A: 1.4 ± 0.7 at week 0 and 0.3 ± 0.5 at WEEK 2,P< 0.00001; group B: 1.3 ± 0.7 at week 0 and 0.3 ± 0.5 at week 2,P< 0.00001). After week 2, the score showed a tendency to increase only in group A. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-fig-0005'] | The pruritus VAS score over time is shown in Figure5and Table S4. In both groups, the pruritus VAS score significantly decreased from week 0 (40.0 ± 26.3 mm in group A, 44.8 ± 23.7 mm in group B) to the end of period I (week 2) (16.5 ± 16.1 mm in group A, 20.1 ± 18.7 mm in group B;P< 0.00001 for both vs week 0). After week 2, the score continued to decrease in group B, but began increasing in group A. At the end of period II (week 8), the value was significantly lower in group B (10.5 ± 9.9 mm) than in group A (28.0 ± 26.0 mm) (P= 0.0018, estimated difference 17.5, 95% confidence interval 8.02–27.0). | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-fig-0006'] | The DLQI score over time is shown in Figure6and Table S5. At week 8, the total DLQI score was significantly lower at 0.7 ± 1.2 in group B compared with 1.4 ± 1.3 in group A (P= 0.0278, estimated difference 0.67, 95% confidence interval 0.07‐1.26). By domain, the “Symptoms and feelings” subscore over time was similar to that of the total score, with a significant intergroup difference at week 8 (1.1 ± 0.9 in group A, 0.5 ± 0.7 in group B;P= 0.0089, estimated difference 0.53, 95% confidence interval 0.14‐0.92). For the other domains (Daily activities, Leisure, Work and school, Personal relationships, and Treatment), the score remained <1 throughout the study period and was essentially unchanged (data not shown). | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-tbl-0003'] | In total, 126 adverse events were reported in 51 of the 71 participants in the safety analysis set (Table3). One participant in group B had two adverse events (rash and erythema) that might have been related to the study product, and this patient was withdrawn from the study. These adverse events resolved after discontinuation of the study product. In total, six serious adverse events were reported in four participants; none of these adverse events were related to the study product. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | ['jde15950-bib-0013', 'jde15950-bib-0013', 'jde15950-bib-0014', 'jde15950-bib-0016', 'jde15950-bib-0017'] | Heparinoid‐containing products are widely used for xerosis caused by various factors, including dialysis, in Japan. However, no reports other than our previous study13have described the effectiveness of such products for xerosis in patients undergoing dialysis as evaluated with an objective indicator such as the WCSC. In the present study, we investigated the time course of the severity of skin dryness and associated changes in pruritus and QOL with comparison between two groups undergoing different lengths of treatment and with an adequate sample size set based on preceding exploratory study results on the WCSC at week 4.13 In this study, xerosis measured by WCSC and skin dryness score improved from week 1 of application of the heparinoid‐containing product and worsened from 1 week after discontinuation of the application. Additionally, between the two groups of patients who continued and discontinued application of the heparinoid‐containing product, the WCSC at week 4 (primary endpoint) and all other time points of evaluation after week 3 showed significant differences. These findings suggest that continued use of a heparinoid‐containing product can improve xerosis in patients undergoing dialysis and maintain the improvement. Moreover, pruritus and xerosis synchronously improved or worsened, which indicates that xerosis plays a role in pruritus in patients undergoing dialysis as previously reported and that improvement of xerosis with a heparinoid‐containing product can lead to reduced pruritus. The DLQI analysis results suggested that treatment of xerosis in patients undergoing dialysis can lead not only to reduced pruritus but also better QOL. In particular, the time course was similar between the “Symptoms and feelings” subscore and the DLQI total score, which indicates that xerosis and pruritus in patients undergoing dialysis may affect the psychological health of the patients. During the study period, one participant experienced two adverse reactions, and both were known reactions to the study product, thus raising no new safety issues with the use of this heparinoid‐containing product for xerosis in patients undergoing dialysis. In this study, all efficacy endpoints showed clear differences in the skin condition over time between participants who continued application of the heparinoid‐containing product and those who discontinued the application, partly because of the favorable treatment adherence in >75% of the participants. In particular, the patients received pretreatment education regarding the appropriate application methods based on the fingertip unit14every day throughout the study period. This probably helped to clarify the appropriate amount of the heparinoid‐containing product to be applied, thereby leading to the observed adequate effectiveness in the treatment period. The results thus imply the importance of proper moisturizer use for maintaining good skin condition in patients undergoing dialysis. The strengths of this study include its design, which was based on the results of an exploratory study. Additionally, the effect of the skin treatment on dialysis patients’ QOL was evaluated using DLQI and the patients’ skin symptoms were visually evaluated by a dermatologist. The limitations of the study included a lack of comparison with a placebo, the use of moisturizers other than heparinoid‐containing products for study treatment, and a lack of enrollment of patients undergoing peritoneal dialysis. Additionally, the efficacy of heparinoid moisturizer in patients with senile xerosis was reported by Hayama et al.16Given that most of the subjects were elderly, the results of this study may reflect an improvement in xerosis accompanying not only dialysis, but also aging. Moreover, xerosis can be caused by environmental factors.17Further research on the characteristics of the study subjects and the study season is therefore required. This study demonstrated that proper application of a heparinoid‐containing product in patients undergoing dialysis can improve xerosis and reduce associated pruritus, and that continued application is required to maintain the improved skin condition. Additionally, improvement in the symptoms of xerosis and pruritus was shown to lead to improved QOL of the participants. It is therefore important to not only prescribe moisturizers to dialysis patients with xerosis, but also to support them in terms of medication compliance. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | The Kidney Disease Clinic of Nippon Medical School, Department of Nephrology of Nippon Medical School, Department of Dermatology of Nippon Medical School, Koyama Memorial Hospital, and Moka Hospital were paid by Maruho Co., Ltd for conducting this study. Yukie Yoshida, who presented the study results at the American Society of Nephrology (ASN) Kidney Week 2019, was paid by Maruho Co., Ltd for travel and accommodation expenses and remuneration. Shuichi Tsuruoka was paid by Maruho Co., Ltd for his advisory tasks in this study. Momoyo Kishida, Hiroshi Nakamura, and Akira Kanakubo are employees of Maruho Co., Ltd. The other authors have no conflicts of interest to declare. | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC8453556'] | ['34041789'] | [] | Parts of the results of this study were presented at the ASN Kidney Week 2019 (November 2019, Washington, DC) and the 40th Annual Scientific Meeting of the Japanese Society of Clinical Pharmacology and Therapeutics (December 2019, Tokyo). | PMC8453556 | Original Article; Original Articles | null | 34,041,789 | Efficacy of a moisturizer for pruritus accompanied by xerosis in patients undergoing dialysis: A multicenter, open-label, randomized verification study | Yoshida Y, Hirama A, Hashimoto K, Sato T, Yokota N, Saeki H, Kishida M, Nakamura H, Kanakubo A, Tsuruoka S. | J Dermatol. 2021 Sep;48(9):1327-1335. doi: 10.1111/1346-8138.15950. Epub 2021 May 26. | Yoshida Y | J Dermatol | 2,021 | 2021/05/27 | PMC8453556 | null | 10.1111/1346-8138.15950 | oa_comm/txt/all/PMC8453556.txt | 490533980c761d853cd07b3aaaf1d5e4 | J Dermatol. 2021 Sep 26; 48(9):1327-1335 | 2021-11-06 06:49:53 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.ref001', 'pmed.1003411.ref002', 'pmed.1003411.ref003', 'pmed.1003411.ref003', 'pmed.1003411.ref004', 'pmed.1003411.ref005', 'pmed.1003411.ref006', 'pmed.1003411.ref007', 'pmed.1003411.ref008'] | Neonatal hypoglycemia is common, affecting up to 15% of newborn babies [1] and 50% of those with risk factors (preterm, infant of a mother with diabetes, or high or low birthweight) [2,3]. First-line treatment with oral 40% dextrose gel in addition to feeding is safe and effective [3], but if hypoglycemia persists, intravenous dextrose is recommended [4]. This commonly requires admission to the neonatal intensive care unit (NICU), separating mother and baby and disrupting the establishment of breastfeeding. Hypoglycemia can cause brain damage and death, and babies born at risk have an increased risk of developmental delay in later life [5]. Even transient and treated hypoglycemia has been associated with impaired visual-motor coordination and executive function at 4.5 years [6], and with poorer performance on standard school testing of literacy and mathematics at 10 years [7]. This suggests that effective treatment may not be sufficient to avoid brain injury and that prevention of neonatal hypoglycemia would be desirable. However, there are currently no strategies, beyond early feeding, for prevention of neonatal hypoglycemia. We have previously shown in a dose-finding study that 40% dextrose gel given prophylactically to babies at risk reduces the incidence of neonatal hypoglycemia [8]. We therefore undertook this multicenter randomized trial to assess whether prophylactic dextrose gel given to babies at risk of neonatal hypoglycemia reduces admission to NICU. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.ref009'] | This multicenter, double-blinded, 2-arm, parallel, placebo-controlled randomized trial was conducted at 18 Australian and New Zealand maternity hospitals (trial registration ACTRN12614001263684). The study protocol has been published previously [9]. Babies were eligible if they were born at risk of hypoglycemia (defined as at least 1 of the following: preterm [<37 weeks’ gestation], infant of a mother with diabetes [any type], small [birthweight < 2.5 kg or <10th centile on population or customized birthweight chart], or large [birthweight > 4.5 kg or >90th centile on population or customized birthweight chart]) and also satisfied all of the following: ≥35 weeks’ gestation; birthweight ≥ 2.2 kg; <1 hour old; no apparent indication for NICU admission; unlikely to require NICU admission for any other reason, e.g., respiratory distress; and mother intended to breastfeed. Babies were not eligible if they had a major congenital abnormality, had received formula feed or intravenous fluids, or had been admitted to NICU, or admission to NICU was imminent. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | This study was approved by the New Zealand Health and Disability Ethics Committee (13NTA8), the Human Research Ethics Committee at the Women’s and Children’s Hospital, Adelaide (HREC/16/WCHN/86), and the institutional review committees at each participating hospital. Parents gave written informed consent, which was sought before birth whenever possible. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | The randomization schedule was prepared by the study statistician, who was not involved with any clinical aspect of the trial, and was stratified by study site and reason for risk of hypoglycemia (infant mother with diabetes, preterm, small, or large) with varied block size using the Plan procedure of SAS (version 9.4; SAS Institute, Cary, NC, US). Staff at the study sites accessed a centralized internet-based randomization service within the first hour after the birth to receive a study number that corresponded to a study treatment pack containing a single pre-packaged syringe of 40% dextrose gel or identical-appearing 2% hydroxymethylcellulose placebo gel (1:1 ratio). Families, study and site staff, and investigators were all blinded to treatment allocation. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.ref008'] | Randomized babies received a single dose of 0.5 ml/kg study gel at 1 hour after birth. This dose (200 mg/kg of 40% dextrose) was selected based on the pre-hPOD dosage trial [8] as having greatest efficacy with fewest limitations. The buccal mucosa was dried with a gauze swab before the study gel was massaged into the mucosa, followed by a breast feed. Blood glucose concentration was measured at 2 hours of age, and then according to hospital standard practice for monitoring babies at risk of hypoglycemia. This usually included pre-feed blood glucose concentration measurements 2–4 hourly for at least the first 12 hours, and until there had been 3 consecutive measurements of blood glucose ≥ 2.6 mmol/l. The study protocol specified that all blood glucose concentrations should be analyzed using a glucose oxidase method, either with a portable blood glucose analyzer (e.g., iSTAT, Abbott Laboratories, Abbott Park, IL, US) or a combined metabolite/blood gas analyzer (e.g., ABL 700, Radiometer, Copenhagen, Denmark). Babies who became hypoglycemic were treated according to standard hospital clinical practice, which in most cases was initially supplementary feeds and then treatment with 40% dextrose gel, followed by intravenous dextrose if required. Parents of included babies were contacted on day 3 (by telephone if already discharged home) to complete a questionnaire about current feeding, and at 6 weeks to complete a questionnaire about current feeding, parental satisfaction with participation in the trial, and health status of the baby. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | The primary outcome was admission to NICU (or Special Care Baby Unit for hospitals that used that name) for >4 hours. Secondary outcomes were hypoglycemia (any blood glucose concentration < 2.6 mmol/l in the first 48 hours), admission to NICU for hypoglycemia, hyperglycemia (any blood glucose concentration > 10 mmol/l), full or exclusive breastfeeding at discharge from hospital, receipt of any formula before discharge from hospital, formula feeding at 6 weeks of age, maternal satisfaction with study participation; cost of care until primary discharge home (to be reported separately), and neurosensory disability at 2 years’ corrected age (follow-up in progress). Adverse events were monitored by an independent safety monitoring committee, and were defined as seizures (serious adverse effect), death (serious adverse effect), hyperglycemia (defined as above), late hypoglycemia (blood glucose concentration < 2.6 mmol/l for the first time after 12 hours of age), delayed feeding (failure to establish breastfeeding without supplements by the end of day 3), and systemic sepsis. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.ref008', 'pmed.1003411.ref003'] | Based on our previous data from Auckland City [8] and Waikato Hospitals [3], we estimated that 10% of at-risk babies would require admission to NICU. A trial of 2,129 babies (1,014 in each arm, with continuity correction and allowing for a 5% dropout rate) would have 90% power to detect a 40% relative reduction (absolute reduction of 4%) in admission to NICU from 10% to 6% with a 2-sided alpha of 0.05. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | The trial was overseen by an independent data monitoring committee and safety monitoring committee. No interim analyses were planned or undertaken. All analyses were prespecified and carried out using a modified intention-to-treat approach, in which babies randomized in error (i.e., who did not meet eligibility criteria at randomization) were excluded, but all other babies were analyzed in the groups to which they were allocated. Babies for whom the primary outcome was not available were assumed to have been admitted to NICU (conservative analysis), but there was no other imputation for missing data. Between-group differences in binary outcomes (admission to NICU, hypoglycemia) were analyzed using mixed-effects general linear models assuming a binary distribution and log link function to obtain robust estimates of relative risk with 95% confidence intervals after prespecified adjustment for randomization stratification variables: study site and prioritized primary reason for risk of hypoglycemia (infant of a mother with diabetes, preterm, small, large) as fixed effects, and maternal unique identifier as a random effect clustering term to account for the non-independence of multiple births. For continuous outcomes the same models were fitted but a Gaussian distribution was assumed and the identity link function was used to obtain mean differences with 95% confidence intervals. In exploratory analyses the following terms were included: study site, maternal unique identifier as a clustering term, and (a) infant of a mother with diabetes and gestational age and birthweightz-score, (b) infant of a mother with diabetes and preterm (<37 weeks’ gestation) and birthweightz-score, (c) sex and mode of birth (vaginal or cesarean section), or (d) open label treatment with 40% dextrose gel. All analyses were prespecified unless otherwise stated. To explore changes in blood glucose concentration over time, a mixed-models approach to repeated measures was used. Time was rounded into hour bins, and time, treatment, and their interaction effects were fitted to a model that included the randomization stratification variables. Significant interaction effects were further explored by between-treatment-group comparison of the adjusted marginal means at each hour with false discovery ratep-values. The primary outcome was tested at the 5% significance level. No adjustment to the critical significance level was made for any secondary, sensitivity, or exploratory analyses other than for the changes in glucose over time described above. All analyses were conducted using SAS (version 9.4, SAS Institute, Cary, NC, US). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.g001', 'pmed.1003411.t001'] | Eighteen participating hospitals recruited 2,149 babies between 9 January 2015 and 5 May 2019 (range 5–535 babies per site). Sixteen babies were randomized in error and were excluded from the analysis, leaving 2,133 in the intention-to-treat analysis, 1,070 randomized to dextrose gel and 1,063 to placebo (Fig 1). This includes 40 babies who were randomized but did not receive study gel, and 15 who withdrew after randomization. Overall mean (SD) birthweight was 3,321 (603) g (infants of mothers with diabetes, 3,385 [503] g; preterm, 2,726 [328] g; small, 2,532 [217] g; large, 4,458 [419] g). Groups were well balanced for maternal and baby demographic variables (Table 1). The most common reason for risk of hypoglycemia was being an infant of a mother with diabetes (81% of each group), and 18% had more than 1 risk factor. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | Most babies (2,093/2,133; 98%) received the allocated study gel. Study gel was well tolerated by 2,044/2,097 (97%) babies (defined as none or only a few drops of gel spilled). Most blood glucose measurements were done using a glucose oxidase method (9,583/11,481; 83.5%), and the mean (SD) number of glucose measurements per baby was 7.8 (4.0) in those who became hypoglycemic and 3.8 (1.5) in those who did not, with no differences between treatment groups. At 6 weeks, 69% of mothers (270/389) in the dextrose gel group correctly guessed their baby’s study group, compared with 44% of mothers (144/331) in the placebo gel group (p< 0.001). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.t002'] | Three families withdrew consent to collect the primary outcome of NICU admission (all in the placebo group) and were therefore assumed to have been admitted to NICU for the intention-to-treat analysis. The overall rate of NICU admission was 9.9%, and was similar in babies randomized to dextrose and placebo gel (Table 2). The mean (SD) age of NICU admission was 11.0 (12.2) hours in babies admitted for hypoglycemia and 22.1 (32.5) hours in babies admitted for other reasons, with no difference between treatment groups. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.t002', 'pmed.1003411.t002'] | Babies randomized to dextrose gel had higher initial blood glucose concentrations (mean difference 0.19 mmol/l; 95% CI 0.13, 0.25 mmol/l;p< 0.001) and were less likely to become hypoglycemic (adjusted relative risk [aRR] 0.88; 95% CI 0.80, 0.98;p= 0.02) (Table 2). However, the rate of treatment for hypoglycemia did not differ between groups (aRR 0.90; 95% CI 0.79, 1.02;p= 0.09), nor did the rate of NICU admission for hypoglycemia (aRR 1.35; 95% CI 0.94, 1.94;p= 0.10). Overall, 30% of babies received treatment for hypoglycemia with open label dextrose gel (644/2,133) and 3.4% received intravenous dextrose (72/2,133), with no differences between treatment groups. There were no differences between treatment groups in delayed breastfeeding, breastfeeding at discharge from hospital, receipt of formula before discharge, or formula feeding at 6 weeks of age (Table 2). No babies became hyperglycemic (blood glucose > 10 mmol/l). Maternal satisfaction with the study at 6 weeks was high, with 95% of each group reporting that they would recommend the study to their friends; slightly more mothers in the dextrose gel group reported that they would take part in the study again (926/973, 95%, versus 882/951, 93%; aRR 1.03; 95% CI 1.00, 1.05;p= 0.03). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.t002'] | Two babies in each group died before discharge home; no deaths were considered likely to be related to the study intervention. One baby randomized to placebo gel had seizures 3 days after discharge, which were thought to be benign. Sepsis was suspected in 17 babies in each group (aRR 0.99; 95% CI 0.52, 1.93;p= 0.99), but confirmed in only 1 baby in the dextrose group. No baby had hyperglycemia (blood glucose > 10 mmol/l). Late hypoglycemia occurred in 213/1,207 (17.6%) babies with glucose measurements after 12 hours of age and was similar in both treatment groups. Breastfeeding was delayed in 38% of each group, and there were no differences between groups in the rate of full or exclusive breastfeeding, formula feeding before hospital discharge, or formula feeding at 6 weeks of age (Table 2). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.g002', 'pmed.1003411.g002', 'pmed.1003411.t003'] | The rate of NICU admission varied widely across study sites (range 6.7% to 32.1%), and was higher in Australian than in New Zealand centers (113/774, 14.6%, versus 98/1,359, 7.2%; aRR 2.12; 95% CI 1.64, 2.75;p <0.001). However, there was no evidence that dextrose gel altered the rate of NICU admission compared to placebo gel in different countries, in level 3 versus level 2 centers, or in the 4 centers that together recruited 78% of the babies (Fig 2A). There was also no evidence that the effect of dextrose compared to placebo gel was different in babies with different risk factors for hypoglycemia or different modes of birth, or for boys compared to girls (Fig 2B). Secondary outcomes were also not affected by study site, primary risk factor for hypoglycemia, or infant sex. However, the rate of hypoglycemia was lower in the dextrose gel group than in the placebo group in babies born vaginally (aRR 0.81; 95% CI 0.70, 0.94;p< 0.01) but not in those born by cesarean section (aRR 0.97; 95% CI 0.83, 1.12;p= 0.65) (Table 3). In post hoc analysis, the initial blood glucose concentration was higher in the dextrose gel group than the placebo group in babies born vaginally (mean [SD] 3.3 [0.8] mmol/l,n= 604, versus 3.0 [0.7] mmol/l,n= 625; adjusted mean difference [aMD] 0.27; 95% CI 0.19, 0.35;p <0.001) but not in those born by cesarean section (mean [SD] 3.0 [0.8] mmol/l,n= 455, versus 2.9 [0.7] mmol/l,n= 424; aMD 0.08; 95% CI −0.02, 0.18 mmol/l;p= 0.11). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | (A) NICU admission; (B) hypoglycemia. Horizontal lines indicate adjusted relative risks (aRRs) and 95% confidence intervals. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.t003', 'pmed.1003411.t003'] | Sensitivity analyses excluding babies with protocol deviations, babies who did not receive any of the assigned study gel (modified per protocol analysis), or babies for whom the primary outcome was not known did not change any of the findings (Table 3). Findings were also similar if only glucose measurements using a glucose oxidase method were included (Table 3). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.g003', 'pmed.1003411.g004'] | Adjustment for other potential confounders (see “Statistical analysis”) did not change any of the key findings, with relative risks for NICU admission of 1.08–1.12 (p= 0.57–0.37) across the 5 prespecified adjustments. There was no evidence that the effect of dextrose gel was related to the rate of NICU admission, or to the rate of hypoglycemia, in individual centers (Fig 3). Blood glucose concentration increased in both groups over the first day (timep< 0.001), and was higher in the dextrose gel group than the placebo group (treatment × timep< 0.001) specifically at 2 hours of age (p< 0.01;Fig 4). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | (A) NICU admission; (B) hypoglycemia. Two study sites are excluded due to small numbers of babies recruited. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | [] | Time is rounded into hour bins. Glucose concentrations are different between groups at 2 hours (p< 0.01). | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC7842885'] | ['33507929'] | ['pmed.1003411.ref008', 'pmed.1003411.ref002', 'pmed.1003411.ref003', 'pmed.1003411.ref010', 'pmed.1003411.ref003', 'pmed.1003411.ref008', 'pmed.1003411.ref008', 'pmed.1003411.ref011', 'pmed.1003411.ref008', 'pmed.1003411.ref003', 'pmed.1003411.ref012', 'pmed.1003411.ref013', 'pmed.1003411.ref014'] | We have previously shown that a single dose of 200 mg/kg prophylactic dextrose gel reduced the incidence of hypoglycemia in babies at risk [8]. We therefore hypothesized that in at-risk but otherwise well babies, prophylactic dextrose gel may reduce NICU admission, with potential health, societal, and cost benefits. However, in this large multicenter randomized trial, dextrose gel prophylaxis did not reduce NICU admission. There are several possible reasons for this. First, our inclusion criteria were intended to exclude babies requiring early NICU admission for reasons other than hypoglycemia, and the relatively older age of those who were admitted (mean 22 hours) suggests that this was effective. Nevertheless, 10% were eventually admitted to NICU, only half of these for hypoglycemia. This suggests that it is difficult in the first hour after birth to identify all “otherwise well” babies who may be most likely to benefit if hypoglycemia can be prevented. Second, the overall incidence of hypoglycemia (40%) was lower than in our previous studies of similar cohorts of babies at risk who were screened according to standard protocols using accurate methods (50%) [2,3]. In this pragmatic multicenter trial, frequency and duration of glucose screening, and thresholds for intervention, were not specified in the trial protocol and varied across study sites. Since detection of hypoglycemia largely depends on how carefully it is sought [10], and many sites used less rigorous screening protocols than previous reports [3,8], it is possible that some hypoglycemia was not detected. However, there was no evidence that the effect of dextrose gel was related to the incidence of hypoglycemia across different study sites, suggesting that this is not likely to have substantially influenced our findings. Third, this trial confirms the efficacy of prophylactic dextrose gel in reducing the incidence of hypoglycemia in babies at risk. However, the effect of a single 200 mg/kg dose of prophylactic dextrose gel in this trial (5% absolute risk reduction, 12% relative risk reduction) was smaller than in our previous study (18% absolute risk reduction, 32% relative risk reduction) [8]. It is common for larger multicenter trials to report smaller effects than smaller early single-center trials [11], and in this case this may relate to site variation in management of babies at risk (e.g., use of formula) as well as in the detection of hypoglycemia, which was done using only accurate glucose oxidase methods in the previous study. This trial also confirms our previous findings that a single dose of 200 mg/kg dextrose gel does not cause adverse effects, is well tolerated by babies, and is acceptable to families [8]. This is reassuring for an intervention being considered for prophylactic use in otherwise well babies, and consistent with previous reports on the use of dextrose gel for treatment of hypoglycemia [3,12]. It is not clear why prophylactic dextrose gel appeared to reduce the incidence of hypoglycemia in babies born vaginally but not in those born by cesarean section. Initial blood glucose concentrations did not differ with mode of birth in babies randomized to placebo gel, suggesting that mode of birth did not in itself alter early blood glucose regulation. Although this was a prespecified subgroup analysis, the data should be interpreted with caution in view of the multiple comparisons undertaken. Strengths of this study include that it was a large, pragmatic, multicenter, placebo-controlled randomized trial that was adequately powered to detect a clinically important effect on the primary outcome of NICU admission. However, the majority of participants were infants of mothers with diabetes, and this may limit generalizability to other groups of infants at risk of hypoglycemia. Another possible limitation is that some families appear to have become aware of group allocation, as more parents whose babies were randomized to dextrose gel correctly guessed the contents of the gel, and would participate in a similar study in the future. Since the dextrose gel tastes sweet, parents may have identified the gel by tasting it directly or on their babies, e.g., by kissing them. However, all study staff remained blinded to treatment allocation, and there is no reason to think that detection of primary and secondary outcomes would be likely to be differentially affected by parents’ beliefs about their baby’s treatment group allocation. We conclude that a single dose of 200 mg/kg prophylactic dextrose gel does not reduce NICU admission in babies at risk. However, it does reduce the incidence of hypoglycemia, with a number needed to treat of 21 (95% confidence interval 11 to 141). Since prophylaxis also appears to be safe and is likely to be cost-effective [13], clinicians and clinical guideline groups should consider whether introduction into clinical practice is warranted at this time. The key reason for screening and treatment of neonatal hypoglycemia is to prevent brain injury, and our preliminary data suggest that use of dextrose gel to prevent hypoglycemia may improve some aspects of development at 2 years of age [14]. Later follow-up of participants in this much larger randomized cohort will be important to further assess the clinical utility of prophylactic dextrose gel in prevention of neonatal hypoglycemia. | PMC7842885 | Research Article; Medicine and Health Sciences; Medical Conditions; Metabolic Disorders; Hypoglycemia; Physical Sciences; Chemistry; Chemical Compounds; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Physical Sciences; Chemistry; Organic Chemistry; Organic Compounds; Carbohydrates; Monosaccharides; Glucose; Medicine and Health Sciences; Epidemiology; Medical Risk Factors; Biology and Life Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Medicine and Health Sciences; Anatomy; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Physiology; Body Fluids; Blood; Blood Sugar; Biology and Life Sciences; Developmental Biology; Neonates; Medicine and Health Sciences; Public and Occupational Health; Preventive Medicine; Prophylaxis; Medicine and Health Sciences; Women's Health; Maternal Health; Breast Feeding; Medicine and Health Sciences; Pediatrics; Neonatology; Breast Feeding; People and Places; Population Groupings; Age Groups; Children; Infants; People and Places; Population Groupings; Families; Children; Infants | null | 33,507,929 | Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial | Harding JE, Hegarty JE, Crowther CA, Edlin RP, Gamble GD, Alsweiler JM; hPOD Study Group. | PLoS Med. 2021 Jan 28;18(1):e1003411. doi: 10.1371/journal.pmed.1003411. eCollection 2021 Jan. | Harding JE | PLoS Med | 2,021 | 2021/01/28 | PMC7842885 | null | 10.1371/journal.pmed.1003411 | oa_comm/txt/all/PMC7842885.txt | fa226a160f12232cf4b09881fd6c8c28 | PLoS Med. 2021 Jan 28; 18(1):e1003411 | 2021-06-19 07:05:26 | CC BY | no |
['PMC6020185'] | ['29940933'] | ['CR1', 'CR2', 'CR3', 'CR4', 'CR5', 'CR6', 'CR9', 'CR6', 'CR10', 'CR10', 'CR11', 'CR12', 'CR13', 'CR14', 'CR17', 'CR18', 'CR19'] | Overactive bladder (OAB) is defined by the International Continence Society (ICS) as urinary urgency in the absence of any known infection or other obvious pathology. OAB is usually characterized by frequency and nocturia, but may or may not cause urinary incontinence [1]. It has been shown to affect up to 36% of adult women in Europe and US [2,3]. Although not life threatening, OAB is a debilitating disease which can substantially impede the quality of life, resulting in low self-esteem, anxiety, depression, impairment of work productivity and increase in the number of falls and fractures [4]. Women with OAB experience increased incidence of sexual problems, sometimes with consequent personal distress and sexual partner compatibility issues. [5]. The impact of OAB symptoms on sexual function in women has been evaluated in a few studies [6–9]. Patel et al. [6] reported that 25% of their female OAB population had some degree of sexual dysfunction, meaning that OAB has a greater effect on female sexual health than it does urinary incontinence. Female sexual dysfunction (FSD) is traditionally classified into disorders of desire, arousal, lubrication, orgasm and pain. In the absence of detailed epidemiological data, current estimates have up to 43% of women complaining of at least one sexual issue [10]. Women are at risk of developing FSD due to physiologic, iatrogenic and psychological factors. Lower tract urinary tract infections are a further, independent FSD cause [10,11]. To identify FSD, appropriate assessment guidelines should be applied. So as to ascertain sexual history and enable assessment, there are a number of self-reporting questionnaires available. The Female Sexual Function Index (FSFI) is a concise, multidimensional “gold standard” tool which is regarded in high-esteem [12]. Recently introduced as an oral treatment for OAB, mirabegron (a β3-adrenergic agonist compound) improves storage capacity of bladder without inducing anticholinergic adverse events [13]. In four, large–scale 12-week phase III studies [14–17], a pooled analysis [18] and 12-month study [19], mirabegron consistently demonstrated superiority over placebo with respect to reductions in incontinence episodes and micturition frequency, with a similar incidence of adverse effects as the placebo. The objective of the current study is to evaluate the effect of the β3-adrenoceptor agonist, mirabegron, as used for OAB treatment on the sexual function of women (employing FSFI-Gr, a validated questionnaire translated into the Greek language). | PMC6020185 | Research Article | null | 29,940,933 | The effect of mirabegron, used for overactive bladder treatment, on female sexual function: a prospective controlled study | Zachariou A, Mamoulakis C, Filiponi M, Dimitriadis F, Giannakis J, Skouros S, Tsounapi P, Takenaka A, Sofikitis N. | BMC Urol. 2018 Jun 25;18(1):61. doi: 10.1186/s12894-018-0377-9. | Zachariou A | BMC Urol | 2,018 | 2018/06/27 | PMC6020185 | null | 10.1186/s12894-018-0377-9 | oa_comm/txt/all/PMC6020185.txt | 3a37c058971db58166c4c499a921543d | BMC Urol. 2018 Jun 25; 18:61 | 2021-06-18 17:23:57 | CC BY | no |
['PMC6020185'] | ['29940933'] | ['CR1', 'CR20', 'CR21', 'CR22', 'CR23'] | Between January 2016 and December 2016, 85 sexually active women with confirmed OAB, had referred to the Urogynecology outpatient clinic and were prospectively enrolled in this study. OAB was determined using the International Continence Society definition [1]. The urination frequency of all women was 8 or more times a day, with urge symptoms independent of incontinence. OAB was present in all women for a minimum of 3 months and none of the women had undergone prior treatment for the condition. Other inclusion criteria were the willing of women to comply with the protocol and the capability to complete the voiding diaries and the questionnaires without assistance. Subjects were excluded from inclusion if they had clinically significant stress urinary incontinence, neurogenic bladder and urinary retention or were at risk of these conditions. Women with a history of pelvic muscle training programs were excluded because it is accepted that pelvic floor muscle exercises improve female sexual function [20]. The protocol for the research project was approved by ELPIS HOSPITAL Ethics Committee and informed consent was taken from all the women. The inclusion criteria also integrated women over the age of 18 being in a sexually active relationship. Women who stated that they were not sexually active were asked to indicate the reason and were excluded from further analysis. Women who considered that there was no need for long-term treatment for OAB or were afraid of regimen’s adverse effects were included in control group. Patients were assessed using a comprehensive history, a detailed general and neurological physical examination, as well FSFI. According to the latest report of the International Consultation on Sexual Medicine, the FSFI remains the “gold standard” assessment tool, has a level of evidence 1 and recommendation grade A, for evaluating female sexual dysfunction [21]. Item selection and categories were based on the American Foundation for Urological Diseases classification system of female sexual dysfunction. Furthermore, FSFI has been translated and validated in the Greek language [22]. All women were asked to complete the Greek version of the FSFI, which evaluates the four phases of female sexual function and categorizes sexual dysfunction in the domains of (a) desire (b) arousal (c) lubrication (d) orgasm (e) satisfaction and (f) pain. The development of a scoring system, whereby higher scores indicate a healthier condition allowed the attainment of individual domain scores. Wiegel et al. [23] found that a total FSFI score of 26.5 is the optimal cut-off score for differentiating women with and without sexual dysfunction. We used the same cut-off scores in order to have comparable results with matching papers. To determine the eligible women all females were asked to answer the question: “Do you have sexual distress associated with sexual dysfunction?” and only women who gave a negative answer were finally recruited for analysis, since sexual distress needs special questionnaires to be evaluated. Patients were divided into two groups. Group A, which is defined as a control group, consisted of 48 women. None of these females with OAB wished to receive any therapy. On the other hand, in Group B, 37 patients with OAB were treated with mirabegron 50 mg daily for 3 months. Patients of Group A (without OAB therapy) completed a 3 day micturition diary prior to and after 3 month-observation-period. Patients of Group B completed a 3 day micturition diary prior to and immediately after the third month of mirabegron treatment. For each episode of urinary symptoms, the patient recorded the date and time, regardless of the presence of urgency and/or incontinence, the volume voided and the influence of the episode (of urinary symptoms) on the patient’s sleep. All women within Group B attended monthly office visits to ensure patients’ compliance with the treatment. In Group A, all women attended monthly office visits to ensure that they did not have any pharmacotherapy or behavioral therapy for OAB. Within Group A and Group B, voiding frequency, nocturia, urgency episodes, incontinent episodes, number of incontinence pads used, and voided volume were measured post-treatment using the 3 day micturition diary. All patients completed the FSFI questionnaire at the beginning and after the completion of the 3 month study. All outcome variables were tested for normality using the Shapiro-Wilk W test. Concretely, the following continues/ordinal variables were tested per group: age, body weight, symptom duration, parity; pre- and post-observation/treatment FSFI domains (desire, arousal, lubrication, orgasm, satisfaction, pain), total score of sexual function and percentage (%) improvement in total score of sexual function; pre- and post-observation/treatment episodes of frequency, urgency, nocturia, incontinence; number of pads needed; and voided volumes. The potential presence of any correlation was investigated between the % of improvement in LUTS/incontinence and in sexual function (separately for each parameter) in order to evaluate the effect of OAB improvement on sexual function. Finally, % improvement in total score of sexual function was compared between groups and a multivariate linear regression analysis was performed in order to investigate the effect of several independent parameters on sexual function. The % improvement in total score of sexual function was used as dependent variable. The % improvements in frequency, urgency, nocturia, incontinence episodes, number of pads needed and voided volume were considered as independent variables. Data were analyzed using IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp. Two-tailedp< 0.050 was considered significant. | PMC6020185 | Research Article | null | 29,940,933 | The effect of mirabegron, used for overactive bladder treatment, on female sexual function: a prospective controlled study | Zachariou A, Mamoulakis C, Filiponi M, Dimitriadis F, Giannakis J, Skouros S, Tsounapi P, Takenaka A, Sofikitis N. | BMC Urol. 2018 Jun 25;18(1):61. doi: 10.1186/s12894-018-0377-9. | Zachariou A | BMC Urol | 2,018 | 2018/06/27 | PMC6020185 | null | 10.1186/s12894-018-0377-9 | oa_comm/txt/all/PMC6020185.txt | 3a37c058971db58166c4c499a921543d | BMC Urol. 2018 Jun 25; 18:61 | 2021-06-18 17:23:57 | CC BY | no |
['PMC6020185'] | ['29940933'] | ['Tab1', 'Tab2', 'Tab3', 'Tab4', 'Tab5', 'Tab6'] | All tested variables showed significant departures from the normal distribution. The only exceptions were the pre- and post-observation/treatment total scores of sexual function and the voided volumes. Consequently, non-parametric tests (Mann Whitney U test and Wilcoxon signed-rank test, respectively) were performed for all comparisons (for uniformity purposes) between and within groups, respectively; all data are presented as medians (interquartile ranges; IQRs). Among the 48 women who reported sexual activity in the last 4 weeks from Group A, 11 women reported during the monthly visits that they had decided to follow pharmacotherapy/behavioral therapy for OAB and were therefore excluded from the study. Furthermore, 2 women from Group A and 2 women from Group B refused to complete the FSFI questionnaire at the end of 3 month period and were also excluded. There were no adverse reactions from mirabegron administration during the study. Demographic characteristics and baseline OAB/sexual scores did not differ significantly between groups (Table1). Sixty-five percent of patients in Group B who were incontinent at baseline became continent by the study-endpoint. Furthermore, all urinary outcomes, all FSFI domain scores and the total score of sexual function improved significantly in Group B at 3 months, in contrast to Group A (Tables2,3and4). Spearman’s rank-order correlation test yielded statistically significant (negative) correlations between % improvement in LUTS/incontinence and % improvement in sexual function were detected exclusively in Group B (frequency-lubrication, nocturia-arousal, incontinence-sexual satisfaction; Table5).Table 1Demographic characteristics and baseline OAB/sexual scores of participantsVariableGroup AGroup BPvalueAge (yr)43.5 (10.0)43 (10)0.838Body weight (kg)59.0 (14.0)55.0 (14.0)0.406Symptom duration (yr)4.2 (1.5)4.2 (3.3)0.821Parity2.0 (2.0)2.0 (1.0)0.738Frequency11.0 (1.0)11.0 (2.0)0.213Urgency episodes6.5 (1.0)7.0 (2.0)0.303Nocturia episodes2.0 (1.0)2.0 (1.0)0.227Incontinence episodes2.0 (1.0)2.0 (1.0)0.287Incontinence pads5.0 (2.0)4.0 (2.0)0.838Voided volume (ml)121.5 (31.0)117.0 (33.0)0.725Desire3.0 (0.6)3.0 (1.2)0.411Arousal3.6 (0.6)3.0 (0.8)0.281Lubrication3.6 (0.9)3.9 (1.1)0.214Orgasm3.6 (0.4)3.6 (0.8)0.253Satisfaction3.2 (0.4)3.2 (0.8)0.099Pain3.2 (0.4)3.2 (0.8)0.068Total Score of Sexual Function20.0 (2.5)20.3 (3.8)0.355Table 2Urinary evaluation of the participantsGroup APre-observationPost-observationPvalueFrequency11.0 (1.0)11.0 (1.0)0.200Urgency episodes6.5 (1.0)7.0 (1.0)0.093Nocturia episodes2.0 (1.0)1.0 (1.0)0.231Incontinence episodes2.0 (1.0)2.0 (2.0)0.332Incontinence pads5.0 (2.0)5.0 (2.0)0.231Voided volume (ml)121.5 (31.0)114.5 (27.0)0.001Group BPre-treatmentPost-treatmentPvalueFrequency11.0 (2.0)9.0 (2.0)< 0.001Urgency episodes7.0 (2.0)4.0 (2.0)< 0.001Nocturia2.0 (1.0)1.0 (1.0)< 0.001Incontinence episodes2.0 (1.0)1.0 (1.0)< 0.001Incontinence pads4.0 (2.0)2.0 (2.0)< 0.001Voided volume (ml)117.0 (33.0)148.0 (26.0)< 0.001Table 3Comparison of pre-observation and post-observation FSFI in Group APre-observationPost-observationPvalueDesire3.0 (0.6)3.0 (0.6)0.524Arousal3.6 (0.6)3.6 (0.6)0.628Lubrication3.6 (0.9)3.9 (0.6)0.713Orgasm3.6 (0.4)3.6 (0.4)0.505Satisfaction3.2 (0.4)2.8 (0.4)0.109Pain3.2 (0.4)3.2 (0.8)0.424Total Score of Sexual Function20.0 (2.5)19.8 (2.0)0.609Table 4Comparison of pre-treatment and post-treatment FSFI in Group ΒPre-observationPost-observationPvalueDesire3.0 (1.2)4.8 (1.2)< 0.001Arousal3.0 (0.8)4.8 (0.9)< 0.001Lubrication3.9 (1.1)4.8 (1.2)< 0.001Orgasm3.6 (0.8)4.8 (1.0)< 0.001Satisfaction3.2 (0.8)4.0 (0.8)< 0.001Pain3.2 (0.8)4.4 (1.2)< 0.001Total Score of Sexual Function20.3 (3.8)26.6 (4.2)< 0.001Table 5Correlation between improvements (%) in lower urinary tract symptoms & female sexual functionDesireArousalLubricationOrgasmSatisfactionPainTotal FSFIrsPrsPrsPrsPrsPrsPrsPGroup AFrequency−0.0880.5530.2200.298− 0.2010.171− 0.2370.1040.0150.918− 0.1050.479− 0.2540.081Urgency0.1680.2530.0410.781−0.1950.199−0.2400.1350.0350.8150.0130.928−0.2240.127Nocturia0.2090.1540.1570.286−0.1880.2010.0620.6740.2400.101−0.0540.7140.1810.219Incontinence−0.0070.9600.1580.2830.1340.364−0.2700.0640.1010.496−0.0760.610−0.0260.858Pads−0.1140.442−0.0760.607−0.0760.609−0.1800.1140.1190.422−0.1280.384−0.2220.150Voided Volume0.0410.782−0.0670.651−0.1140.441−0.0100.9480.2280.1190.1260.3930.0770.603Group BFrequency0.1030.545−0.2840.089−0.4290.0080.1390.413−0.0370.826−0.2300.170−0.2670.110Urgency0.0050.977−0.0020.9910.1630.335−0.1190.4840.2530.1320.0110.9460.0080.638Nocturia−0.0410.808−0.3520.032−0.1450.391−0.0620.7160.1610.3400.0800.640−0.0560.743Incontinence0.1780.292−0.3360.042−0.0090.957−0.2090.2140.2500.1300.2060.2210.0680.687Pads0.1230.468−0.2530.1310.0680.6890.1250.4610.2980.0730.2020.2300.1560.357Voided Volume0.1860.271−0.1700.314−0.0740.6630.2690.1080.2050.2230.1610.3400.1770.294 Total score of sexual function improvement (%) differed significantly between groups (Group A vs. Group B: 1.0 (3.7) vs. 32.6 (7.9);p< 0.001). Multivariate linear regression analysis run to predict % improvement in total score of sexual function from group, as well as % improvements in frequency, urgency, nocturia, incontinence episodes, number of pads needed and voided volume revealed that Group and % improvements in frequency statistically significantly predicted % improvement in total score of sexual function, F(7, 77) = 141.970,p< .001, R2= 0.928. All seven variables added statistically significantly to the prediction,p< 0.001. The multivariate linear regression model is presented in Table6.Table 6Multivariate linear regression analysis modelVariableBSE BβPvalue95.0% CIConstant1.1620.7520.126−0.3362.660Group24.1933.6880.741< 0.00116.84931.538Frequency−0.1550.079−0.1070.050−0.312− 0.001Urgency0.0030.0490.0050.951−0.0950.101Nocturia−0.0010.012−0.0030.931−0.0250.023Incontinence0.0040.0180.0090.843−0.0320.039Number of pads−0.0150.031−0.0360.629−0.0770.047Voided volume0.1130.0650.1230.086−0.0160.243 | PMC6020185 | Research Article | null | 29,940,933 | The effect of mirabegron, used for overactive bladder treatment, on female sexual function: a prospective controlled study | Zachariou A, Mamoulakis C, Filiponi M, Dimitriadis F, Giannakis J, Skouros S, Tsounapi P, Takenaka A, Sofikitis N. | BMC Urol. 2018 Jun 25;18(1):61. doi: 10.1186/s12894-018-0377-9. | Zachariou A | BMC Urol | 2,018 | 2018/06/27 | PMC6020185 | null | 10.1186/s12894-018-0377-9 | oa_comm/txt/all/PMC6020185.txt | 3a37c058971db58166c4c499a921543d | BMC Urol. 2018 Jun 25; 18:61 | 2021-06-18 17:23:57 | CC BY | no |
['PMC6020185'] | ['29940933'] | ['CR24', 'CR7', 'CR25', 'CR26', 'CR27', 'CR28', 'CR29', 'CR30', 'CR6', 'CR30', 'CR7', 'CR25', 'CR28', 'CR31', 'CR32', 'CR33', 'CR34', 'CR35', 'CR36', 'CR37', 'CR35', 'CR35', 'CR38', 'CR39', 'CR40', 'CR40', 'Fig1'] | This study is one of the few, to our knowledge, to demonstrate the effect of mirabegron, the first β-3 adrenoceptor agonist, on sexual function of women suffering from OAB. Our data has indicated that after 3 months evaluation, females with OAB receiving mirabegron 50 mg revealed statistically significant changes in FSFI total score and all subscales. OAB symptoms, urinary incontinence and sexual health in general are topics many find difficult to discuss. Not only may stigma make sufferers reluctant to approach a health professional, but it may also make health professionals embarrassed to confront patients. Self-reporting rather than interview-administered questionnaires greatly reduce this barrier. As FSFI allows a quantitative evaluation and can be used to study sexuality changes after therapeutic intervention, it has a distinct advantage over other assessment tools like diaries or calendars [24]. This tool is a reliable self-reporting measure of FSD which only requires 15 min to complete. Although it excludes issues involving personal stress, it measures outcomes of therapeutic response by design. Female sexual dysfunctions can interfere with intimacy, affect a marital relationship and ultimately erode well-being and overall health. Although sexual dysfunction is more likely in women than men, clinical FSD trials are rare compared to the available burgeoning data on men. Furthermore, the amount of data related to the effect of treatment agents used for OAB on the sexual function of women is insufficient in the literature while study comparisons should be made with caution because of differences in study designs and population. The use of anticholinergics as a first-line treatment for OAB is well documented. However, many large trials exclude sexual function change assessment after their administration. Tolterodine and oxybutynin are two anticholinergic medications with high quality evidence supporting improvement in sexual function with use. According to Hajebrahimi et al. [7], tolterodine IR significantly improved all domains of sexual function of women with OAB. The FSD was evaluated with the Arizona Sexual Experience Scale (ASEX), a five-topic questionnaire. Rogers et al. [25] evaluated the effect of short term treatment with tolterodine ER on FSD using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ) and Sexual Quality of Life – Female (SQOL-F). OAB symptoms improved with tolterodine ER, as did the scores of sexual health and anxiety measures in sexually active women with OAB. Rogers et al. [26] revealed that in a population of racially diverse, sexually active women, long term tolterodine ER treatment for OAB resulted in a relief of symptoms as ascertained in bladder diaries. Their study also validated improved sexual health. Using three items from the King’s Health Questionnaire and one item from the Beck Depression Inventory, Sand et al. [27] showed that transdermal oxybutynin treatment for OAB improved sexual function. Young et al. [28], in a prospective study using the FSFI questionnaire, demonstrated that OAB symptom management using solifenacin had a positive outcome on female sexual function, especially on the domains of arousal, desire and satisfaction. On the other hand, according to Jha [29] treatment of OAB symptoms with anticholinergics, in female patients evaluated with the PISQ questionnaire, does not guarantee improvement in sexual health. The small sample size and the uncontrolled design of the studies may not permit the demonstration of a causal relationship between the regimen used for OAB treatment and FSD. Other factors can have a greater effect on sexual life than urinary incontinence associated with intercourse. However, the enjoyment of intercourse can be adversely effected by urgency and frequency issues, along with the fear of leakage during stimulation and intercourse [30]. After 3 months of mirabegron treatment, results indicated statistically significant improvements in sexual function. These improvements may have played a critical role in overall women’s sexual health wellness, as revealed by total FSFI scores and individual sexual domain scores, in Group B. Thus, the improvement of FSFI scores, in the current study, may at least partly be attributable to the established improvements in urgency and frequency. Numerous studies have demonstrated that sexual function is negatively affected in women with bladder dysfunction [6,30]. It is obvious that the improvement in lower urinary tract symptoms results in improvement of women’s sexual life [7,25–28]. These previous studies are consistent with our findings, demonstrating a positive influence of OAB symptom treatment with mirabegron on sexual health and quality of life. The fact that the number of incontinence pads used by patients was significantly reduced after treatment, might help women feel more desirable and willing to experience sexual relationships and may represent another mechanism to explain the improvement of FSFI demonstrated in the current study after mirabegron administration. Extensive data exists on theβ3-adrenergic receptor subtype of the sympathetic nervous system [31,32]. In a recent study,β3-receptor stimulation caused rat aorta vasorelaxation via the activation of NO synthase and the associated increase of tissue levels of cGMP [33]. Gur et al. [34] demonstrated that mirabegron markedly relaxed isolated human corpus cavernosum (HCC) and rat corpora cavernosa by activatingβ3-adrenoceptors independently of the NO-cGMP pathway. Moreover, Cirino et al. [35] showed that the activation of theβ3-receptors present in human corpus cavernosum elicits a cGMP dependent but NO-independent vasorelaxation which involves the inhibition of the RhoΑ/Rho-kinase pathway and facilitates erectile function. An up-regulation of Rho kinase-β protein in alloxan-induced diabetic rabbit corporal tissue [36] and in the human corpus cavernosum [37] has recently been shown to control corporal smooth muscle contraction induced by endothelin-1. This suggests that the RhoA/Rho kinase pathway plays a mediatory role in increased sensitivity and force generation of corporal smooth muscle. Additionally, β3 receptor-mediated corporal smooth muscle relaxation involves the inhibition of RhoA/Rho-kinase [35]. Smooth muscle relaxation associated with phosphorylation and the resulting inhibition of RhoA is caused by the NO–cGMP signaling pathway mediated by the activation of the cGMP-dependent protein kinase [35,38,39]. As the cGMP-dependent protein kinase is found in human corpora cavernosa, this second mechanism is likely to occur in humans too. It seems, therefore, that the state of human corpus cavernosum tumescence may be regulated by the physiological function of these two pathways. The clitoris is a complex structure that simulates the structure of penis, which is composed of two erectile bodies known as the corpora cavernosa. During sexual arousal, both the clitoris and the labia minora become engorged with blood. In addition, both vaginal and clitoral length and diameter increase. To date, the vascular contributions in FSD remain to be elucidated. The main blood supply to female genital tissue is via the internal pudendal artery (IPA) and clitoral artery (CA). A better understanding of female sexual arousal would be made possible if more was known about both these arteries. Allahdadi et al. [40] demonstrated that internal pudendal artery and clitoral artery are sensitive to the potent vasoconstrictor peptide, endothelin-1. Rho-kinase, however is a key component in endothelin-1 signaling. Furthermore, the inhibition of Rho-kinase in the internal pudendal artery and clitoral artery reduces ET-1-mediated constriction [40]. We may hypothesize that mirabegron, as aβ3-adrenoreceptor agonist, induces relaxation of the corpus cavernosum that may enhance blood flow in the female region-clitoris which might be accompanied by increased stimulation. This proposed mechanism of mirabegron explains our results, in which mirabegron treatment caused statistically significant improvements in arousal, desire, orgasm and satisfaction female sexual function domains, as well as in total FSFI score (Fig.1).Fig. 1Possible mechanism of mirabegron’s effect, used for overactive bladder treatment, on female sexual function. β3- adrenergic receptor activation by mirabegron agonist is coupled to the generation of the second messenger cGMP, which causes human corporal cavernosum smooth muscle relaxation by lowering intracellular levels of free calcium. β3 receptor-mediated corporal smooth muscle relaxation involves inhibition of RhoA/Rho-kinase [34]. The Rho pathway is initiated by ET-1 agonist binding in the GPCR receptor, which activates RhoGEF, facilitating RhoA–GDP conversion to RhoA–GTP. RhoA–GTP binds to ROCK, facilitating autophosphorylation of ROCK that enhances its ability to phosphorylate and deactivate MLCP, promoting vasoconstriction. Relaxation is largely mediated by cGMP, which causes phosphorylation of RhoA, preventing interaction with ROCK and thereby inhibiting vasoconstriction. Endothelin-1-induced contraction of corporal smooth is mediated by an up-regulation of Rho kinase-β protein in alloxan-induced diabetic human corpus cavernosum [36]. Internal pudendal artery and clitoral artery are sensitive to the potent vasoconstrictor peptide, endothelin-1 (ET-1). The inhibition of Rho-kinase in the internal pudendal artery and clitoral artery reduces ET-1-mediated constriction [39].m. Abr. cGMP: cyclic GMP, GPCR: G-protein-coupled receptor, MLCP: myosin light chain phosphatase, RhoGEF: Rho guanine exchange factor, ROCK: Rho-associated protein kinase, sGC: soluble guanylyl cyclase, Y-27632: (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide, ET-1: Endothelin-1 However, the present study has some limitations. Our study had a control group with women not taking mirabegron treatment but there is no placebo group. Thus, there is no evaluation about the effect of placebo on sexual function. It was not possible to use a randomization method since the decision of female patients to receive mirabegron or not, was the reason for being in certain group. Someone could claim that it is a random process of selection although that can by chance lead to disparities. In spite of these limitations, significant results have been obtained, which are of value for clinicians working in this field. | PMC6020185 | Research Article | null | 29,940,933 | The effect of mirabegron, used for overactive bladder treatment, on female sexual function: a prospective controlled study | Zachariou A, Mamoulakis C, Filiponi M, Dimitriadis F, Giannakis J, Skouros S, Tsounapi P, Takenaka A, Sofikitis N. | BMC Urol. 2018 Jun 25;18(1):61. doi: 10.1186/s12894-018-0377-9. | Zachariou A | BMC Urol | 2,018 | 2018/06/27 | PMC6020185 | null | 10.1186/s12894-018-0377-9 | oa_comm/txt/all/PMC6020185.txt | 3a37c058971db58166c4c499a921543d | BMC Urol. 2018 Jun 25; 18:61 | 2021-06-18 17:23:57 | CC BY | no |
['PMC6020185'] | ['29940933'] | [] | Females with OAB should be assessed for their sexual function to provide better quality of life. According to the aforementioned data, OAB treatment with mirabegron improves female sexual function. The above documented improvement in female sexual function might be due to the improvement in the consequences of OAB pathophysiology. However an alternative mechanism may be raised attributing these beneficial effects in the women who received mirabegron treatment to mirabegron action per se. Our study is adherent to CONSORT guidelines. | PMC6020185 | Research Article | null | 29,940,933 | The effect of mirabegron, used for overactive bladder treatment, on female sexual function: a prospective controlled study | Zachariou A, Mamoulakis C, Filiponi M, Dimitriadis F, Giannakis J, Skouros S, Tsounapi P, Takenaka A, Sofikitis N. | BMC Urol. 2018 Jun 25;18(1):61. doi: 10.1186/s12894-018-0377-9. | Zachariou A | BMC Urol | 2,018 | 2018/06/27 | PMC6020185 | null | 10.1186/s12894-018-0377-9 | oa_comm/txt/all/PMC6020185.txt | 3a37c058971db58166c4c499a921543d | BMC Urol. 2018 Jun 25; 18:61 | 2021-06-18 17:23:57 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B1-nutrients-11-00640', 'B2-nutrients-11-00640', 'B3-nutrients-11-00640', 'B1-nutrients-11-00640', 'B4-nutrients-11-00640', 'B5-nutrients-11-00640', 'B6-nutrients-11-00640', 'B7-nutrients-11-00640', 'B8-nutrients-11-00640', 'B9-nutrients-11-00640', 'B10-nutrients-11-00640', 'B11-nutrients-11-00640', 'B12-nutrients-11-00640', 'B13-nutrients-11-00640', 'B14-nutrients-11-00640', 'B15-nutrients-11-00640', 'B16-nutrients-11-00640', 'B17-nutrients-11-00640', 'B18-nutrients-11-00640', 'B19-nutrients-11-00640', 'B6-nutrients-11-00640', 'B20-nutrients-11-00640', 'B21-nutrients-11-00640', 'B22-nutrients-11-00640', 'B23-nutrients-11-00640', 'B24-nutrients-11-00640', 'B25-nutrients-11-00640', 'B26-nutrients-11-00640', 'B27-nutrients-11-00640', 'B28-nutrients-11-00640', 'B29-nutrients-11-00640', 'B30-nutrients-11-00640', 'B31-nutrients-11-00640', 'B32-nutrients-11-00640', 'B33-nutrients-11-00640', 'B34-nutrients-11-00640', 'B22-nutrients-11-00640', 'B35-nutrients-11-00640', 'B27-nutrients-11-00640', 'B29-nutrients-11-00640', 'B36-nutrients-11-00640', 'B37-nutrients-11-00640', 'B38-nutrients-11-00640', 'B39-nutrients-11-00640', 'B40-nutrients-11-00640', 'B41-nutrients-11-00640', 'B42-nutrients-11-00640', 'B36-nutrients-11-00640', 'B40-nutrients-11-00640', 'B43-nutrients-11-00640', 'B44-nutrients-11-00640', 'B45-nutrients-11-00640', 'B46-nutrients-11-00640', 'B47-nutrients-11-00640'] | Cardiovascular disease (CVD) is the leading cause of death worldwide. The annual mortality from CVD is higher than from any other cause [1,2]. In the last 40 years, a rapid increase in the prevalence of cardiovascular diseases has been observed. In 2030, it is estimated that approximately 23.3 million people will die from CVD, which is likely to remain the world’s foremost cause of death [3]. Most cases of CVD, however, are preventable through the reduction of behavioural risks (tobacco use, unhealthy diet, physical inactivity or harmful use of alcohol) [1,4]. Atherosclerosis, which is also known as atherosclerotic vascular disease (ASVD), is one of the most important causes of CVD. The development of atherosclerosis involves a number of pathophysiological mechanisms [5,6], including endothelial dysfunction (ED) [7]. ED, which is greatly underdiagnosed in the general population, plays a pivotal role in the early stages of ASVD, and is later associated with plaque progression and the occurrence of cardiovascular (CV) events [8]. Flow-mediated dilatation (FMD) is an accepted technique to quantify endothelial function and has been shown to have prognostic value to future CV events in symptomatic [9,10] and apparently healthy or asymptomatic subjects [11,12,13]. With regard to blood pressure, it is well known that prehypertension often leads to hypertension [14,15] and an increased risk of CVD and future CV events [16]. Furthermore, the relationship between blood pressure and the risk of CV events is continuous, consistent, and independent of other cardiovascular risk factors [17]. Therefore, the prevention and treatment of hypertension is key for reducing the burden of CV morbi-mortality [18,19]. The role of oxidative stress (OS) in the pathophysiology of CVD is well established [6,20,21]. OS is one of the primary mechanisms involved in the development of ASVD. The circulating level of oxidised low-density lipoproteins (oxLDL) is one of the most important markers in the atherogenic process [22]. These lipoproteins contribute significantly to the development of ASVD, and they not only promote the formation of atherosclerotic plaque [23], but also participate in its progression [24,25,26] and destabilization [27,28,29,30]. This action is carried out through several mechanisms, including the promotion of ED [31,32,33,34]. Consequently, elevated levels of circulating oxLDL are associated with all stages of atherosclerosis, from the peripheral early atherogenesis stage, through coronary artery disease, until acute coronary syndromes and ischaemic stroke [22]. Therefore, the level of circulating oxLDL is a predictor of future CV events in apparently healthy or asymptomatic subjects [35] and in symptomatic subjects [27,29]. Polyphenols are gaining increasing acceptance as therapeutic agents for use in diverse diseases, including CVD [36] and its risk factors [37,38,39,40,41,42]. Several studies have reported an inverse correlation between the consumption of polyphenols and the risk of CV events [36] and overall mortality [40]. Among these compounds, hydroxytyrosol (HT, from olives) [43,44,45] and punicalagin (PC, from pomegranates) [46,47] have been attributed as having cardioprotective properties. The intake of adequate amounts of these bioactive compounds may therefore help reduce the morbidity-mortality associated with CVD. The aim of the present work was to determine the effect of supplementation with HT and PC on endothelial dysfunction and other early atherosclerosis markers in apparently healthy middle-aged subjects. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | [] | The present study was registered athttp://clinicaltrials.govunder the number NCT02042742. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B48-nutrients-11-00640'] | One hundred and five subjects aged 45–65 years were recruited for the present study by the Nutrition Department of La Paz University Hospital (HULP), Madrid (Spain). The inclusion criteria to be eligible for the study were as follows: aged between 45 and 65 years, having a suitable understanding of the clinical trial level, agreeing to voluntarily participate in the study, and signing the informed consent. The exclusion criteria were as follows: a BMI of ≥30 kg/m2; subjects receiving drug treatment for CV risk (dyslipidaemia, hypertension, diabetes mellitus, and others); those who had been diagnosed with metabolic syndrome, who had a mental illness or low cognitive ability; and those who suffered severe liver or kidney disease, or cancer. Subjects were also excluded if they had a family background of premature vascular disease, or if they were taking supplements (antioxidants, ω-3, vitamins, minerals, or probiotics). Women still experiencing menstrual cycles and subjects who planned to stop smoking or lose weight during the study were also excluded, as were subjects who had problems with complying with the general dietary recommendations, those who undertook intensive physical activity, those who consumed >30 g/day alcohol, and those who had allergies to olive and pomegranate by-products. All subjects gave their informed consent to take part in the study, which was approved by the Scientific Research and Ethics Committee of the HULP (Code 3799) in accordance with the ethical standards of the Declaration of Helsinki [48]. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | [] | The study took the form of a randomized, controlled, double-blind, crossover clinical trial lasting 20 weeks. Subjects (n= 84) were randomly assigned (maintaining the gender ratio of the sample) to one of two treatment sequences involving an oral supplementation (9.9 mg of HT plus 195 mg of PC, and 995.1 mg of maltodextrin per day) or a placebo (1.200 mg of maltodextrin per day) for 8 weeks, followed by a 4-week wash-out interval and then a cross-over. During the 8-week intervention period, subjects consumed 3 capsules/day (containing either the oral supplement SAx or the placebo) with their meals. Neither the researchers nor the subjects knew which treatment sequence the subjects had been assigned to; the researchers were unblinded only at the end of the study. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B44-nutrients-11-00640', 'B49-nutrients-11-00640', 'B50-nutrients-11-00640', 'B51-nutrients-11-00640'] | The doses administered in the present work were in agreement with those reported in the literature [44,49,50,51]. Each supplement capsule (SAx) contained 3.3 mg of HT from a standardized olive fruit extract (Mediteanox®, Euromed S.A., Barcelona, Spain), 65 mg of PC from a standardized pomegranate fruit extract (Pomanox®P30, Euromed S.A., Barcelona, Spain), and 331.7 mg of maltodextrin. Each Placebo capsule contained 400 mg of maltodextrin. Probelte Pharma S.A. (Murcia, Spain) prepared the supplement capsules (with specified concentrations of HT and PC) and the placebo capsules specifically for this study. Both types of capsules were packaged in blister packs of 15, and the blister packs were labelled as either L1 or L2 to maintain blinded conditions. Subjects received all the capsules needed to complete the 8-week intervention period (SAx or placebo) during repeat appointments at the HULP. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B52-nutrients-11-00640'] | All subjects were told to maintain their normal dietary habits and not to increase their consumption of foods rich in antioxidants. The diet of each subject was recorded during the week prior to the beginning and end of each intervention period. All food and beverages consumed inside and outside the home were recorded over three consecutive days (including one day of the weekend) [52]. Subjects were instructed to record the weight of the food consumed or, if this was not possible, to record household measurements (spoonfuls, cups, etc.). At each visit, all records were thoroughly reviewed by a nutritionist in the presence of the subject to ensure that the information collected was complete. The energy and nutritional content of the foods and beverages consumed were then calculated using DIAL software (Alce Ingeniería, Madrid, Spain). | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B53-nutrients-11-00640'] | Anthropometric measurements were taken at the beginning and end of each intervention period using standard techniques, adhering to international norms set out by the WHO [53]. All measurements were made by trained personnel in the morning with the subject barefoot and wearing only underwear. Body composition was determined using a specialized bioelectrical impedance analyser, the EFG ElectroFluidGraph analyser (Akern s.r.l., Florence, Italy). Height was determined using a height meter with an accuracy of 1 mm (range, 80–200 cm). BMI was calculated using the following formula: [weight (kg)/height (m)2]. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | [] | Information was collected on medical conditions and the consumption of medications. Blood pressure and heart rate were measured on the right arm using a Spot Vital Signs 420 automatic monitor (Welch Allyn, Madrid, Spain) (accuracy ±5 mmHg). Three measurements were taken at 5-min intervals, and the means were calculated. Populations were classified according to whether the subjects exhibited prehypertension or high blood pressure that was non-diagnosed and was not being treated pharmacologically. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B9-nutrients-11-00640', 'B10-nutrients-11-00640', 'B11-nutrients-11-00640', 'B12-nutrients-11-00640', 'B13-nutrients-11-00640', 'B54-nutrients-11-00640', 'B55-nutrients-11-00640'] | Flow-mediated dilatation (FMD) in the brachial artery was used as an indicator of endothelial function. FMD has been shown to be an independent predictor of CV events [9,10], even in apparently healthy subjects [11,12,13]. Measurements were performed based on recommendations described in published guidelines [54] using a Doppler ultrasound device with a 10-MHz linear probe (Biosound MyLab 25 Portable Ultrasound System, Esaote, Genoa, Italy). Briefly, the subject lay in the supine position in a room at 20–22 °C. A sphygmomanometer cuff was positioned just below the axilla, and the Doppler probe was placed 3 cm above the right elbow (with the arm extended) at an angle of 60 °. After a 10-min resting period, basal capillary flow was measured (t0). Thereafter, distal ischaemia was induced for 5 min by inflating the cuff to a pressure of 250 mmHg. The cuff was then deflated and, after 70 s, the flow was recorded (td). All images were captured by the same qualified operator. All variables were measured in triplicate, and their means were calculated. The area under the curve (AUC) for t0 and td was then determined. The FMD was calculated using the following equation: FMD = (AUCtd − AUCt0) × 100/AUCt0, and the subjects were classified according to the presence or absence of ED (ED = FMD < 10%) [55]. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B56-nutrients-11-00640', 'B57-nutrients-11-00640', 'B58-nutrients-11-00640'] | At the beginning and end of each intervention period, blood samples were collected early in the morning at the La Paz University Hospital Extraction Unit. Samples were kept at 4–6 °C until analysis, which was always performed within 48 h. The concentration of plasma-soluble vascular cell adhesion molecule-1 (sVCAM-1) was determined using a Luminex®200TMmultianalyte profiling system and commercially available immunoassay panels in the HCVD2MAG-67K Milliplex Map Kit (EMP Millipore Corp., Boston, MA, USA). Plasma Ox-LDL levels were measured using ELISA with human apoB-100 modified by Malondialdehyde (MDA-LDL) (Immundiagnostik AG, Bensheim, Germany). Total plasma lipid peroxides were measured using the thiobarbituric acid reactive substances (TBARS) method [56]. Plasma antioxidant capacity was analysed using a ferric reducing antioxidant power (FRAP) assay [57]. Quantitative measurements of Paraoxonase-1 (PON-1) were made using a Human Serum PON-1 ELISA Kit (Aviscera Bioscience, Santa Clara, CA, USA). Plasma 8-isoprostanes (8-iso-PGF2α) was measured using an OxiSelectTM8-iso-PGF2αELISA kit (Cell Biolabs, San Diego, CA, USA). Nitrate/Nitrite (NOx) was analysed in plasma using a commercially available colorimetric assay kit (Cayman Chemical Company, Ann Arbor, MI, USA) according to the Griess method [58]. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | [] | Subjects received the exact number of capsules (in blister packaging) required for each intervention period during a pre-period appointment, and they were asked to return all empty and non-empty blister packages. Compliance was measured at the middle of each intervention period during an interview and at the end of each intervention period by comparing the number of capsules provided and the number returned. A subject was considered compliant when he/she consumed ≥90% of the capsules provided. Adverse events were recorded on the final visit of each intervention period. An adverse event was defined as any unfavourable, unintended effect. All such events were recorded along with the symptoms involved (nausea, vomiting, diarrhoea, and constipation). | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B59-nutrients-11-00640'] | A sample size of 38 patients was calculated as the sample size that was necessary to provide 90% power (at α = 0.05) to determine an absolute difference of 2% in FMD [59] (potential 20% dropout included). Quantitative data are presented as the means ± standard deviations (SD). Qualitative data are presented as counts and percentages. The Kolmogorov–Smirnov test was used to determine whether the data were normally distributed. Levene’s test was used to assess the equality of variance. The denominator degree of freedom was approximated using the Satterthwaite formula. The type class variables considered in the primary model included the treatment, period, treatment × period interaction, risk, and the treatment × risk interaction; these variables were added as fixed effects. The type class variables considered in the second model included the start–end, treatment, start–end × treatment interaction, period, treatment × period interaction, start–end × treatment × period interaction, the risk, treatment × risk interaction, and the start–end × treatment × risk interaction; these variables were added as fixed effects. For both models, the subject was considered in sequence as a random effect and a “variance components” covariance matrix. The type III tests of fixed effects table lists the hypothesis tests for the significance of each of the fixed effects specified in both models; in particular, the carryover effect was assessed in the primary model by the treatment × period interaction effect. If the carryover effect was significant for a given variable, then only the first period was considered for the analysis. Least squares means of the primary model were computed and compared for the treatment and the treatment × risk interaction variables. Least squares means of the second model were computed and compared for the treatment × start–end interaction and the start–end × treatment × risk interaction. Multiple comparisons were adjusted using the Bonferroni method. Two-sided tests were used, and ap-value < 0.05 was considered statistically significant. Statistical analyses were performed using the linear mixed model in the SAS statistical software package, version 9.3 (SAS Institute Inc., Cary, NC, USA). | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['nutrients-11-00640-f001'] | The study was performed between February and June 2013. Eighty-four apparently healthy subjects (17 men [20.2%], 67 women [79.8%]) were eligible for inclusion. Seventeen subjects were lost to follow-up (8 in the placebo/SAx sequence and 9 in the SAx/placebo sequence) due to personal causes (n= 15) and failure to follow treatment instructions (n= 2). Thus, 67 subjects (14 men [20.9%], 53 women [79.1%]) completed the 20-week study, and only their results were included in the subsequent analyses (Figure 1). | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['nutrients-11-00640-t001'] | The mean age of the population was 53.0 ± 4.5 years old. The mean BMI was 24.6 ± 3.1 kg/m2. At the start of the study, no significant differences existed between subjects assigned to the supplementation (SAx) and placebo sequences in terms of their anthropometric, vascular function, oxidative status, and other variables (gender, age, and smoking) (Table 1). | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['nutrients-11-00640-t002'] | No significant differences were detected in any dietetic or anthropometric variables between the start and end of the intervention periods, nor between the periods in terms of changes in these variables (Table 2). | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['nutrients-11-00640-t003', 'nutrients-11-00640-f002'] | Table 3shows the values of the vascular function variables examined. A significant reduction in systolic blood pressure (SBP) was observed at the end of the SAx period (SAx period—start 111.3 ± 12.9, end 101.9 ± 12.0 mmHg,p< 0.001). The reduction in SBP observed after the supplementation treatment was significantly greater than that recorded for the placebo treatment (SAx −9.42 ± 10.3 vs. placebo −2.79 ± 11.2 mmHg,p< 0.05). After the SAx treatment, subjects with systolic prehypertension or hypertension exhibited significantly decreased SBP (SAx period—start 123.9 ± 4.2, end 108.2 ± 10.8 mmHg,p< 0.001); no such significant reduction was observed at the end of the placebo period (from 129.8 ± 2.8 to 127.2 ± 10.4 mmHg). In addition, in these subjects with systolic prehypertension or hypertension, the reduction in SBP that was observed following the SAx treatment was significantly greater than that recorded for the placebo treatment (SAx −15.75 ± 9.9 vs. placebo −2.67 ± 12.0 mmHg,p< 0.05). A significant reduction in diastolic blood pressure (DBP) was also observed at the end of the SAx period (from 74.34 ± 10.1 to 71.60 ± 10.4 mmHg,p< 0.001); no such significant reduction was observed at the end of the placebo period (from 72.68 ± 10.1 to 71.42 ± 9.7 mmHg). These improvements were observed as well in the subgroup of diastolic prehypertension and hypertension after SAx treatment (from 84.4 ± 6.5 to 78.04 ± 10.8 mmHg,p< 0.001); no such improvement was observed after the placebo period (from 83.0 ± 5.6 to 79.9 ± 8.8 mmHg, NS). Subjects with normal blood pressure remained stable. Significant differences were also observed in the FMD between the start and the end of the SAx period (from 8.04 ± 4.0 to 9.46 ± 4.0%,p< 0.05); no such improvement was observed for the placebo period (from 8.08 ± 3.3 to 8.62 ± 4.0%, NS). In subjects with ED, a significant increase in FMD was observed after the SAx period (from 6.57 ± 2.9 to 8.93 ± 3.8%,p< 0.001) but not after the placebo period (from 6.54 ± 2.3 to 7.30 ± 3.4%, NS). The increase in FMD that was observed following the SAx treatment was significantly greater than that recorded for the placebo treatment (SAx 2.36 ± 3.9 vs. placebo 0.76 ± 3.5 %,p< 0.05) (Figure 2). No significant changes in FMD were observed in subjects without ED in either intervention period (SAx from 10.86 ± 4.5 to 10.70 ± 4.2%; placebo from 11.16 ± 2.9 to 11.26 ± 3.7%). No differences were recorded in heart rate (HR) or soluble sVCAM-1 in any comparison. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['nutrients-11-00640-t004'] | Table 4shows the values of the oxidative status variables recorded. Circulating oxLDL levels were reduced significantly after the SAx period (from 108.9 ± 126.2 to 97.44 ± 121.7 ng/mL,p< 0.05); however, no significant reduction was recorded after the placebo period (from 98.86 ± 128.1 to 105.9 ± 139.9 ng/mL). The reduction in oxLDL observed after the SAx treatment was significantly greater than that recorded for the placebo treatment (SAx −11.46 ± 28.1 vs. placebo 7.05 ± 55.6 ng/mL,p< 0.05). In subjects with higher levels of oxLDL, these levels were reduced significantly after the SAx treatment (from 258.2 ± 138.0 to 229.5 ± 149.5 ng/mL,p< 0.05); no significant reductions were observed after the placebo period (from 235.4 ± 162.5 to 261.0 ± 170.8 ng/mL). In these subjects, the reduction in oxLDL that was observed following the SAx period was significantly greater than that recorded for the placebo treatment (−28.74 ± 40.2 vs. 25.64 ± 93.8 ng/mL,p< 0.001). No significant differences were observed for the remaining variables. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | [] | All subjects ingested >90% of the capsules provided. No significant differences were observed in the number of capsules consumed between the different intervention periods or treatment sequences. No adverse events resulting from the intake of either type of treatment capsule were reported. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | ['B43-nutrients-11-00640', 'B44-nutrients-11-00640', 'B45-nutrients-11-00640', 'B60-nutrients-11-00640', 'B61-nutrients-11-00640', 'B46-nutrients-11-00640', 'B47-nutrients-11-00640', 'B24-nutrients-11-00640', 'B25-nutrients-11-00640', 'B26-nutrients-11-00640', 'B27-nutrients-11-00640', 'B28-nutrients-11-00640', 'B60-nutrients-11-00640', 'B62-nutrients-11-00640', 'B63-nutrients-11-00640', 'B9-nutrients-11-00640', 'B10-nutrients-11-00640', 'B11-nutrients-11-00640', 'B12-nutrients-11-00640', 'B13-nutrients-11-00640', 'B55-nutrients-11-00640', 'B55-nutrients-11-00640', 'B55-nutrients-11-00640', 'B41-nutrients-11-00640', 'B47-nutrients-11-00640', 'B62-nutrients-11-00640', 'B64-nutrients-11-00640', 'B31-nutrients-11-00640', 'B41-nutrients-11-00640', 'B16-nutrients-11-00640', 'B65-nutrients-11-00640', 'B66-nutrients-11-00640', 'B18-nutrients-11-00640', 'B19-nutrients-11-00640', 'B39-nutrients-11-00640', 'B67-nutrients-11-00640', 'B68-nutrients-11-00640', 'B40-nutrients-11-00640', 'B44-nutrients-11-00640', 'B67-nutrients-11-00640', 'B69-nutrients-11-00640', 'B70-nutrients-11-00640', 'B71-nutrients-11-00640', 'B69-nutrients-11-00640', 'B40-nutrients-11-00640', 'B44-nutrients-11-00640', 'B44-nutrients-11-00640', 'B45-nutrients-11-00640', 'B72-nutrients-11-00640', 'B67-nutrients-11-00640', 'B67-nutrients-11-00640', 'B70-nutrients-11-00640', 'B71-nutrients-11-00640', 'B73-nutrients-11-00640', 'B74-nutrients-11-00640', 'B31-nutrients-11-00640', 'B35-nutrients-11-00640'] | This is the first clinical trial to study the effect of the regular intake of a supplement rich in HT and PC on early atherosclerosis markers in middle-age subjects. The consumption of three capsules per day containing HT and PC (9.9 mg of HT and 195 mg of PC) for 8 weeks significantly improved endothelial function and blood pressure and reduced LDL oxidation in middle-aged subjects. These improvements were observed primarily in subjects who were at risk of developing cardiovascular disease. No adverse effects were observed. Several studies have shown that HT [43,44,45,60,61] and PC [46,47] possess cardioprotective properties that may reduce the risk of developing CVD. However, most of these studies were performed in vitro or with experimental animals [24,25,26,27,28]; some studies have investigated the effects of these compounds in humans [60,62], and no studies have examined the combined effect of HT and PC. The present results reveal a significant improvement in FMD among subjects with ED. One of the major objectives of a CVD detection programme must be to identify those apparently healthy subjects who have asymptomatic arterial disease; such identification may reduce the risk, delay the onset, and perhaps even induce the regression of atherosclerotic disease. The importance of new imaging methods for the detection of subjects at a high risk for suffering CV events has been recognized [63]. FMD is a non-invasive imaging technique that is accepted for quantifying endothelial function; in addition, FMD is the most widely used technique for testing endothelial function. FMD has been shown to have prognostic value for predicting future CV events in symptomatic subjects [9,10] and apparently healthy or asymptomatic subjects [11,12,13]. In fact, Kuvin et al. [55] observed that FMD measurements of the brachial artery were highly predictive of CVD, with an increase in the odds ratio of 1.32 for each percentage decrease in FMD below 10% [55]. The FMD also has a significant potential as a screening tool for CVD in individuals with an apparent low CV risk assessed by traditional risk factors [55]. The improvement in endothelial function from HT, PC, or foods rich in these compounds has been observed in many studies [41,47,62,64]. In addition, some authors suggest a possible inverse relationship between FMD and oxLDL levels [31,41]. In the present study, simultaneous improvements in FMD and oxLDL were observed. It therefore appears that subjects with ED could benefit from supplementation with HT and PC, even if they are not diagnosed. In this regard, there remains a high prevalence of undiagnosed ED. Indeed, in this study of apparently healthy subjects, the percentage of subjects who were eventually diagnosed with ED reached 69.2%. In subjects with ED, these benefits could potentially help to reduce their risk of CVD and the future burden they may pose to the health system. In the present work, SBP and DBP significantly improved in the total population after intake of the supplement for 8 weeks. However, this effect was observed primarily in subjects suffering from prehypertension or hypertension. This finding is important because, in addition to hypertension, prehypertension also increases the risk of CVD and CV events [16]. Hypertension is usually inadequately controlled [65], and antihypertensive drugs can produce adverse effects that often lead to patient abandonment [66]. Therefore, the prevention and treatment of hypertension is key for reducing the burden of CV morbi-mortality [18,19]. In this context, various studies in which HT or PC were provided via functional foods or foods rich in these compounds also reported significant improvements in blood pressure [39,67]. Even the European Medicines Agency (EMA) recognized the hypotensive activity of olive leaf; however, the EMA mentioned that there are not sufficient data from well-designed clinical trials to support this indication [68]. Therefore, the present study contributes additional evidence suggesting that the hypotensive action after the consumption of foods, functional foods, or supplements containing HT or PC (or both) may help regulate blood pressure. On the other hand, numerous studies have reported a reduction in oxLDL levels after the intake of foods rich in HT or PC [40,44,67,69,70,71]. In a crossover clinical trial in healthy subjects, it was reported that the consumption of 25 mL/day virgin olive oil (~3.75 mg/day phenolic compounds) for 3 weeks significantly reduced plasma oxLDL levels [69]. In the EUROLIVE study, a crossover clinical trial in healthy subjects reported that the consumption of 25 mL/day high-phenolic-content virgin olive oil (366 mg/L phenolic content) for 3 weeks induced a greater reduction in oxLDL levels compared with olive oils with a lower phenolic content [40]. In this regard, the EFSA recognized a cause and effect relationship between the daily consumption of 5 mg of HT and its derivatives from olive oil and the protection of c-LDL particles from oxidative damage [44]. The results of the present work are in line with these studies regarding HT as a protection strategy against c-LDL oxidative damage [44]. One mechanism through which HT may reduce oxLDL levels is by modulating the expression of genes involved in atherogenesis [45,72]. Other authors have reported that the long-term consumption of 50 mL/day pomegranate juice (~85 mg of PC) significantly reduces oxLDL levels in patients with carotid artery stenosis [67]. PC may provide this benefit through a direct antioxidant effect on c-LDL, by increasing serum PON-1 levels, and/or by reducing the capacity of macrophages to oxidize c-LDL [67,70,71]. However, in the present work, although supplementation with HT and PC reduced the formation of oxLDL, no change was observed in serum PON-1 levels or, indeed, in any other oxidative status variables (TBARS, FRAP, 8-iso-PGF2α, and NOx). This discrepancy may be explained by the fact that previous studies have involved subjects with CVD-related pathologies, whereas the subjects in the present study were apparently healthy. Similarly, PON-1 activity has been observed to be decreased in subjects with diabetes [73] but not in those with pre-diabetes or a new diagnosis of diabetes [74]. A high level of circulating oxLDL is a marker of ED [31] and a predictor of future CVD events in apparently healthy or asymptomatic subjects [35]. Therefore, the regular intake of supplements containing both HT and PC, which reduce the formation of oxLDL in subjects with elevated oxLDL levels, may help to reduce the CV risk in these subjects. One possible limitation of this study is the sample size. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6470561'] | ['30884808'] | [] | In summary, the consumption of a supplement containing HT and PC (9.9 mg of HT and 195 mg of PC per day) for 8 weeks could help reducing c-LDL oxidation and improved SBP, DBP, and FMD in middle-aged subjects. These improvements in FMD, blood pressure, and circulating oxLDL levels were most pronounced in subjects with alterations in these atherosclerotic markers. Therefore, the regular intake of a supplement containing HT and PC may reduce the risk of CV in these subjects. Further clinical trials are warranted to confirm the beneficial effect of these polyphenols in humans. | PMC6470561 | Article | null | 30,884,808 | Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial | Quirós-Fernández R, López-Plaza B, Bermejo LM, Palma-Milla S, Gómez-Candela C. | Nutrients. 2019 Mar 16;11(3):640. doi: 10.3390/nu11030640. | Quirós-Fernández R | Nutrients | 2,019 | 2019/03/20 | PMC6470561 | null | 10.3390/nu11030640 | oa_comm/txt/all/PMC6470561.txt | 4880ef8e074ed82ab40c9b22d3284a61 | Nutrients. 2019 Mar 16; 11(3):640 | 2021-06-19 03:48:10 | CC BY | no |
['PMC6051678'] | ['29924768'] | ['B1', 'B2', 'B3', 'B4', 'B5', 'B5', 'B6', 'B4', 'B5', 'B7', 'B8', 'B9'] | Since the discovery of adult mesenchymal stem cells (MSCs), extensive research has been conducted to determine their mechanisms of differentiation and effectiveness in cell therapy and regenerative medicine. MSCs can be isolated from several cell extracts, and some of the most accessible extracts are from the oral cavity (OMSCs). These have been isolated from deciduous teeth, dental follicle, apical papilla, periosteum, dental ligament (LMSCs) and dental pulp (PMSCs) (1-2). MSCs are multipotent stromal cells that can be safely cryopreserved, used with several scaffolds, and extensively proliferate. They have long lifespans and can build in vivo adult bone with Havers channels and the appropriate vascularisation (3). Importantly, they can avoid the isolation, differentiation, expansion, and proliferation required in previous cell culture methods, which were not compatible with clinical practice due to the extensive manipulation of pulp tissue and its lengthy preparation process. To facilitate clinical management, the Rigenera Protocol (Human Brain Wave srl, Torino, Italy) allows the production of adult mesenchymal stem cells from a minimum quantity of connective tissue of adult dental origin. A medical device, Rigenera Machine®, and Rigeneracons® sterile filters can disaggregate dental tissue and perform the filtering necessary to promote the expulsion of older differentiated cells and the enrichment of younger progenitor cells present within LMSC (4) and PMSC (5) populations. In this approach, the dental tissue experiences a phase of collection, foll-owed by mechanical disaggregation, filtering of the MSC cell suspension, and immediate application to clinical practice (5). This technical procedure neither expands nor manipulates the resulting cells. They constitute autologous tissues, such that the patient can be both donor and recipient (6). A large gap between basic and translational research publications is present in the literature regarding OMSCs, with very few reports of clinical trials and clinical cases of bone or periodontal repair with LMSCs (4), PMSCs (5,7,8), and MSC derivatives of periosteum (9). To characterise the regenerative potential of autologous dental pulp mesenchymal stem cells (ADPMSCs) with the Rigenera® Protocol, we designed an independent, randomised, split-mouth clinical trial. We compared the bone healing efficacy of ADPMSCs, delivered in a resorbable collagen matrix, when implanted in impacted inferior third molar (ITM) post-extraction sockets (experimental group, EG) against the bone healing response of the alveolar sockets of the contralateral impacted ITM in which only collagen matrix is implanted (control group, CG). We tested the null hypothesis that bone healing in the EG and CG behaves similarly, with a maximum difference in proportions of 0.4. | PMC6051678 | Research; Oral Surgery | null | 29,924,768 | Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: A split-mouth randomised clinical trial | Barbier L, Ramos E, Mendiola J, Rodriguez O, Santamaria G, Santamaria J, Arteagoitia I. | Med Oral Patol Oral Cir Bucal. 2018 Jul 1;23(4):e469-e477. doi: 10.4317/medoral.22466. | Barbier L | Med Oral Patol Oral Cir Bucal | 2,018 | 2018/06/21 | PMC6051678 | null | 10.4317/medoral.22466 | oa_comm/txt/all/PMC6051678.txt | 332875d8062e740e887396f015f70492 | Med Oral Patol Oral Cir Bucal. 2018 Jul 21; 23(4):e469-e477 | 2021-06-18 17:29:13 | CC BY | no |
['PMC6051678'] | ['29924768'] | ['B10', 'F1', 'F2', 'B11', 'B11', 'F3', 'F1', 'F2'] | We designed an independent, single-centre, double-blind, randomised, split-mouth controlled clinical trial. The trial was approved by the Ethical Committee of Clinical Investigation of Cruces University Hospital (Protocol number EC20141) and registered on the EudraCT database (number: 2014-001913-18). It was conducted in compliance with current legislation, the ethical principles of the Declaration of Helsinki, and good clinical practice. We included patients with ages ranging from 18 to 30 years who attended the outpatient clinic of the Department of Maxillofacial Surgery at our hospital. For all patients, bilateral extractions of impacted mandibular third molars for mechanical reasons were indicated. Patients with systemic diseases, risk factors for bacterial endocarditis, recurrent oral diseases, septic mouth, an infectious process, or who had undergone antibiotic treatment within 10 days of extraction were excluded from the study. Allergic patients, patients with known intolerance to any study medication, and pregnant or lactating women were also excluded from the study. Patients who showed cysts in radiographic images of either ITM, and those with possible roots in the inferior dental canal, were also excluded. All excluded patients were removed prior to randomisation. Patients who chose to drop out of the clinical trial, as well as those who were not followed-up, were excluded post-randomisation. Sample size was calculated prior to the start of the study with the statistical software STATA 14 (StataCorp LP, College Station, TX, USA). Based on previous research studies, we assumed that post-extraction physiological bone resorption may reach 50% (10); thus, we considered it clinically relevant to assess whether resorption could be reduced to 10% by using the proposed ADPMSC treatment. A sample of 30 patients was required to compare the hypothesis with a 1-type error of 0.05 and 80% power for a difference in proportions of ≥0.4, assuming possible losses of 10% (33 patients). Consecutive patient sampling was performed. Patients who met the inclusion criteria were asked to sign the informed consent form in order to participate in the clinical trial. Extraction sockets assigned to the EG were treated with ADPMSC, prepared according to the Rigenera® Protocol, incorporated into an absorbable lyophilised collagen matrix Hemo-Klee® (Directive 93/42 EEC. Euroklee S.L. Cerdañola del Valles Barcelona, Spain), whereas those assigned to the CG were treated with collagen matrix alone. The decision of which socket (left or right) received the ADPMSC treatment was made with codes generated by an independent professional, who used randomisation software. The independent professional concealed the allocations in sealed and sequentially numbered envelopes. A maxillofacial surgeon (MS1) performed the standardised procedure for both third molar extractions. A second maxillofacial surgeon (MS2) prepared and implanted ADPMSCs in the EG and collagen matrix in the CG, then sutured the flaps. MS2, who did not participate in the analysis of the results, was the only non-blinded researcher in this study. To assess the bone repair achieved, at 6 months after ITM extraction, two CT scans were performed (Philips Brilliance 16; Philips HealthSystems, Amsterdam, Netherlands): one on the day of the surgery (t0) and the other 6 months later (t6). Socket density (in Hounsfield units, HU) and resorption response (in height, mm, of the interdental distal septum to the second molar) were assessed. Response variables were bone density (BDD) and bone resorption (BRS). BDD was assessed by subtracting the final average socket density (measured in a region of interest in the lower half of the socket at t6) from the initial average density measured in the same area at t0 (Fig.1). Figure 1Top image t0 in multiplanar format, with windows for bone density assessment in intact post-extraction sockets. Average densities are measured in the lower half of both sockets. Bottom image t6, with alveolar repair on both sides. BRS was assessed by calculating the mean height (mm) of the interdental distal septum to the second molar at 6 months and the mean height recorded immediately after the extraction (Fig.2). Figure 2Results at day t0. Images in multiplanar format with windows for bone density assessment. Measurements of left post-extraction cavity were made in the three planes, represented by the area in red colour. -Procedure During the first contact with patients who could be recruited for the clinical trial, MS1 studied possible candidates. Bilateral impaction of both ITM and gingival coverage (enabling flap closure without tensions) were confirmed radiologically and clinically, respectively. The inexistence of any possible reason for exclusion was assessed in the clinical history. Patients were provided with information regarding the surgical procedure and clinical trial. The informed consent form was explained to them and they were each provided with a copy. During the second visit, the surgical procedures were performed after repeat confirmation that patients met the inclusion criteria and had signed the informed consent form. Patients were then assigned a sequential patient number. During this second appointment, we also recorded data regarding demographic, clinical, radiological, and surgical variables. Demographic variables included age (corresponding to the age of the patient on the day of the intervention), sex (male or female), and ethnicity (Caucasian, Black, Asian, others) of patients. Clinical and radiological variables included the use of contraceptives (response: yes or no) in the last month, the use of psychotropic drugs (response: yes or no) and whether they were taken in the last month, and tobacco smoking (expressed as number of cigarettes per day at the time of the intervention). After the local anaesthetic nerve block was performed, a millimetre periodontal probe (SM 13 Bontempi®) of thickness 0.5–11.5 mm was used to record the depth (mm) at three points distal to the second molar in both ITMs. The ITM was classified as type I when the crown showed no bone coverage on radiographic analysis and clinical analysis showed that the gingival coverage would allow flap closure without tensions; as type II when the crown was partly covered by bone and gum; and as type III when the third molars were fully covered by bone and gum. The angulation and depth of the impacted mandibular third molars were determined by using the classifications of Pell & Gregory and Winter (11). All operations were performed by the same maxillofacial surgeon (MS1) with a standardised procedure for both third molars, beginning on the right side in all cases. The mouth was previously rinsed with for 20 sec with Lacer® 0.12% chlorhexidine mouthwash (Lacer S.A. Cerdañola del Vallés, Barcelona, Spain). Local and regional anaesthesia were performed with 3.6 ml articaine (Ultracain®; Normon S.A. Tres Cantos, Madrid, Spain) and epinephrine (40/0.01 mg/mL) for blocking inferior alveolar and buccal nerves. A full thickness mucoperiosteal flap was elevated and reflected. The incision was made with a No. 15 surgical scalpel blade, forming an envelope flap that extended from the mesial aspect of the second molar to the ramus, with lateral divergence of the posterior extension. Bone removal and tooth sectioning were performed by using a hand piece with a round bur and saline irrigation. After the extraction, the sockets were debrided and necrotic tissue was removed. The area was irrigated with 3 ml 0.12% Lacer® chlorhexidine and saline solution for 1 min (11). MS1, who performed the extractions, did not consider which groups (EG or CG) patients belonged to. Subsequently, after extracting each ITM, MS2 placed the ITM in a tray with sterile gauze soaked in 0.12% chlorhexidine for 2 min. By using a round bur, hand piece, and saline irrigation, an indentation was made in the enamel-cementum line, which gradually became a groove. When the groove was sufficiently deep, odontosection of the molars was completed by pressing with a chisel, thereby providing access to the pulp chamber. The pulp from both pulp chambers was collected with a sterile curette and deposited in a Rigeneracons® capsule; then, 1 mL saline solution was added. The capsule was agitated for 1 min in the Rigenera® Machine. MS2 collected the PMSC suspension by aspiration with a syringe, incorporated it into the collagen matrix Hemo-Klee®, left it standing for 8 min, and implanted it in the left or right socket after opening the randomisation envelope. The collagen matrix was exclusively implanted contralaterally with 1 mL saline solution. Lastly, flap closure was performed with a 3/0 absorbable suture, ensuring complete flap closure to avoid alveolar permeability. An Augmentine® 875/125 mg tablet (GlaxoSmithKline S.A. Tres Cantos, Madrid, Spain) was prescribed to all patients 1 h before the extractions. They also received a prescription of one tablet every 8 h for another 5 days to limit possible infectious and inflammatory complications. All patients were administered Enantyum® 25 mg film-coated tablets (Menarini SA, Badalona, Barcelona, Spain) every 8 h until complete remission of pain, and performed rinsing with Lacer® 0.12% chlorhexidine mouthwash every 8 h for 7 days. Surgical variables recorded include the surgical time, tooth sectioning, and ostectomy. Surgical time was measured by using a stopwatch from the first incision until the last suture was completed. Tooth sectioning was recorded as yes or no. No pulp cavity was invaded during the extraction. With regards to ostectomy, a score of 0 was assigned when ostectomy was unnecessary; 1/3 was assigned when ostectomy was necessary to uncover the crown; and 2/3 was assigned when ostectomy was performed to uncover the crown and part of the root. Written postoperative instructions were distributed. A 24-hour telephone number and a clinical trial participation card were also provided. Immediately after the extractions, multi-slice CT scanning without contrast was performed with the Phillips Brilliance 16-slice CT scanner (Phillips, Amsterdam, Netherlands) at the Department of Radio-logy, with low energy, low power, and an exposure time of seconds with high image quality. The following technical characteristics were used: 1 mm slice thickness, 16 × 0.75 degree of collimation, 178 mm field of view (FOV), 512 × 512 matrix, 90 kV dose, 100 mAs, Level iDose 3, 6 mGy volume CT dose index (CTDI), according to the standard “As low as reasonably achievable.”ALARA. From this CT scan, two neuroradiologists, who did not know whether the socket was for a patient in the EG or CG, independently made the following measurements with the advanced analysis platform IntelliSpace Portal (Phillips, Amsterdam, Netherlands). 1.- Residual volume of both extraction sockets (mm3) on the day of extraction t0: three diameters, namely the latero-lateral (LL), anteroposterior (AP), and craniocaudal (CC) diameters, were measured. The volume was calculated by using the formula LL × AP × CC/2 (Fig.3). This volume was used to analyse the homogeneity between the CG and EG. Figure 3Distal interdental septum of the second molar at t0 and t6. Images acquired by using bone windows. Measurement of distal interdental septum height (mm) in second molars at the times t0 and t6. 2.- Density (HU) of the residual sockets: this was assessed by using the mean of measurements taken in one region of interest (Fig.1). 3.- Bone resorption: This was assessed by measuring the height (mm) from the occlusal plane to the highest point of the interdental septum distal to the second molar (Fig.2). During the third appointment, at 6 months after the intervention, a second CT scan was performed, in the same manner as the original scan. Both neuroradiologists, who did not know which sockets were treated with the ADPMSC suspension, independently assessed the variable response, including the density (HU) of the regenerated alveolus and the bone resorption of the interdental septum distal to the second molar (mm). The values of the clinical, demographic, radiological, and surgical variables of the 64 ITMs from the CG and EG were recorded in an Excel spreadsheet. The values assessed by each neuroradiologist for each measurement, immediately after the surgery (t0, volume, density, and height) and 6 months after the surgery (t6, density and height) were also recorded. Adverse events were recorded. Quantitative variables were assessed by their mean values while qualitative variables were assessed by calculating absolute frequencies. The homogeneity of ITM characteristics from the CG and EG were assessed by chi-squared tests, Fisher’s exact tests, and analysis of variance, depending on the nature of the variables (qualitative or quantitative). Inter-observer agreements (between neuroradiologists 1 and 2) of variables (volu-me, density, and height) recorded immediately after the surgery, and of response variables BRS and BDD, were assessed by using the mean Kendall rank correlation coefficient. To analyse the response variables BRS and BDD, we assessed fit-to-normality with the Shapiro-Wilk Test. We tested the null hypothesis of no difference in reparative response between the EG and CG, by using the t-test when the variable followed a normal distribution, and by Mann-Whitney U test when the variable did not follow a normal distribution. Significance level was pre-set to 0.05. Stata14 (StataCorp LP, College Station, TX, USA) was the statistical software used. | PMC6051678 | Research; Oral Surgery | null | 29,924,768 | Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: A split-mouth randomised clinical trial | Barbier L, Ramos E, Mendiola J, Rodriguez O, Santamaria G, Santamaria J, Arteagoitia I. | Med Oral Patol Oral Cir Bucal. 2018 Jul 1;23(4):e469-e477. doi: 10.4317/medoral.22466. | Barbier L | Med Oral Patol Oral Cir Bucal | 2,018 | 2018/06/21 | PMC6051678 | null | 10.4317/medoral.22466 | oa_comm/txt/all/PMC6051678.txt | 332875d8062e740e887396f015f70492 | Med Oral Patol Oral Cir Bucal. 2018 Jul 21; 23(4):e469-e477 | 2021-06-18 17:29:13 | CC BY | no |
['PMC6051678'] | ['29924768'] | ['T1', 'T2', 'T3'] | Recruitment began in March 2015. The first patient underwent extractions in May 2015 and the last patient underwent extractions in February 2017. In total, 32 patients were recruited; two were excluded because they were unable to undergo a CT scan at 6 months after the extraction. The final sample consisted of 30 patients and 60 molars (30 in the EG and 30 in the CG). Because this was a split-mouth study, demographic variables were identical for the ITMs from the EG and CG. The patients were Caucasian, eight men and 22 women. Their mean age was 23 years (range: 18–30 years). Seven patients were taking contraceptives, one was undergoing treatment with psychotropic drugs, four patients smoked < 10 cigarettes per day, and five smoked 10–20 cigarettes per day. No significant differences in clinical, radiological, and surgical characteristics of ITMs were found between the CG and EG (Table 1). We concluded that there was an agreement between the independent observations of the two neuroradiologists in the records analysed (Table 2). We analyse the normality-adjusted values of response variables, BDD and BRS, assessed by both neuroradiologists. Bone repair, in terms of BDD and BRS, showed no significant differences between the control and experimental groups, either when analysing density (BDD:p=0.4203 neuroradiologist 1;p=0.2525 neuroradiologist 2) or when analysing the interdental septum height (BRS:p=0.2280 neuroradiologist 1;p=0.4784 neuroradiologist 2) (Table 3). Table 1Homogeneity between study groups. Table 2Inter-observer agreement in this study. Table 3Analysis of the response variable, density, and height between the experimental group with autologous dental pulp mesenchymal stem cells (ADPMSCs) and the control group without ADPMSCs. No morbidity was observed during the clinical trial, and no information was gathered from other studies that discouraged continuation of the trial. | PMC6051678 | Research; Oral Surgery | null | 29,924,768 | Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: A split-mouth randomised clinical trial | Barbier L, Ramos E, Mendiola J, Rodriguez O, Santamaria G, Santamaria J, Arteagoitia I. | Med Oral Patol Oral Cir Bucal. 2018 Jul 1;23(4):e469-e477. doi: 10.4317/medoral.22466. | Barbier L | Med Oral Patol Oral Cir Bucal | 2,018 | 2018/06/21 | PMC6051678 | null | 10.4317/medoral.22466 | oa_comm/txt/all/PMC6051678.txt | 332875d8062e740e887396f015f70492 | Med Oral Patol Oral Cir Bucal. 2018 Jul 21; 23(4):e469-e477 | 2021-06-18 17:29:13 | CC BY | no |
['PMC6051678'] | ['29924768'] | ['B12', 'B13', 'B14', 'B7', 'B8', 'B4', 'B5', 'B6', 'B9', 'B4', 'B5', 'B6', 'B9', 'B15', 'B16', 'B2'] | This manuscript was written in accordance with the recommendations of the CONSORT 2010 Declaration (12). Our objective was to assess the effect of ADPMSCs on limiting socket bone resorption after ITM extraction. Regenerative medicine aims to repair damaged tissues with cell therapy procedures. It is based on the use of stem cells from different origins; these cells can be differentiated into specific mesenchymal tissues by using different procedures. Adult dental pulp stem cells are one of the sources used in the repair and regeneration of bone and periodontal and dental defects. One of the limitations of application to clinical practice could be the prolonged time between the collection of dental pulp and isolation of PMSCs, which likely explains why few clinical trials are registered in the European Medicines Agency (www.ema.europa.eu) and in the National Institutes of Health of the United States of America (https://www.nih.gov). In an experimental animal model, D’Aquinoet al.de-monstrated the capacity of a suspension of digested dental pulp cells, cultured in a low-density liquid, to induce osteogenesis, angiogenesis, and vascularization of bone tissue (13). The same research team simplified the procedure by demonstrating the capacity to produce bone nodules, without the requirement for prior expansion of PMSCs, in an experimental animal model (14). A controlled split-mouth clinical trial was published regarding bone repair in post-extraction sockets of the ITM in seven patients. To collect pulp tissue, the upper third molars were removed; pulp cells were mechanically dissociated, filtered, and cultured. After 21 days of culture, ADPMSCs were obtained and, by using a collagen matrix, these cells were implanted in the experimental post-extraction socket of the ITM; collagen alone was implanted in the control socket. Consequently, bone regeneration was higher by 25% in the experimental group (7). A study conducted three years later on the same samples concluded that the regenerated bone in the ADPMSC group was evenly vascularised and more compact than that in the control group, where a collagen sponge alone was implanted (8). Following these preliminary studies, the Rigenera® Protocol was developed and applied clinically (4,5,6,9). ADPMSCs obtained from dental ligament-derived tissue were added to a collagen sponge and implanted in the post-extraction cavity of an ITM; the contralateral cavity was implanted with collagen alone. After 6 months, clinical beginning/ending differences were noted in probing at the experimental site (12 mm/3 mm), compared with the control site (11 mm/7 mm) (4). A report of a case where the sinus cavity was filled with grafted ADPMSCs indicated that the density of the newly formed bone was approximately twice that of the native bone (5). Application of the protocol to adult periosteal tissue demonstrated that progenitor cells for use in tissue regeneration could be produced (6). In a subsequent controlled multi-centre clinical trial of 35 patients, a suspension of autologous periosteal progenitor cells was grafted with a collagen matrix in the post-extraction socket; outcomes in these patients were compared with those in a control group where collagen alone was used. That study demonstrated that the autologous periosteal progenitor cells accelerated ossification and reduced bone reabsorption in the alveolar crest, thus preserving the socket (9). By using the Rigenera® Protocol, we have analysed the ability of ADPMSCs to limit bone resorption in a model of ITM extraction, which is frequently used to assess the efficacy of anti-inflammatory and analgesic medicines. For this purpose, we conducted an independent clinical trial with a double-blind design, strict randomisation, and analysis of the inter-observer agreement of response variables, thereby providing solid internal validity. The image-measuring instrument used was the advanced display platform IntelliSpace Portal, which generates actual measurements of bone density and interdental septum height. Recruitment was slower than expected due to the need to extract ITMs from each of the patients who had similar clinical and radiological characteristics. We recruited young patients aged between 18 and 30 years, from a healthy population, to minimise a possible effect of a decreased frequency of mesenchymal stem cells with age (15). When third molars are included, the pulp collected from the pulp chamber is, theoretically, free of disease. The split-mouth model allowed each patient to have control. The ADPMSC suspension was delivered in a collagen matrix, which is the most commonly used vehicle in this type of research (16). The limitations of our clinical trial include the narrow age range, from 18 to 30 years. Furthermore, we did not perform immunohistochemical studies on the newly formed tissue, and we only evaluated the results once, at 6 months after surgery. A recent systematic review found some standardisation gaps in the method of isolation of stem cells from the oral cavity and stated that methodological heterogeneity should be assessed to create a protocol standardising their isolation and differentiation (2). We agree with the findings of the systematic review. Within the context of the aforementioned limitations, we were not able to demonstrate that autologous dental pulp mesenchymal stem cells have the ability to limit socket resorption after impacted lower third molar extraction. Source of Funding: Project PI13/00541, funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, “Away to make Europe/Investing in your future”). | PMC6051678 | Research; Oral Surgery | null | 29,924,768 | Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: A split-mouth randomised clinical trial | Barbier L, Ramos E, Mendiola J, Rodriguez O, Santamaria G, Santamaria J, Arteagoitia I. | Med Oral Patol Oral Cir Bucal. 2018 Jul 1;23(4):e469-e477. doi: 10.4317/medoral.22466. | Barbier L | Med Oral Patol Oral Cir Bucal | 2,018 | 2018/06/21 | PMC6051678 | null | 10.4317/medoral.22466 | oa_comm/txt/all/PMC6051678.txt | 332875d8062e740e887396f015f70492 | Med Oral Patol Oral Cir Bucal. 2018 Jul 21; 23(4):e469-e477 | 2021-06-18 17:29:13 | CC BY | no |
['PMC6964112'] | ['31969977'] | ['CR1', 'CR2', 'CR3', 'CR4', 'CR5', 'CR6', 'CR7', 'CR8', 'CR9', 'CR10', 'CR11', 'CR12', 'CR13', 'CR14', 'CR8', 'CR10', 'CR11', 'CR14', 'CR15', 'CR16', 'CR17', 'CR18', 'CR20', 'CR21', 'CR22', 'CR8', 'CR9', 'CR17'] | Autism spectrum disorder (ASD) is characterized by lifelong impairments in social and communicative functioning, and the presence of stereotyped behaviors and interests [1]. In the past decade, intranasal administration of the neuropeptide oxytocin (OT) has increasingly been explored as a potential pharmacological treatment for targeting the core characteristics of ASD. Endogenous OT is synthesized in the hypothalamus where neurons of the paraventricular nuclei project to various areas of the central nervous system involved in complex (social) behaviors (e.g., amygdala). In typically developing individuals, OT has been linked to interpersonal bonding, parental care, and the ability to establish trust and form social attachments [2,3]. With respect to ASD, initial clinical trials have demonstrated that a single dose of OT can induce behavioral enhancements on tasks assessing repetitive behavior [4], affective speech comprehension (emotional intonations) [5], facial emotion recognition [6], and social decision making (cyberball computer game) [7]. Multiple-dose trials assessing the effects of OT treatment in adults with ASD have also shown beneficial effects. Anagnostou et al. [8] assessed the safety and efficacy of 6 weeks of intranasal OT treatment on core autism symptom domains (social cognition/function and repetitive behaviors) in 19 adults with ASD (16 men, three women), and showed improved emotion recognition, quality of life, and tentative improvements in repetitive behaviors after OT treatment. In another study with 20 adult men with ASD, Watanabe et al. [9] studied the effects of 6 weeks of intranasal OT administration on core autism characteristics and showed significant improvements in social reciprocity and social functioning (social-judgment task). In a more recent large-scale trial, Yamasue et al. [10] also assessed the effects of 6 weeks of intranasal OT treatment on core autism symptom domains in 106 adult men with ASD and showed significant improvements in repetitive behaviors. However, a more mixed pattern of results emerged from studies assessing the effects of multiple-dose OT treatment in children with ASD. For example, Dadds et al. [11] assessed behavioral effects of a 4-day intranasal OT treatment in 38 boys with ASD (7 to 16 years old) during parent-child interaction training, but found no OT-specific improvements in repetitive behaviors or social responsiveness. Later, also Guastella et al. [12] failed to show beneficial effects after an 8-week OT treatment on core ASD characteristics in slightly older boys (12 to 18 years old). On the other hand, a more recent trial assessing the effects of 5 weeks of intranasal OT treatment on core ASD characteristics in 31 children with ASD (27 boys, four girls) was able to demonstrate improved social responsiveness as reported by the parents [13]. Similarly, Parker et al. [14] investigated whether a 4-week intranasal OT treatment could improve core autism characteristics in 32 children (6–12 years old) with ASD and showed an increase in parent-reported social responsiveness. Taken together, findings of these initial multiple-dose trials provided indications for a more consistent (positive) pattern of results for OT trials with adults with ASD [8–10], compared to trials with children with ASD [11–14]. To date, however, potential long-term effects of OT treatment that outlast the period of actual administration have not yet been addressed in adults with ASD. These assessments, however, would be of high relevance since repeated administrations over an extended period might induce long-lasting, experience-dependent adaptations within neural circuits. With respect to ASD, it has been postulated that early-life impairments in social attention/orienting may deprive patients of adequate social learning experiences that normally drive the typical development of social brain networks [15]. Considering that OT is hypothesized to increase the saliency of social cues [16], OT therapy might induce an enrichment of social experiences that stimulates long-term adaptations in social behaviors. In this pilot study, we assessed—for the first time—the possibility of long-term retention effects of 4 weeks of intranasal OT administration on core autism symptom domains (including social responsiveness and restricted and repetitive behaviors), attachment characteristics, and general aspects of quality of life in adult men with ASD. While prior multiple-dose trials mainly explored the effects of treatment on these core autism symptom domains, a recent study from our lab [17] showed that 2 weeks of OT treatment in typically developing young-adult men reduced self-reported feelings of attachment avoidance and increased self-reported feelings of secure attachment toward peers. Against this background and given the growing body of research demonstrating an important role of the oxytocinergic system in interpersonal trust and attachment [18–20], the current study also included an initial assessment of attachment measures to evaluate the long-term effects of OT treatment in adults with ASD. With respect to ASD, Rutgers et al. [21] suggested that most children with ASD (53%) are able to form a secure attachment to caregivers, but that they are significantly less likely to do so compared to typically developing children. In addition, a recent meta-analysis concluded that more severe autism characteristics are associated with less secure attachment in children with ASD [22]. The effects of treatment on core autism characteristics and attachment were assessed immediately after the 4-week treatment period, and at follow-up sessions, 4 weeks and 1 year post-treatment, to assess the possibility of retention effects that outlast the period of actual administration. In line with prior multiple-dose studies [8,9,17], we hypothesized that multiple doses of OT would improve self-report and informant-based ratings of social responsiveness and repetitive behaviors, and ameliorate self-ratings of attachment characteristics and quality of life. A key question was to evaluate whether any beneficial effects of multiple-dose OT treatment would outlast the period of actual administration until 1 month (4 weeks) and/or 1 year post-treatment. | PMC6964112 | Research | null | 31,969,977 | Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up | Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. | Mol Autism. 2020 Jan 15;11(1):6. doi: 10.1186/s13229-020-0313-1. eCollection 2020. | Bernaerts S | Mol Autism | 2,020 | 2020/01/24 | PMC6964112 | null | 10.1186/s13229-020-0313-1 | oa_comm/txt/all/PMC6964112.txt | 4f1b87bb5194c7a07b8becc3f905d158 | Mol Autism. 2020 Jan 15; 11:6 | 2021-06-19 04:55:42 | CC BY | no |
['PMC6964112'] | ['31969977'] | ['Fig1'] | This two-arm, double-blind, randomized, placebo-controlled parallel study was performed at the Leuven University Hospital (Leuven, Belgium) to assess multiple-dose effects of intranasal oxytocin (OT) administration on core autism characteristics and experience of attachment in adult men with ASD. A specific aim of this pilot clinical trial was to assess whether any treatment-induced effects would outlast the period of actual administration. To do so, changes-from-baseline (T0) in self-report and informant-based questionnaire scores were assessed immediately after 4 weeks of OT treatment (T1), and at two follow-up sessions, 4 weeks (T2) and 1 year post-treatment (T3) (see Fig.1, CONSORT Flow diagram for number of participants randomized and analyzed). Written informed consent was obtained from all participants prior to the study. Consent forms and study design were approved by the local Ethics Committee for Biomedical Research at the University of Leuven, KU Leuven (S56327) in accordance to The Code of Ethics of the World Medical Association (Declaration of Helsinki). The trial was registered with the European Clinical Trial Registry (Eudract 2014-000586-45) and the Belgian Federal Agency for Medicines and Health products. Note that the data presented in the current report are part of a larger clinical trial in which neural measures (i.e., task-based and resting-state magnetic resonance imaging (MRI)) were assessed in addition to the presented questionnaire data. These MRI modalities are however not part of the current report and will be reported elsewhere (manuscripts in preparation).Fig. 1CONSORT Flow diagram. Data were analyzed using an intention-to-treat format with last-observations-carried-forward to replace missing data. For participants with missing baseline data, analysis for that measure was excluded list-wise.SRS-ASocial Responsiveness Scale adult version,RBS-RRepetitive Behavior Scale Revised,SAAM: State Adult Attachment Measure,IPPAInventory of Parent and Peer Attachment,WHO-QOLWorld Health Organization Quality of Life | PMC6964112 | Research | null | 31,969,977 | Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up | Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. | Mol Autism. 2020 Jan 15;11(1):6. doi: 10.1186/s13229-020-0313-1. eCollection 2020. | Bernaerts S | Mol Autism | 2,020 | 2020/01/24 | PMC6964112 | null | 10.1186/s13229-020-0313-1 | oa_comm/txt/all/PMC6964112.txt | 4f1b87bb5194c7a07b8becc3f905d158 | Mol Autism. 2020 Jan 15; 11:6 | 2021-06-19 04:55:42 | CC BY | no |
['PMC6964112'] | ['31969977'] | ['CR1', 'CR23', 'CR24', 'CR25', 'Tab1', 'MOESM1', 'Fig1', 'CR8', 'CR9', 'CR17'] | Forty high-functioning adult men with a formal diagnosis of ASD were recruited between April 2015 and December 2016 from the Autism Expertise Centre at the Leuven University Hospital. The diagnosis was established by a multidisciplinary team (child psychiatrist and/or expert neuropediatrician, psychologist, speech/language pathologist, and/or physiotherapist) based on the strict criteria of the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders) [1]. Prior to the intervention, the Autism Diagnostic Observation Schedule (ADOS or ADOS-2) [23,24] and estimates of intelligence (6-subtest short version of the Wechsler Adult Intelligence Scale-IV Dutch version: Block design, Digit span, Similarities, Vocabulary, Symbol search and Visual puzzles) [25] were acquired from all participants (Table1). Inclusion criteria comprised a clinical diagnosis of autism spectrum disorder; gender (male); and age (18–35 years old). Exclusion criteria for participation comprised any neurological disorder (e.g., stroke, epilepsy, concussion); demonstrated genetic disorder; or any contraindication for MRI (note that the MRI data analyses are not part of the current report). Current psychoactive medication use and the presence of comorbid psychiatric disorders were screened (Additional file1: Table S1). Forty participants were randomly allocated to either the OT (n= 22) or the placebo (PL) group (n= 18) (see Fig.1, CONSORT Flow diagram). The initial sample size (n= 40) was set to be comparable to three prior studies showing significant effects of multiple-dose OT treatment on similar outcome measures [8,9,17].Table 1Participant characteristicsOxytocinPlaceboTvaluepvalueNumber of participants2218Age25.00 ± 4.8624.00 ± 5.550.620.54IQTotal IQ102.27 ± 12.45104.61 ± 21.59-0.430.67VIQ105.57 ± 9.27108.72 ± 16.83-0.740.47PIQ104.76 ± 18.35102.39 ± 22.900.360.72ADOS(2)Total7.18 ± 4.228.06 ± 4.26-0.650.52Communication2.05 ± 1.402.39 ± 1.54-0.740.46Social interaction4.82 ± 3.505.67 ± 3.33-0.780.44Use of psychostimulant medication62Comorbidity82Data are shown as mean ± standard deviation.IQintelligence quotient,VIQverbal IQ,PIQperformance IQ,ADOS(2) Autism Diagnostic Observation Schedule(2). Detailed information on medication use and comorbidities is provided in Additional file1: Table S1. Note that for one participant of the OT group only total IQ information was available, but not VIQ or PIQ, so that the mean (± standard deviation) information of the VIQ and PIQ of the OT group are based on data from 21 participants | PMC6964112 | Research | null | 31,969,977 | Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up | Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. | Mol Autism. 2020 Jan 15;11(1):6. doi: 10.1186/s13229-020-0313-1. eCollection 2020. | Bernaerts S | Mol Autism | 2,020 | 2020/01/24 | PMC6964112 | null | 10.1186/s13229-020-0313-1 | oa_comm/txt/all/PMC6964112.txt | 4f1b87bb5194c7a07b8becc3f905d158 | Mol Autism. 2020 Jan 15; 11:6 | 2021-06-19 04:55:42 | CC BY | no |
['PMC6964112'] | ['31969977'] | ['CR26', 'CR27', 'CR6', 'CR28', 'CR29', 'CR29', 'CR17', 'CR30', 'MOESM1', 'Tab2', 'MOESM1', 'MOESM1'] | Participants were assigned to receive the OT or PL treatment based on a computer-generated randomized order. Except for the manager of randomization, all research staff conducting the trial, participants, and their parents and/or partners were blinded to treatment allocation. OT (Syntocinon®, Sigma-tau) and PL (saline natrium-chloride solution) were administered in amber 15 ml glass bottles with metered pump (ACA Pharma). Each puff per nostril contained four international units (IU) of OT. Participants self-administered a daily dose of 24 IU (three puffs/nostril) over four consecutive weeks (28 doses in total). This dose is in accordance with prior OT administration studies in neurotypical (young) adults [26,27] and adults and adolescents with ASD [6,28,29]. At this dosage, no side effects or contraindications of OT have been described [29]. All participants received clear instructions about the use of the nasal spray [17,30] and were monitored onsite until approximately 2 h after first nasal spray administration. During the course of the treatment, participants were asked to administer the nasal spray in the morning, to keep a daily record of the time point of nasal spray administration, and whether or not they were alone or in company of others the first 2 h after administration. Percentage of days at which the spray was administered in the presence of others was not significantly different between treatment groups (OT: 36.8 % (SD 29.9); PL: 36.0 % (SD 25.1);t(37) = .09;p= .93). Participants administered the nasal spray (OT or PL) daily during four consecutive weeks and at the end of each week participants were screened for potential adverse events, side effects (Additional file1: Table S2), or changes in mood with the Profile of Mood States (POMS) questionnaire (Table2and Additional file1: Figure S1). Finally, at the end of the trial, participants were asked if they thought they had received OT or PL. The majority of participants thought they had received the PL treatment (79.5%). The proportion of participants that believed they had received the OT treatment was not significantly larger in the actual OT group (28.57%), compared to the PL group (11.11%) (p= .18). Nonetheless, secondary analyses were performed to explore whether treatment effects were modulated by the participants’ own belief about the received treatment (Additional file1: Supplementary Results).Table 2Outcome measures and effects of oxytocin treatment. Mean pre-to-post change scores are listed separately for each treatment group (oxytocin, placebo) and assessment session (T1, T2, T3). Cohen’s d effect sizes ofbetween-groupdifferences are reported separately for each outcome measure and assessment session.Tandpvalues correspond to single-samplettests assessingwithin-groupchanges from baseline separately for the oxytocin and placebo groupOutcome measureOxytocinPlaceboBetween-group differenceNMean ± SDTvaluepNMean ± SDTvaluepCohen’s dMultiple-dose effect (T1)Primary outcomesSRS-A self-report22− 5.55 ± 11.40− 2.280.03318− 1.06 ± 10.01− 0.450.66−0.42SRS-A informant-based170.0 ± 15.860.001.0015− 0.87 ± 12.83− 0.260.800.10Secondary outcomesRBS-R22− 4.77 ± 6.47− 3.460.00217− 1.76 ± 4.75− 1.530.15− 0.63SAAM avoidance22− 0.40 ± 0.71− 2.630.016180.06 ± 0.980.240.81− 0.61SAAM security220.27 ± 0.771.620.1218− 0.05 ± 0.66− 0.310.760.63SAAM anxiety22− 0.14 ± 0.75− 0.900.38180.28 ± 0.951.240.23− 0.62IPPA Peers221.45 ± 3.851.770.091180.56 ± 4.050.580.570.30IPPA Mother21− 0.52 ± 2.71− 0.880.39180.44 ± 3.450.550.59− 0.39IPPA Father210.43 ± 3.300.600.5618− 0.61 ± 3.81− 0.680.500.29WHO-QOL221.77 ± 8.041.030.3117− 1.35 ± 6.74− 0.830.420.63Profile of mood statesTension22− 2.00 ± 2.29− 4.100.000518− 2.39 ± 3.03− 3.340.0040.14Anger220.00 ± 4.050.001.0018− 0.61 ± 2.73− 0.950.350.18Depression22− 1.14 ± 4.50− 1.190.2518− 0.33 ± 2.81− 0.500.62− 0.21Vigor22− 1.00 ± 2.53− 1.860.07718− 2.94 ± 3.64− 3.430.0030.62Fatigue22− 2.09 ± 3.99− 2.460.02318− 1.11 ± 5.12− 0.920.37− 0.21One-month retention effect (T2)Primary outcomesSRS-A self-report22− 5.64 ± 12.57− 2.100.04818− 7.67 ± 12.09− 2.690.0150.22SRS-A informant-based17− 9.59 ± 10.98− 3.600.00215− 1.20 ± 10.73− 0.430.67− 0.83Secondary outcomesRBS-R22− 4.91 ± 6.33− 3.640.00217− 2.35 ± 3.43− 2.830.012− 0.50SAAM avoidance22− 0.38 ± 0.70− 2.580.01818− 0.06 ± 0.76− 0.350.73− 0.53SAAM security220.04 ± 1.010.180.8618− 0.40 ± 0.99− 1.700.110.62SAAM anxiety220.08 ± 1.050.360.72180.11 ± 0.870.540.60− 0.05IPPA Peers221.32 ± 3.711.670.11180.06 ± 3.700.060.950.45IPPA Mother21− 0.38 ± 3.43− 0.510.62180.06 ± 4.350.050.96− 0.14IPPA Father210.52 ± 3.590.670.5118− 0.33 ± 3.87− 0.370.720.31WHO-QOL221.14 ± 5.480.970.34170.35 ± 4.530.320.750.24Profile of mood statesTension22− 2.64 ± 2.80− 4.410.000218− 2.11 ± 3.22− 2.760.013− 0.17Anger220.36 ± 3.680.460.6518− 0.39 ± 3.91− 0.420.680.20Depression22− 0.82 ± 2.63− 1.460.16180.22 ± 3.410.280.79− 0.34Vigor220.14 ± 3.580.180.8618− 1.44 ± 4.33− 1.420.170.40Fatigue22− 2.69 ± 2.71− 4.630.000118− 2.33 ± 4.47− 2.210.04− 0.09One-year retention effect (T3)Primary outcomesSRS-A self-report22− 8.59 ± 20.95− 1.920.0718− 6.72 ± 21.01− 1.360.19− 0.12SRS-A informant-based17− 7.41 ± 19.26− 1.590.1315− 4.13 ± 24.64− 0.650.53− 0.18Secondary outcomesRBS-R22− 4.91 ± 9.46− 2.430.0217− 0.41 ± 4.27− 0.400.70− 0.98SAAM avoidance22− 0.52 ± 1.18− 2.070.05180.0 ± 0.750.001.00− 0.80SAAM security220.20 ± 1.52− 0.620.5418− 0.14 ± 0.66− 0.910.37− 0.05SAAM anxiety220.17 ± 0.940.830.42180.11 ± 1.210.390.700.06IPPA Peers220.68 ± 6.260.510.61181.28 ± 4.171.300.21− 0.20IPPA Mother210.33 ± 3.910.390.70181.50 ± 5.441.170.26− 0.30IPPA Father210.57 ± 4.080.640.5318− 0.50 ± 4.53− 0.470.650.33WHO-QOL221.14 ± 8.370.640.53170.29 ± 4.210.290.780.27Profile of mood statesTension22− 1.86 ± 2.29− 3.810.00118− 2.28 ± 3.46− 2.790.0120.14Anger220.59 ± 3.690.750.46180.06 ± 3.840.060.950.14Depression220.50 ± 2.630.890.3818− 0.28 ± 3.51− 0.340.740.25Vigor221.14 ± 3.881.370.1818− 0.61 ± 3.27− 0.790.430.50Fatigue22− 0.23 ± 6.04− 0.180.86180.39 ± 4.730.350.73− 0.11SRS-ASocial Responsiveness Scale adult version,RBS-RRepetitive Behavior Scale-Revised,SAAMState Adult Attachment Measure,IPPAInventory of Parent and Peer Attachment,WHO-QOLWorld Health Organization Quality of Life questionnaire. Screening for mood changes are based on the Profile of Mood States (POMS) questionnaire. For SRS-A, RBS-R, SAAM avoidance, SAAM anxiety, and POMS tension, anger, depression and fatigue; negative scores indicate pre-to-post improvement. Cohen’s d effect sizes (change from baselineOT–change from baselinePL)/pooled SD) are reported where 0.2 is indicative of a small effect, 0.5 a medium effect and 0.8 a large effect. Data printed in bold show Cohen’s d effect sizes equal to or larger than .50 (medium-sized effect) | PMC6964112 | Research | null | 31,969,977 | Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up | Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. | Mol Autism. 2020 Jan 15;11(1):6. doi: 10.1186/s13229-020-0313-1. eCollection 2020. | Bernaerts S | Mol Autism | 2,020 | 2020/01/24 | PMC6964112 | null | 10.1186/s13229-020-0313-1 | oa_comm/txt/all/PMC6964112.txt | 4f1b87bb5194c7a07b8becc3f905d158 | Mol Autism. 2020 Jan 15; 11:6 | 2021-06-19 04:55:42 | CC BY | no |
['PMC6964112'] | ['31969977'] | ['MOESM1', 'CR31', 'CR32', 'CR33', 'CR34', 'CR35'] | The Social Responsiveness Scale (for adults) (SRS-A) total score was used as the primary outcome measure (self-report and informant-based versions). The other behavioral questionnaires were considered secondary: Repetitive Behavior Scale-Revised (RBS-R); State Adult Attachment Measure (SAAM); Inventory of Parent and Peer Attachment (IPPA); Quality of Life questionnaire of the World Health Organization (WHO-QOL) (all self-report). More detailed information on each of the adopted questionnaires is provided in Additional file1: Supplementary Methods. In short, the SRS-A (64 items) [31] comprises four subscales examining social communication, social awareness, social motivation and rigidity/repetitiveness, using a four-point Likert-scale. SRS-A raw total scores were adopted. The RBS-R (43 items) [32] examines a heterogeneous set of repetitive behaviors including stereotypic behavior, self-injurious behavior, compulsive behavior, ritualistic behavior, sameness behavior and restricted interests behavior, using a four-point Likert-scale. RBS-R raw total scores were adopted. The SAAM [33] comprises three subscales examining attachment security (e.g., “I feel like I have someone to rely on”) (seven items); attachment anxiety (e.g., “I feel a strong need to be unconditionally loved right now”) (seven items); and attachment avoidance (e.g., “If someone tried to get close to me, I would try to keep my distance”) (seven items) using a seven-point Likert-scale. SAAM raw subscale scores were adopted. The IPPA [34] examines trait attachment to (i) mother (12 items), (ii) father (12 items), and (iii) peers (12 items), using a four-point Likert-scale. The IPPA assesses attachment security along three dimensions: degree of mutual trust, quality of communication, and extent of anger and alienation. IPPA raw subscale scores were adopted. Finally, the abbreviated version of the WHO-QOL [35] assesses general quality of life related to physical health, psychological health, social relationships, and environment using a five-point Likert scale. WHO-QOL raw total scores were adopted. All questionnaires were assessed at baseline (T0), immediately after four consecutive weeks of nasal spray administration (approximately 24 h after the last nasal spray administration) (T1), and at follow-up sessions, 4 weeks (T2) and 1 year post-treatment (T3). Given that this is an exploratory pilot study evaluating the possibility of long-term retention effects of OT treatment, no primary time point was pre-specified. | PMC6964112 | Research | null | 31,969,977 | Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up | Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. | Mol Autism. 2020 Jan 15;11(1):6. doi: 10.1186/s13229-020-0313-1. eCollection 2020. | Bernaerts S | Mol Autism | 2,020 | 2020/01/24 | PMC6964112 | null | 10.1186/s13229-020-0313-1 | oa_comm/txt/all/PMC6964112.txt | 4f1b87bb5194c7a07b8becc3f905d158 | Mol Autism. 2020 Jan 15; 11:6 | 2021-06-19 04:55:42 | CC BY | no |
['PMC6964112'] | ['31969977'] | ['Fig1', 'Tab2', 'CR36', 'Tab2'] | For each questionnaire, baseline differences between groups were assessed using two-samplettests. To assessbetween-group differences, pre-to-post difference scores were calculated for each assessment session (T1, T2, T3) and difference scores were subjected to a linear mixed-effects model (one-tailed) with the random factor “subject,” and the fixed factors “treatment” (OT, PL), “session” (T1, T2, T3) and “treatment × session” interaction. An intention-to-treat format and last-observations-carried-forward to replace missing data was adopted. For participants with missing baseline data, analysis for that measure was excluded list-wise (Fig.1CONSORT Flow diagram). Cohen’s d effect sizes of between-group differences (change from baselineOT–change from baselinePL)/pooled standard deviation) are reported in Table2, separately for each outcome measure and assessment session, where 0.2 is indicative of a small effect, 0.5 a medium effect, and 0.8 a large effect [36]. Additionally, pre-to-post difference scores were subjected to single-samplettests to assess within-group changes (compared to baseline) in the OT group and PL group separately (Table2). All statistics were executed with Statistica 8 (StatSoft. Inc. Tulsa, USA). Given that this is an exploratory pilot study evaluating long-term effects of OT treatment, the significance level was set atp< .05 for all analyses, without correction for multiple comparisons. | PMC6964112 | Research | null | 31,969,977 | Behavioral effects of multiple-dose oxytocin treatment in autism: a randomized, placebo-controlled trial with long-term follow-up | Bernaerts S, Boets B, Bosmans G, Steyaert J, Alaerts K. | Mol Autism. 2020 Jan 15;11(1):6. doi: 10.1186/s13229-020-0313-1. eCollection 2020. | Bernaerts S | Mol Autism | 2,020 | 2020/01/24 | PMC6964112 | null | 10.1186/s13229-020-0313-1 | oa_comm/txt/all/PMC6964112.txt | 4f1b87bb5194c7a07b8becc3f905d158 | Mol Autism. 2020 Jan 15; 11:6 | 2021-06-19 04:55:42 | CC BY | no |
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