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Methods | PMC10673712 | |||
Patients and tumor samples | tumor, PAOLA-1 BRCAwt tumors | TUMOR | The first cohort consisted of FFPE-derived DNA from 449 AOC samples from the PAOLA-1/ENGOT-ov25 trial in the frame of the EHEI. The procedure consisted in preliminary evaluation of the academic test performance on 85 PAOLA-1 BRCAwt tumors by comparing to the Myriad MyChoice diagnostics, followed by final PFS based test evaluation on 364 additional patient samples (phase 3) [The second cohort consisted of 109 consecutive FFPE AOC samples (8 to 20 slides of 5 µm according to the tumor area) sent to Myriad Genetics central laboratory (Salt Lake City, UT, USA), from March 2021 to January 2022, as part of the routine clinical management process. All patients have a recent diagnosis of high grade AOC and the samples contained more than 30% of tumor cells. The third cohort consisted of 31 consecutive FFPE AOC samples issued from the routine laboratory of Poitiers Hospital previously analyzed by MyChoice test in Myriad Genetics central laboratory. | PMC10673712 |
Shallow WGS workflow | ® | Genomic DNA was extracted from the FFPE samples. 50 µl of DNA samples were mechanically sheared using Covaris ME220 Focused-ultrasonicator. Libraries were prepared from 100 ng of DNA using Agilent SureSelect XT HS and XT Low Input Library Preparation kit (Agilent, Santa Clara, CA, USA, ref: G9703A) according to the manufacturer’s instructions. This process included ligation, PCR amplification, and purification on AMpure XP beads (Beckman Coulter, Indianapolis, IN, USA, ref: A63882). DNA concentration was measured using either Thermo Fisher Scientific Qubit® dsDNA HS Assay Kit (ref: Q32854) or Qubit® dsDNA BR Assay Kit (Thermo Fisher Scientific, Waltham, MA, USA, ref: Q32853). Library quality and quantity were assessed using the Agilent TapeStation and D1000 ScreenTape. A pre-capture library pool with concentrations of 4 nM or 1.8 nM was generated for NextSeq 550 S or NovaSeq 6000 Sequencing systems (Illumina Inc, San Diego, CA, USA), respectively.In Poitiers Hospital, DNA from FFPE samples were extracted on a Maxwell® 16-IVD using FFPE Plus LEV DNA Purification Kit (Promega, Madison, WI, USA, ref: AS1135). 200 ng of FFPE DNA were used for generating pre-capture libraries on a Magnis NGS Prep System using the SureSelect XT HS Low Input kit (ref: G9731D). 100 µl of molecular biology grade water were added to the QC strip wells (blue strip) and quantification was performed with on a Qubit® 3 fluorometer using the 1x dsDNA HS Assay Kit (ref: Q33230). The pre-capture library pool was sequenced at 1 nM on a NextSeq 550 platform (Illumina). After sequencing, FASTQ files were generated and analyzed by | PMC10673712 | |
ShallowHRDv2 bioinformatics pipeline | LGA, tumor, ±2 | TUMOR | After DNA extraction and whole genome sequencing at low coverage (~1X), read counts profile (bin size ~50 kb) normalized and corrected for GC-content was obtained by ControlFreec [Main steps of CNA processing (Supplementary Fig. Three-way sample quality attribution: CNA profile classification according to tumor content (four categories), intrinsic sWGS noise (three categories) and FFPE noise (four categories) with final integrative classification in three categories: “good”, “fair” and “low” (Supplementary Fig. Noise reduction and optimization of breakpoints in the CNA profile: filtering small segments and assembling segments with small differences or local correlations to the FFPE noise profile (obtained from ~100 normal profiles from FFPE samples, Supplementary Fig. Broad CNA profile characterization by:genome complexity, where the “simple” genome has two most abundant copy number (CN) levels accounting for more than 70% of the genome, otherwise, the genome is classified as “complex” or “complex+” (significant and almost equal contribution of four CN levels);a set of binary attributes, such as a set of parameters characterizing the breakpoints, including the number of large genomic alterations (LGA), that largely contributes to the HRD diagnostics; LGA are defined as CN breaks between genomic segments of more than 9 Mb (segment sizes are rounded to the integer value); a set of ancillary LGA indexes, such as extra-large LGA, telomeric LGA, LGA between two the most abundant CN levels, LGA involving one of the three most abundant CN levels and the number of chromosome arms with LGA.Step-wise HRD diagnostics based on:LGA-score, which is essentially the number of LGA modified by PENALTY and/or BONUS, where PENALTY is defined by binary attributes and is subtracted from the LGA number (PENALTY is set to 0, 5 or 8 if none, one or more than one binary attributes hold true, respectively) and BONUS is defined by the genome complexity and is added to the LGA number (BONUS is set to 5 for “simple” genome and to 0 otherwise);the threshold of 20 with margins (±2) for clear-cut HRD diagnostics, namely 18 and 22, with the LGA-score <18 for “clear-cut” nonHRD and LGA-score >22 for “clear-cut” HRD;LGA-score modification, which is applied to resolve the borderline cases (18 ≤ LGA-score ≤ 22). Briefly, the LGA-score is shifted to 19 if evidence for nonHRD (such as PENALTY > 0, ancillary LGA indexes below the threshold, genome is classified as “complex+”, etc) and to 21 if evidence for HRD (PENALTY = 0, ancillary LGA indexes above the threshold, genome is classified as “simple”) (Supplementary Fig. | PMC10673712 |
Decision rules | LGA, tumor | TUMOR | Decision rules are multi-step, depend on sample quality attribution and include selection of the thresholds for LGA call. Two thresholds were utilized to call LGA at CNA breakpoint: stringent (implying simple genome) and soft (implying complex genome), which are applied in conservative manner for good quality cases (LGA-score was based on LGA number with soft/stringent thresholds for nonHRD/HRD clear-cut diagnostics), and are fixed to the stringent/soft ones for noisy/low tumor content samples, respectively. Simplified decision rules for bad quality samples consist in giving the diagnosis only for clear-cut nonHRD cases with small overall number of the breakpoints. Robust decision rules for fair quality samples consist in giving the diagnosis only for clear-cut cases, leaving the borderline cases with not determined (ND) diagnosis. | PMC10673712 |
Comprehensive output (report) | LGA | Final diagnosis is reported along with quality assessment and warning messages (Supplementary Fig. Circular binary segmentation of CNA profile has a stochastic component and can result in between-run variation in LGA-score, which may affect the diagnostics if close to the thresholds. Thus, LGA number is represented by the confidence intervals estimated from 20 segmentation/optimization runs. | PMC10673712 | |
Statistical analysis | The Kaplan–Meier method was used to estimate the PFS and overall survival (OS), with the stratified log-rank test used to assess the difference between the ola+bev and bev arms [ | PMC10673712 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41388-023-02839-8. | PMC10673712 | ||
Acknowledgements | cancers | CANCERS | All investigators and operational staff of GINECO, MITO, GEICO, AGO-Austria, GOTIC, BGOG, MANGO, NSGO, and AGO study group who contributed to the PAOLA-1 trial. We thank Christine Montoto-Grillot, Deborah Cardoso, Alexandre Degnieau, Eloise Glais, and Bénédicte Votan from ARCAGY for their assistance for accesses to samples and clinico-biological data. We thank all patients who participated in this study and their families. This project was supported in part by the ARC Foundation—DefImmunPD1 project [PGA1 RC20170205307]. Prior presentation: Presented in part at the ESMO gynecological cancers congress, Barcelona, Spain, February 23–24, 2023. | PMC10673712 |
Author contributions | MR | CC, MR, TP, MHS, EPL, and IRC made substantial contributions to conception and design, and revising the manuscript, and final approval for publication. CC, AB, MR, MHS, TP, AE, EF, and VR contributed to acquisition of data, analysis and interpretation of data, and drafted the manuscript. CC, MR, EF, VR, TP, and MHS participated in manuscript preparation and revision. All other authors made substantial contributions to acquisition of data, revising the manuscript, and final approval. | PMC10673712 | |
Data availability | sWGS | The raw data from sWGS have been deposited at ENA under accession PRJEB61549. | PMC10673712 | |
Competing interests | TUMORS | CC, TP, AE, and M-HS are co-inventors of the ShallowHRDv2 method (European Patent Application number EP23170829, filed on April 28th, 2023, and entitled “METHODS FOR DIAGNOSING A HOMOLOGOUS RECOMBINATION DEFICIENCY IN HUMAN TUMORS”). TP and M-HS are co-inventors of the LST method (US20170260588, US20150140122 and exclusive Licensing to Myriad Genetics). | PMC10673712 | |
References | PMC10673712 | |||
Subject terms | ® | There is an emergent need to develop functional cosmetic ingredients for the topical management of skin barrier function. This study aimed to investigate the efficacy of a lotion containing fermented lysates VHProbi® Mix R for enhancing the skin barrier. In vitro studies demonstrated that fermented cultures of both | PMC10558477 | |
Introduction | impairment of skin barrier | MALNUTRITION | As the largest organ of the body, skin serves as the interface between the body and the external environment, exerting multiple pivotal protective functions against exposome aggressions, e.g., air pollution, climate stimuli, solar radiation, lack of sleep, malnutrition, etc.The impairment of skin barrier has a huge influence on the quality of life of individuals. Unfortunately, there is no simple regimen to enhance skin barrier function. In some cases, chemicals or steroids, including tacrolimus, trans-4-tert-butylcyclohexanol, phenoxyethanol, pimecrolimus, or corticosteroids, can be used to relieve the symptomsAn increasing number of evidence-based reports advance the hypothesis that certain probiotics are beneficial to the skin immune system, barrier function, and cutaneous microbiota, leading to a health status of skin homeostasisIn our previous study, we validated the efficacy of the fermented lysate from | PMC10558477 |
Materials and methods | PMC10558477 | |||
In vitro studies | PMC10558477 | |||
Bacterial strains and cells | The bacterial strains of E15and Y21 were isolated from kimchi. The bacterial strains of E06and E12 were isolated infant feces samples. All of strains were identified using the method described by Zhang and DuanTo obtain the fermented lysate, bacterial strains were inoculated in fermentation medium (2% molasses, 0.1% peptone, 5% collagen, 0.3% (NHA human keratinocyte cell line, HaCaT cells, purchased from BeNa Culture Collection (Beijing, China), was grown in Dulbecco’s modified essential medium (DMEM; Sigma-Aldrich, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS; Sigma-Aldrich, USA) and incubated at 37 °C in a 5% CO | PMC10558477 | ||
Scavenging capability of E06 and E12 for 2,2-diphenyl-1-picryl-hydrazyl (DPPH) | The antioxidation assay was conducted using the method described by Sanchez-Moreno et al. with slight modification | PMC10558477 | ||
Proliferation assay for Lysate on HaCaT cells | HaCaT cells were plated at 2 × 10 | PMC10558477 | ||
Cell viability assay for protective effect of lysate | To evaluate the protection effect of E06 and E12 on HaCaT cell viability, For the HFor the UVB radiation-induced damage model, cells were treated with the lysates of E06 and E12 individually at a MOI of 100 and were incubated at 37 °C for 3 h. Next, the cells were treated with UVB radiation system (LONGPRO, Shanghai, China) using the dose of 60 mJ/cm | PMC10558477 | ||
Clinical studies | PMC10558477 | |||
Lotion formula | ® | The ingredients of the lotion were: 3% VHProbi® Mix R, 4% propylene glycol, 4% caprylic/capric triglyceride, 4% mineral oil, 3.5% cetearyl alcohol, 1.5% PEG-100 glyceryl stearate, 1.5% stearic acid, 0.6% glyceryl stearate, 0.5% 1,2-hexanediol, 0.3% phenoxyethanol, 0.2% xanthan gum, 0.15% chlorphenesin, % L-arginine, and 100 mL aqua. The VHProbi® Mix R was formulated using the lysate of E06, E12, E15, and Y21. These contents, except for VHProbi® Mix R, were used as preservatives, chelating agents, and thickeners in the lotion. | PMC10558477 | |
Subjects | A total of 52 eligible adult subjects, including males and females, were enrolled after verification of the criteria (Table Inclusion/exclusion criteria for the clinical study. | PMC10558477 | ||
Study procedures and assessments | redness | The subjects applied an equal amount to 0.6–0.8 g per time of the investigational lotion twice daily to their face for 30 days. After 15 min of resting in a room, the subjects were asked to complete the BoSS questionnaire on the repairing effect of the sensitive skin barrier. The dermatology assessments, including transepidermal water loss (TEWL), moisturization, and redness were conducted using the S0083 TEWL Probe, S0033 Moisture Measurement Probe, and S0043 Melanin Measurement Probe of CK-MPA® system (CK-MPA10, Courage + Khazaka electronic GmbH, German), respectively. Probes were lightly and quickly pressed on the surface of skin. The evaluation of redness profile indicator that was calculated by evaluating the dense and red areas integrated was performed by using the VISIA®-CR system (Canfield Scientific Inc., NJ, USA). The indicators described above plus BoSS (Table | PMC10558477 | |
Statistical analysis | Data were initially analyzed by EpiData ver3.1 and exported to SPSS ver26.0 (SPSS Inc., USA) for further analysis. Data distribution was assessed by the 1-sample Kolmogorov–Smirnov test. Parametric values are expressed as means ± standard deviations. The Wilcoxon test or paired samples t- test for paired samples was performed to evaluate changes between the data obtained at baseline and outcome data. | PMC10558477 | ||
Ethical statement | Ethics review and approval was not required for this study on the human participants in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate this study. Written informed consent was obtained from individuals for the publication of any potentially identifiable images or data included in this study. | PMC10558477 | ||
Results | PMC10558477 | |||
In vitro studies | PMC10558477 | |||
DPPH radical scavenging activity of E06 and E12 | The DPPH free radical scavenging activity of E06 and E12 is shown in Table DPPH radical scavenging activity.Means ± standard deviation. | PMC10558477 | ||
Antioxidant effect of E06 and E12 in C. elegans | Survival of Survival of | PMC10558477 | ||
Enhancing proliferation effect of lysate on keratinocytes | PROLIFERATION | The ability of E06 and E12 to enhance the proliferation of HaCaT cells is shown in Fig. Absorbance variations of HaCaT Cells treated with or without lysate. ( | PMC10558477 | |
Protective effect of lysate on HaCaT cells | To determine the protective effect of the lysates on the viabilities of HaCaT cells, three different stimulants, including Protection of the lysate on HaCaT cells against different stimulants. ( | PMC10558477 | ||
Clinical studies | PMC10558477 | |||
Detection of TEWL | Detailed scores on the TEWL indicator for individuals from baseline to the final visit are presented in Table Improvement of cutaneous statuses related to sensitive skin. ( | PMC10558477 | ||
Skin moisturization | Detailed scores on moisturization for individuals from baseline to the final visit are presented in Table | PMC10558477 | ||
Skin redness | skin redness | SKIN REDNESS | Detailed scores on skin redness for individuals from baseline to the final visit are presented in Table Microscopic and macroscopic images of skin redness area captured under cross-polarized light using CK and VISIA instruments. D0: day 0; D30: day 30. | PMC10558477 |
Skin redness profile | redness | Detailed scores on redness profile for individuals from baseline to the final visit are presented in Table | PMC10558477 | |
BoSS and self-assessment questionnaire | In terms of BoSS questionnaire (see Table BoSS questionnaire of skin parameters.D0: day 0; D30: day 30; SD: standard deviation; The self-assessment questionnaire also illustrated that the VHProbi® Mix R may play an important role in improving skin quality (see Table | PMC10558477 | ||
Discussion | impairment of skin barrier function, xerosis, cutaneous disorder | PROLIFERATION, XEROSIS | The impairment of skin barrier function is a common cutaneous disorder raising challenges for dermatologists, patients, and the cosmetic industry. Increasing advancements in elucidating the mechanism of action for strengthening skin barrier provide promising interventions for the management of these individualsIn this study, in vitro experiments substantiated that the fermented cultures of E06 and E12 each displayed promising DPPH scavenging capacities. The investigational strains can produce many antioxidative agents including superoxide dismutase, glutathione peroxidase, multivitamins, and etcetera after fermentation. DPPH is a kind of free radical. It is probably that the scavenging agents existing in fermented cultures reacted with the DPPH. Furthermore, using Furthermore, the lysates of both E06 and E12 both enhanced the proliferation of HaCaT cells, and the promotion of proliferation was closely correlated with the concentration of the lysate. The lysates of E06 and E12 also conferred a protective effect on HaCaT cells, ameliorating the loss of cell viability caused by Subsequently, we performed a clinical study to investigate whether the lotion containing VHProbi® Mix R could strengthen the skin barrier function or not. The water retention capacity of skin, including the TEWL and moisturization, was markedly improved following treatment with the investigational product. The indictor of TEWL represents the water loss of skin through epidermis. The decrease of TEWL indicates the recovery of skin barrier integrity. And the skin moisturization indicates the water content of skin stratum corneum. A better recovery of TEWL would lead to an increase of skin moisturization. An impaired skin barrier function is mostly associated with the xerosis, or “dry” skin, giving rise to an increase in TEWLIn recent years, topical postbiotic applications have attracted considerable attention from scientific and industrial communities. Gueniche et al. conducted an in vitro study and a human trial using The field of postbiotics is continuously evolving. Increasing clinical and experimental research provides evidence that postbiotics can not only exert healthy effects on gastrointestinal function, but can also be used for dermal application owing to their distinctive properties. Given these aspects, the development of postbiotics for topical applications represents a promising treatment and/or intervention for the management of skin barrier function. However, there are some limitations in this study, including the absence of a control group and placebo effects in the clinical trial, no elucidation of the skin microbiota variations in the subjects, and only a relatively short duration of the intervention was examined. We acknowledged that the rigorous evidence may not be obtained from this study due to lacking the placebo group. Some positive changes for the subjects using the investigational products from baseline to the endpoint of the study would lay foundation for us conducting a randomized, placebo control trail. | PMC10558477 |
Conclusion | ® | The results from this study implied that the lotion containing VHProbi® Mix R fermented lysate is well tolerated in strengthening skin barrier and may be able to mitigate the severity of sensitive skin after 30 days of intervention. Detailed immunomodulatory studies are needed to determine whether the components of VHProbi® Mix R could influence the pro-inflammatory and anti-inflammatory immune response, thereby affecting the development of sensitive skin. Further randomized, placebo controlled clinical studies are also required to validate the findings here and to better understand the mechanisms of postbiotics in the topical management of common dermatological conditions. | PMC10558477 | |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-43336-y. | PMC10558477 | ||
Acknowledgements | We would like to thank the volunteers, investigators, and staff who were involved in this study. | PMC10558477 | ||
Author contributions | All authors have permitted the orders in this article. | PMC10558477 | ||
Funding | This study received funding from Qingdao Vland Biotech Co., Ltd. The funder was not involved in the study design, collection, analysis, data interpretation, the writing of this article and decision to submit this manuscript for publication. | PMC10558477 | ||
Data availability | The original contributions presented in this study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author. | PMC10558477 | ||
Competing interests | Hongchang Cui, Congrui Feng, Tao Zhang, Sidao Cheng, Shumin Cheng, Zhi Duan1were employed by the Qingdao Vland Biotech Co., Ltd and declare no other competing interests. No other author has conflict of interest. | PMC10558477 | ||
References | PMC10558477 | |||
Key words | OBESE | The present study aimed to determine the effect of whole meat GSM powder on gut microbiota abundance, body composition and iron status markers in healthy overweight or obese postmenopausal women. This was a 3-months trial involving forty-nine healthy postmenopausal women with body mass index (BMI) between 25 and 35 kg/m | PMC10214140 | |
Method and materials | PMC10214140 | |||
Study participants | A total of forty-nine New Zealand women aged 55–75 years old who were at least 5 years post-menopause were included in the study. A further inclusion criterion was having a body mass index (BMI) of between 25 and 35 kg/mThis study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving human subjects/patients were approved by the Massey University Human Ethics Committee: Southern A, Application 20/03. Written informed consent was obtained from all subjects/patients. The study was registered with the Australian New Zealand Clinical Trials Registry with the number ACTRN12620000413921p. | PMC10214140 | ||
Study design | Nelson | NELSON, RECRUITMENT | Participants who met the inclusion criteria were randomly assigned to either the GSM or placebo group, stratified by age (55–64, 65–75 years) and BMI (25–29⋅9 kg/mBoth GSM powder and placebo were encapsulated in hard-shell capsules by a commercial facility (Alaron, Nelson, NZ) and stored under nitrogen in the dark at room temperature or lower until use. The GSM and placebo capsules were identically matched in the shape, size and colour of the hard-shell encapsulant. Activated carbon sachets for absorbing moisture and odour were put in bottles to conceal any ‘fishy’ odour.A randomisation list was generated by Excel and maintained by the project's supervising investigator, who did not interact with the study subjects or conduct the primary data analysis. Both the primary researcher and participants were blinded to treatment group allocation until all analyses were completed. Data were collected during participants’ visits at the baseline and the end of the study (week 12). All participants self-reported an omnivorous diet and the majority had the intake of probiotic products at least once a week in their diet before the study and were instructed to maintain their normal diet and physical activity throughout the trial. Recruitment, screening and data collection took place at the Human Nutrition Research Unit (HNRU) at Massey University, Palmerston North, New Zealand from August 2020 to September 2021. | PMC10214140 |
Demographic and anthropometric, and body composition measurements | The data on demographic characteristics were collected from participants at the baseline. The anthropometric measurements including body weight and standing height were measured using a beam balance to the nearest 0⋅2 kg and a stadiometer to the nearest 0⋅1 cm, respectively, at the baseline and the end of the study. BMI was calculated as weight (kg) divided by height squared (m | PMC10214140 | ||
Assessment of physical activity | Physical activity was assessed by the New Zealand Physical Activity Questionnaire – Short Form (NZPAQ-SF)MET values and formula for calculation of MET-minutes were assessed and used as below:
Walking MET-minutes/week at work = 3⋅3 × walking minutes × walking days at work.Moderate MET-minutes/week at work = 4⋅0 × moderate intensity activity minutes × moderate intensity days at work.Vigorous MET-minutes/week at work = 8⋅0 × vigorous intensity activity minutes × vigorous.Total work MET-minutes/week = sum of walking + moderate + vigorous MET-minutes/week scores at work. | PMC10214140 | ||
Dietary intake assessment | Each participant's daily nutrient intake from the diet was measured using a 3-d food record including two weekdays and one weekend day at the midpoint of the trial. The 3-d food record has been recommended and considered the ‘gold standard’ for dietary assessment. Instructions on how to accurately complete the food record were provided | PMC10214140 | ||
Faecal sample collection, DNA isolation and gut microbe quantification | LYSIS | Participants were provided with a stool sample collection kit at the baseline and the end of the study. Each kit contained a container, an anaerobic bag with anaerobic sachet plus a freezer pack. Samples were delivered to the HNRU and stored at −80 °C. Bacterial DNA was extracted using an Isolate Faecal DNA kit (Bioline, NSW, Australia) at the completion of the study. Briefly, 250 μl of each homogenised faecal sample was mixed with 750 μl of lysis buffer in a tube containing bashing beads and processed with a beater at a maximum speed for 10 min to disrupt the cells following the manufacturer's instructions. The faecal DNA was eluted from the column and stored at −80 °C for later analysis. The concentration and purity of extracted DNA were measured using a Nanodrop 2000 Spectrophotometer (Thermo Fisher Scientific, USA). The quantitative real-time polymerase chain reaction (qRT-PCR), using SYBR™ Green Master Mix, was performed on a LightCycler® 480 Real-Time PCR instrument (Roche Applied Science). The specific primers for bacteria are presented in Primers used for quantitative real-time polymerase chain reaction (qRT-PCR) | PMC10214140 | |
Biochemical analysis | inflammation | INFLAMMATION | Non-fasted blood samples were collected at the baseline and the end of the study to measure iron status markers including serum iron, transferrin, ferritin, sTfR, iron saturation, iron binding as well as C-reactive protein (CRP) levels as a marker of inflammation. All biomarkers were analysed at Medlab Central-Palmerston North, New Zealand. In this study, participants were defined as iron-deficient or depleted if they had ferritin <30 μg/l or sTfR was >1⋅76 mg/l. Systemic inflammation was defined as a CRP concentration >5 mg/l. These values are according to hospital-based clinical laboratory reference, and previously published cut-offs | PMC10214140 |
Compliance | Compliance was checked at week 6 and the end of the study by examining the participant's records of their daily intake of study supplements. Compliance was assessed using cumulative capsule counts at the completion of the study, and adherence was measured as a percentage: (number of capsules provided − number of unused capsules)/number of capsules provided ×100. Adherence below 80 % was considered a protocol violation. | PMC10214140 | ||
Statistical methods | SECONDARY | The microbial analyses were secondary objectives of the original trial, and the sample size calculation was not based on detecting significant changes in either gut microbiota abundance, body composition parameters or iron status markers. In brief, the sample size was based on urinary C-telopeptide of type II collagen (CTX-II)/creatinine and serum cartilage oligomeric matrix protein (COMP) as the primary outcomes of the study. The sample size was calculated to detect a 20 % difference between the groups using the standard deviation from the latest lab result. For urinary CTX-II/creatinine a sample size of 60 and for serum COMP a sample size of 17 were required to detect a 20 % difference between groups with a power of 95 %. The serum COMP required a small sample size, thus the average of two outcomes was used for the sample size of 48 ( | PMC10214140 | |
Results | PMC10214140 | |||
Baseline characteristics | ± | Out of fifty-five participants who enrolled in the study, six participants withdrew during the trial due to health issues or being non-compliant. A total of forty-nine participants (GSM, Baseline characteristics of participants who completed the study across the treatment groups (BMI, body mass index; MET, metabolic equivalent of task; sTfR, soluble transferrin receptors; CRP, C-reactive protein.Values are presented as mean ± standard deviation and median presented as (25th and 75th percentile) for normally distributed and non-normally distributed variables, respectively, and Data were available for forty-eight subjects (placebo, Cut-off value according to hospital-based clinical laboratory reference range and previously published.The daily nutrient intake of participants is presented in The daily energy and nutrients intake from the diet (without supplements) of participants across treatment groupsSFA, saturated fatty acids; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; EPA. eicosapentaenoic acid; DHA, docosahexaenoic acid. | PMC10214140 | |
Evaluation of treatment on gut microbiota abundance | ± | The baseline abundance of each selected bacteria is demonstrated in The abundance (mean ± The abundance of bacteria at the baseline and the end of the study were measured by real-time PCR. Data are presented in log scale ng/g faeces (mean ± | PMC10214140 | |
Evaluation of treatment on iron markers and CRP level | The baseline, endpoint and % change from baseline in iron markers of study population across the treatment groups are presented in The baseline, endpoint and % change from the baseline of iron markers and CRP level over the 12 weeks of study across treatment groups (The difference between the groups was compared using the Student's A significant time effect was noted for ferritin using two-way repeated measure ANOVA (The baseline mean ± | PMC10214140 | ||
Evaluation of treatment on body composition parameters | The baseline, endpoint and % change from baseline in body composition parameters across the treatment groups are shown in The baseline, endpoint and % change from the baseline in body composition parameters over the 12 weeks of study across treatment groups (The difference between the groups was compared using the Student's | PMC10214140 | ||
Safety and adverse events | nausea, abdominal pain, reflux | ADVERSE EVENTS, REFLUX | There was no evidence of a change between groups for their lipid profile, liver enzymes and kidney function tests. The majority of participants were tolerant without any side effects. In contrast, five subjects in the GSM group and two subjects in the placebo group reported adverse events including moderate indigestion, reflux, mild abdominal pain and nausea. | PMC10214140 |
Acknowledgements | INFLAMMATION | The authors thank Louise Shaw and Chris Kendrick (Massey University) for phlebotomy and Shampa De (Massey University) for supporting in DNA extraction, PCR analysis. Gabrielle Plimmer for operation of dual-energy X-ray absorptiometry scan.This study was funded by the National Science Challenge, High Value Nutrition (HVN) ‘Musseling-up 2.0: Greenshell™ mussels for inflammation, metabolism and muscular skeletal function (HVN1904)’, as a collaboration between Massey University, Cawthron Institute, Plant and Food Research Ltd, AgResearch and Sanford Ltd. HVN is underwritten by the Ministry of Business, Innovation and Employment (MBIE). The funder has no role or ultimate authority over any of the trial-related management, analysis, writing of the report or the decision to submit the report for publication.M. C. K., J. C. and F. M. W.: Conceptualisation, methodology, supervision; M. A.: Chief investigator, writing original draft preparation. J. C., F. M. W. and P. H.: Writing and reviewing and editing. M. R. M. and H. S. T.: Funding acquisition, review and editing. All authors read and approved the final manuscript.The authors declare no conflict of interest.The data that support the findings of this study are available on request from the corresponding author. | PMC10214140 | |
References | PMC10214140 | |||
Background | DIABETIC MACULAR EDEMA | To investigate the efficacy of injecting suprachoroidal triamcinolone acetonide (SCTA) plus intravitreal bevacizumab (IVB) into patients with center-involving diabetic macular edema (CI-DME). | PMC9881520 | |
Methods | In this phase 2/3 randomized controlled pilot trial, sixty-six eyes with CI-DME and best-corrected visual acuity (BCVA) of at most 20/50 Snellen chart were randomly assigned into two groups. Monotherapy arm received sham injection plus 3 monthly IVB doses and combination arm received a single dose of SCTA and 3 monthly IVB doses. The mean improvements in BCVA and Central subfield thickness (CST), over the three-month was considered the main efficacy outcomes. | PMC9881520 | ||
Results | The mean BCVA improvements were obtained respectively as − 0.20 ± 0.20 log [minimum angle of resolution (MAR)] ( | PMC9881520 | ||
Conclusion | Significant improvements in BCVA and retinal anatomical outcomes demonstrated the additive effects of SCTA to those of anti-vascular endothelial growth factors with no short-term side effects and this combination appears to be a promising option in the management of patients with CI-DME. | PMC9881520 | ||
Trial registration | The trial was registered in Iranian Registry of Clinical Trials (IRCT20200314046761N1). | PMC9881520 | ||
Keywords | PMC9881520 | |||
Background | diabetic retinopathy, Diabetes mellitus | DIABETIC RETINOPATHY, DIABETES MELLITUS | Diabetes mellitus is estimated to involve over 500 million individuals in upcoming decades. The highly-prevalent diabetic retinopathy should also be considered a threat to vision in human in the near future [Many studies have investigated the pharmacologic aspects of the suprachoroidal space (SCS) for delivering pharmacological agents, especially triamcinolone acetonide (TA), to the eye [This manuscript investigated the effect of the novel combination of SCTA and intravitreal bevacizumab (IVB) on managing DME. | PMC9881520 |
Methods | PMC9881520 | |||
Study design | This prospective phase 2/3 triple-blind, uni-center parallel-group randomized controlled pilot trial was conducted to investigate the efficacy of a combination of SCTA and IVB administered in patients with DME. The study designed as per the Declaration of Helsinki was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (IR.MUI.MED.REC.1398.410). All the participants were briefed on the benefits/risks of the study, asked to sign informed consent forms and then included in the study. The trial was registered in Iranian Registry of Clinical Trials (IRCT20200314046761N1, first registration date: 21/03/2020). | PMC9881520 | ||
Participants | dystrophies, lens opacity, optic disc lesions, retinal or glaucoma, uveitis, Diabetic Retinopathy, retinal and macular dystrophies, corneal haziness, cataract, ocular pathologies, vitreous hemorrhage, hypersensitivity, vision loss | UNCONTROLLED HYPERTENSION, DYSTROPHIES, SCAR, UVEITIS, DIABETIC RETINOPATHY, RETINA, EYE, CATARACT, CHOROIDAL NEOVASCULARIZATION, DIABETIC MACULAR EDEMA, VITREOUS HEMORRHAGE, HYPERSENSITIVITY, TYPE 2 DIABETES MELLITUS | The present study population comprised patients aged at least 18 years with vision loss caused by type 2 diabetes mellitus presenting to the retina clinic of Feiz Eye Hospital affiliated to Isfahan University of Medical Sciences. The eligibility criteria consisted of having center-involving diabetic macular edema (CI-DME) diagnosed with spectral domain optical coherence tomography (SD-OCT) (SECTRALIS, Heidelberg), a central subfield thickness (CST) of at least 320 μm and a baseline best-corrected visual acuity (BCVA) of at most 20/50 Snellen chart, approximately equivalent to 65 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores [The exclusion criteria encompassed uncontrolled hypertension, history of intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections and focal/grid/pan-retinal laser photocoagulation of at most 3 months in the study eye prior to the first visit, history of intravitreal or peribulbar corticosteroid injections over the previous 6 months and prior suprachoroidal corticosteroid injections or intravitreal corticosteroid implants in the study eye, having the study eye undergo a cataract surgery within the previous 3 months or a significant lens opacity confirmed through expert examinations potentially requiring surgeries within the following 6 months, history of retinal or glaucoma surgery in the study eye, requiring anti-glaucoma drops for lowering IOP, other ocular pathologies in the study eye with potential inadvertent effects on the visual and anatomical outcomes, including corneal haziness and dystrophies, uveitis, retinal and macular dystrophies, active proliferative diabetic retinopathy with or without vitreous hemorrhage, choroidal neovascularization, macular scar and optic disc lesions, systemic conditions contraindicating to using corticosteroids, hypersensitivity to TA or bevacizumab, pregnancy and breastfeeding. | PMC9881520 |
Sample size and randomization | The sample size was calculated as 30 per group with a test power of 80% and a type I (two-sided) error of 5% corresponding to a mean BCVA difference of 10 ± 15 as our primary outcome reported in ETDRS letter scores for two study arms [Randomized sequences generated using a random number generator in SPSS and permuted blocks of size 4 at a 1:1 ratio were transferred to sealed envelopes, which revealed the next treatment assignment once a participant was included. | PMC9881520 | ||
Intervention protocol | STERILE, ANTERIOR, SCLERA | Every participant received three consecutive anesthetic drops every five minutes before beginning the procedure. During the first injection session, after placing an eyelid speculum and disinfecting the ocular surface with a 10% povidone-iodine solution for 30 seconds in all study eyes, 0.1 ml (4 mg) of TA (Exir Pharmaceutical Co., Iran) was injected into SCS 3–4 mm posterior to the limbus supratemporally with a 900–1000 μm terminally sharp sterile 30-gauge custom made needle in the combination arm. Detailed steps of preparing the needles was shown in Fig. Detailed steps of preparing the custom made needle to perform suprachoroidal triamcinolone acetonide injection. A different syringe was then used to inject 1.25 mg per 0.05 ml of IVB (Avastin, Roche) into the superior/temporal quadrant 3–4 mm posterior to the limbus. Anterior chamber paracentesis was ultimately performed to reduce IOP. A sham injection performed by pressing the sclera with a needleless syringe was followed by injecting (1.25 mg/0.05 ml) of IVB into the supratemporal quadrant 3–4 mm posterior to the limbus in the monotherapy arm. The patients were monitored in the clinic for about 30 minutes after the injections. Two days later, the injection was performed into the other eye of the patients whose both eyes were included in the study. All the participants received the same dose of IVB per month as that of the first session the following 2 months.The patients were examined at baseline, and the first injection was performed within 7 days. Follow-ups were performed on the 28-35th day, and 90-100th day of the first injection session. Visual acuity was evaluated with and without refraction using a standard Snellen chart with the distance of 20 ft (6 m). Detailed ophthalmologic examinations of the individual study eyes included slit-lamp biomicroscopy, dilated fundus examination, IOP measurement and SD-OCT, which was used to evaluate CST and macular volume (MV) were then performed. Experts blinded to the grouping and data collected from the previous examinations each performed a single study task. | PMC9881520 | |
Outcomes | cataract, hemorrhage | CATARACT, HEMORRHAGE, BACTERIAL ENDOPHTHALMITIS, ADVERSE EVENTS | The superior efficacy of the combination of SCTA and IVB compared to that of IVB alone, was the primary outcome of this three-months, randomized pilot study which will be achieved through between group analysis of the mean BCVA changes after the study was completed. Secondary outcomes were obtained from comparing the following between the study arms: (1) mean changes in BCVA, 4 weeks after baseline (2) proportion of patients with at least 15 ETDRS letter scores improvement in BCVA after twelve weeks (3) mean changes in CST and MV, four and twelve weeks after baseline (4) proportion of participants requiring additional treatments such as continuing monthly IVB injections, intravitreal corticosteroid injections and focal/grid laser photocoagulation based on expert diagnoses owing to persistent DME after three monthly injections. Persistent DME respectively defined as CST of at least 320 and 305 μm in the males and females was diagnosed through SD-OCT (Heidelberg, Spectralis) [Incidence of acute bacterial endophthalmitis, mean changes in IOP, four and twelve weeks after baseline, incidence of cataract progression and incidence of sub-conjunctival hemorrhage, were considered the possible adverse events. | PMC9881520 |
Statistical analysis | SD | The continuous and categorical data were reported as mean ± SD and frequency and relative frequency. The normality of the continuous data was evaluated using the Kolmogorov-Smirnov test and Q-Q plots. The non-normal positively-skewed data underwent a logarithmic transform. Continuous, categorical, demographic and clinical characteristics of the study participants were compared between the two groups using the independent t-test and Chi-squared test. Within-group and between-group comparisons were performed in terms of the main outcomes using a linear mixed-effects model. The effects of confounding factors were controlled by adjusting for the baseline outcomes in cases of significant practical or statistical differences. An analyzer blinded to the grouping analyzed the data in SPSS Statistics for Windows, version 16.0 (SPSS Inc., Chicago, Ill., USA). | PMC9881520 | |
Results | PMC9881520 | |||
Efficacy | PMC9881520 | |||
Retinal thickness and volume | Significant reductions were observed in CST between baseline and the study endpoints in the monotherapy arm. The mean decrease in CST was 76 μm (95% CI 15 to 138, The graph showed mean values of central subfield thickness at baseline and the study endpoints in both study arms. CST: central subfield thickness, IVB: Intravitreal bevacizumab, SCTA: Suprachoroidal triamcinolone acetonideOn the 12th week, a normal CST was observed based on its gender-specific normal threshold values in 8 (25%) and 14 (53.8%) eyes in the monotherapy and combination arms, respectively. The statistical analyses revealed the synergistic effects of a single dose of SCTA, which significantly increased the normal CST values with an odds ratio of 3.5 (95% CI 1.2 to 10.6, In addition to CST, MV significantly decreased in both study arms. After four and twelve weeks, the mean resolution in MV was respectively obtained as 0.7mmThe graph showed mean values of macular volume at baseline and the study endpoints in both study arms. MV: macular volume, IVB: Intravitreal bevacizumab, SCTA: Suprachoroidal triamcinolone acetonide | PMC9881520 | ||
Adverse events | CAVITY, ACUTE ENDOPHTHALMITIS | Acute endophthalmitis was observed in none of the study eyes. TA was inadvertently injected into the vitreous cavity of 2.2% (There was no significant IOP rising which needed medical or surgical treatment (over 10, 25 or 30 mmHg) observed in any of the participants. The mean IOP respectively obtained as 14.9 ± 2.7, 15 ± 1.9 and 15.5 ± 2.2 mmHg at baseline and after four and twelve weeks in the monotherapy arm and as 15.3 ± 3.2, 16 ± 3.1 and 16.1 ± 2.6 mmHg in the combination arm. There was no significant IOP rising noticed in each groups during the study period (Table | PMC9881520 | |
Discussion | diabetic retinopathy, retinal tumors, retinal diseases, hyperglycemia, diabetes | DIABETIC RETINOPATHY, AGE-RELATED MACULAR DEGENERATION, RETINAL VEIN OCCLUSION, RETINAL DISEASES, PATHOPHYSIOLOGY, HYPERGLYCEMIA, ADVERSE EFFECTS, RETINA, INFLAMMATIONS, SCLERA, MACULAR EDEMA, DIABETES | This two-arm randomized pilot trial was conducted to evaluate the efficiency of adding a single dose of SCTA to IVB, as a popular anti-VEGF agent especially in developing countries, in managing CI-DME in treatment-naive eyes. The findings showed significant clinical and statistical improvements in BCVA and retinal anatomical outcomes in the eyes injected with this novel combination compared to in those receiving IVB.Today, anti-VEGF agents are commonly used as the first-line therapy for macular edema caused by retinal diseases such as age-related macular degeneration, retinal vein occlusion, certain retinal tumors and diabetic retinopathy [Reviewing the pathophysiology of DME can clarify the high unresponsiveness rates observed. Das et al. explained the pathophysiology of diabetic retinopathy by reporting four major biochemical mechanisms induced by hyperglycemia [Compared to IVB alone, IVB in combination with fusadil hydrochloride as a Rho/Rho kinase inhibitor was found by Ahmadieh et al. to cause better and prolonged visual outcomes and no significant adverse effects on patients with CI-DME [The properties of corticosteroids have been well addressed in literature. SCS lies between the choroid and sclera in healthy eyes. Exploring the safety and pharmacodynamics of SCTA injections in rabbit models, Chen et al. reported a significantly-higher drug concentration in the posterior retina than in the anterior segment. They also found that the resolution of both anterior and posterior segment inflammations was also significantly higher in suprachoroidal drug delivery compared to in posterior sub-tenon injection of TA [According to the Tanzanite clinical trial, SCTA plus intravitreal aflibercept (IVA) was well tolerated compared to IVA alone in patients with retinal vein occlusion. The number of injections also significantly decreased and BCVA and retinal thickness significantly improved in the combination arm [The present study limitations mainly comprised its small sample and relatively short-term follow-ups. Given the COVID-19 pandemic in Iran, the eight-week follow-up was not completed in the majority of the participants, resulting in unreliable data. Lack of a group with the combination injection of posterior subtenon triamcinolone acetonide and IVB was another limitation of this study.To the best of the authors’ knowledge, this study pioneered the investigation of the synergistic effects of SCTA and IVB in patients with diabetes. The strengths of the present research encompassed its randomization, the patients and evaluators masking to avoid possible bias, adherence to the study protocol and not depriving the patients from a confirmed treatment (ant-VEGFs). It is recommended that large clinical trials with longer-term follow-ups be performed to investigate the synergistic and sole effects of SCTA injections and report its potential adverse effects in patients with DME. | PMC9881520 |
Acknowledgements | The authors would like to express their special thanks to Tavangar H, MD, for his valuable assists for medical writing of this article. | PMC9881520 | ||
Authors’ contributions | F.F. and M.F. contributed to the design of the study. F.F. M.M. B.O. M.T. and M.F. contributed to the data gathering. A.F. and M.F. contributed to the data analysis. A. F and M.F. contributed to the writing of the manuscript. F.F. and M.M. contributed to the revising of the manuscript. All the authors read and approved the final manuscript. | PMC9881520 | ||
Funding | The study was supported by Vice Chancellery for Research and Technology, Isfahan University of Medical Sciences, Isfahan, Iran. Funding organization participated in ethical and scientific approval, before the study began. | PMC9881520 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC9881520 | ||
Declarations | PMC9881520 | |||
Ethics approval and consent to participate | The research was conducted in full compliance with ethical principles and in accordance with the World Medical Association Declaration of Helsinki and it was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran (IR.MUI.MED.REC.1398.410). The patients signed written informed consents for participation. | PMC9881520 | ||
Consent for publication | The patients signed written informed consents for publication of their clinical information and photos. | PMC9881520 | ||
Competing interests | The authors declare that they have no competing interests. | PMC9881520 | ||
References | PMC9881520 | |||
Objective | MALE SEXUAL DYSFUNCTION | Academic Editor: Samar Tharwat Female sexual dysfunction is a common distressing problem among women, which may result from reducing circulating endogenous estrogen. | PMC10125751 | |
Methods | In the current randomized clinical trial, study populations consisted of 63 postmenopausal women who were randomly categorized into two groups. In the hop group ( | PMC10125751 | ||
Results | sexual pain | No statistically significant differences in FSFI scores (sexual desire, sexual arousal, vaginal lubrication, satisfaction, orgasm, sexual pain, and total FSFI) ( | PMC10125751 | |
Conclusion | sexual dysfunction | ADVERSE EVENTS | Vaginal hop was as effective as estradiol in improving the sexual dysfunction among postmenopausal women with no adverse events. This trial is registered with | PMC10125751 |
1. Introduction | digestive disorders, Female sexual dysfunction, anxiety, Since sexual dysfunction, sexual dysfunction, insomnia, depression | MALE SEXUAL DYSFUNCTION, ESTROGEN DEFICIENCY, DIGESTIVE DISORDERS | Female sexual dysfunction is a common distressing problem among about 30 to 50% of women, which could have consequences on the couple's overall relationship [Humulus lupulus L., commonly known as hop, is a plant belonging to the Cannabaceae family, widely grown in Europe, Asia, and North America. Hop has traditionally been used in the brewing industry. Hop also has been known for numerous biological activities, such as sedative, antimicrobial, and estrogenic properties. Hence, hop has been used to relieve insomnia, irritation, anxiety, depression, and digestive disorders [Since sexual dysfunction among postmenopausal women may be related to estrogen deficiency, hop, as a natural product with estrogenic properties, may be administrated as a well-tolerated and efficacious treatment for relieving sexual dysfunction. The current study aimed to investigate hop as an alternative to estrogen to treat sexual dysfunction among postmenopausal women. | PMC10125751 |
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