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DBS and venous characteristics associated with agreement between measurements | SAID | Of the DBS characteristics covariates tested, all impacted the association between serum and DBS measurements of at least one analyte. This means that models with an interaction between DBS values and the covariate in question significantly differed to the same nested model without said interaction. The number of spots influenced the agreement between venous and venous-equivalent DBS measures of HbA1c, the quality of DBS spots influenced the agreement between CRP measures, whether sample processing was delayed impacted HbA1c and total cholesterol, the number of days between collection of the DBS sample and − 70 °C storage also impacted HbA1c and total cholesterol such that adverse conditions tended to be associated with higher equivalence values. Days between venous blood collection and lab delivery was not significantly associated with any analyte (Supplementary Material | PMC10415328 | |
Using DBS data to assess disease prevalence | overestimation of disease, diabetes | DISEASE, DIABETES | Using total cholesterol, HbA1c and CRP data, we compared the prevalence of disease in venous and venous-equivalent DBS. Comparable measurements should lead to a similar prevalence of disease in nurse and self-collection mode. However, participants who reported doctor diagnosed diabetes were less likely to provide a venous sample than take part in the nurse home visit. In the population that provided a venous sample, reported any diabetes diagnosis and had HbA1c values measured, 5.7% of participants report that a doctor told them they have diabetes compared to 8.7% who had diagnosed diabetes in those that provided a self-collected DBS sample and had their HbA1c values analysed (Table Unweighted and weighted percentages for those diagnosed with diabetes and above clinical cut points in serum-equivalent DBS based measures of HbA1c, total cholesterol and C-reactive protein.In venous-equivalent DBS measurements an overestimation of disease for diabetes prevalence may have occurred. However, there may also be an underestimation of diabetes in the nurse visit as the prevalence of doctor diagnosed diabetes is lower than in DBS arm of the experiment. Further, it was noted that higher proportion of HbA1c values above 3SD were found in those reporting doctor diagnosed diabetes in the nurse visit than in from those reporting doctor diagnosed and providing a DBS (Supplementary Materials | PMC10415328 |
Discussion | hypercholesterolaemia | DISEASE, HYPERCHOLESTEROLAEMIA | Our findings suggest that, while response rates for self-collected DBS samples are around half that in a nurse visit, characteristics of participants are unbiased with respect to educational attainment, self-rated health and longstanding illness. While measurement quality of HbA1c and HDL-cholesterol may be inconsistent by DBS, a high proportion of DBS samples were classified as ‘good’, and DBS can be a cost-effective alternative in large-scale surveys/studies to assess sub-clinical and clinical disease burden.Our findings suggest that DBS collection is a feasible collection method. The analyses presented generally accord with findings from other population studies that have introduced self-collection and observed reduced response ratesWe developed reliable methods for the collection of DBS and measurement of total cholesterol, triglycerides, CRP and HbA1c in DBS but less successfully for the measurement of HDL-cholesterol in accordance with someDespite these constraints, equivalence of the DBS data to predict prevalence of disease from the self-collected study samples suggested that equivalence was sufficient for us to accurately describe population prevalence of hypercholesterolaemia and elevated CRPOur study has a number of strengths. Unlike previous studies we randomly assigned households to receive a nurse visit to collect a venous and DBS sample. Our findings of similar clinical characteristics by mode of collection, as would be expected in a well randomised study, provide more robust findings of equivalence. Thus, our study is not subject to the biases associated with earlier observational studies. Our study is large, spans the adult age range and our sampling strategy means that we can make population level inferences through the use of inverse probability weighting. The analysis of a proportion of samples was delayed with the closure of laboratories during the COVID-19 pandemic, which enabled us to examine delay of measurement in our analyses previously described to impact integrity of measurements in the DBSWe conclude that while self-collection of DBS samples is feasible, there are lower response rates than in face-to-face sample collection. However, the use of DBS permits large scale collection in an unbiased way that would enable comparable population disease estimates as from venous samples collected by a nurse. We recommend DBS for large scale studies of cardiovascular risk factors collected by participants themselves. Research supports the collection of samples for a wider range of analytes and measures | PMC10415328 |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-39674-6. | PMC10415328 | ||
Acknowledgements | We would like to thank Shavanthi Rajatileka and Melissa Smart for their significant contribution to the design and management of IP12, and Annette Jäckle for her contribution as Director of the Innovation Panel. | PMC10415328 | ||
Author contributions | M.K. conceived the idea for this paper and led the design with input from A.A., T.A.B., M.B., J.B. and T.C. K.S.J., A.K. and D.A.P. designed and led the analyte measurements. A.A. undertook all data analysis with input from M.K. M.K. and A.A. drafted the paper, with all authors critically revising the manuscript. All authors have approved the final version. | PMC10415328 | ||
Funding | MK, AA, TAB, JB, TFC, MB and data collection for this study is funded by ESRC (ES/N00812X/1). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Understanding Society:UKHLS is an initiative funded by the Economic and Social Research Council (ES/S007253/1) and various Government Departments, with scientific leadership by the Institute for Social and Economic Research, University of Essex, and survey delivery by NatCen Social Research and Kantar Public. The research data are distributed by the UK Data Service. KSJ, DAP, and AK are supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (IS-BRC-1215- 20014). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. | PMC10415328 | ||
Data availability | Data from the | PMC10415328 | ||
Competing interests | The authors declare no competing interests. | PMC10415328 | ||
References | PMC10415328 | |||
BACKGROUND: | premature cardiovascular events | HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA, HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA, GENETIC DISEASE, HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA | Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. | PMC10815002 |
METHODS: | ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C–lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. | PMC10815002 | ||
RESULTS: | The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was −1.68% (95% CI, −29.19% to 25.83%; | PMC10815002 | ||
CONCLUSIONS: | HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA | Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. | PMC10815002 | |
REGISTRATION: | URL: | PMC10815002 | ||
Clinical Perspective | PMC10815002 | |||
What Is New? | This 24-month study evaluated the efficacy, safety, and tolerability of inclisiran in patients with homozygous familial hypercholesterolemia and elevated low-density lipoprotein cholesterol (LDL-C) levels despite maximum tolerated doses of LDL-C–lowering therapies with or without lipoprotein apheresis.There was no statistically significant difference in LDL-C reduction from baseline to day 150 between the placebo and the inclisiran group despite a reduction in PCSK9 (proprotein convertase subtilisin/kexin type 9) levels of 60% that was sustained throughout the study. | PMC10815002 | ||
What Are the Clinical Implications? | LDL-C reduction | GENETIC DISEASE, HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA, HOFH, HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA | Although this study did not show a statistically significant reduction in LDL-C level in patients with homozygous familial hypercholesterolemia, inclisiran demonstrated a sustained reduction in PCSK9 levels and was well-tolerated, with a safety profile consistent with previous studies.Despite the lack of significant LDL-C reduction with inclisiran, the observations in the subsets with some residual
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease that affects ≈1 in 300 000 people worldwide.Lowering LDL-C levels in patients with HoFH reduces the incidence of cardiovascular eventsThe phase 2 ORION-2 (URL: | PMC10815002 |
METHODS | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC10815002 | ||
Study Design and Treatment | ORION-5 (URL: The study had 2 sequential parts. Part 1 consisted of a 6-month double-blind placebo-controlled phase in which eligible patients were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) subcutaneously or placebo at day 1 and day 90. Part 2 consisted of an 18-month open-label, single-arm phase in which patients already receiving inclisiran continued treatment, and placebo-treated patients from part 1 were transitioned to inclisiran and received their first dose of inclisiran subcutaneously on day 180. All patients in part 2 received subsequent doses of inclisiran on days 270, 450, and 630, with an end-of-study visit on day 720. The study design of ORION-5 is presented in | PMC10815002 | ||
Study Population | xanthoma | XANTHOMA, HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA, HOFH | The study included participants aged ≥18 years with genetic confirmation or clinical diagnosis of HoFH on the basis of a history of an untreated LDL-C concentration >500 mg/dL (13 mmol/L) together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents. Patients were eligible for inclusion if they had a fasting LDL-C level ≥130 mg/dL (≥3.4 mmol/L) despite receiving a maximally tolerated dose of statin therapy with or without ezetimibe. Patients receiving anti-PCSK9 therapies within 90 days of screening were excluded. Details on the inclusion and exclusion criteria are provided in the All patients were instructed to follow a National Cholesterol Education Program Adult Treatment Panel III (or comparable) diet and required to maintain their current LDL-C–lowering drug therapy for the duration of the study.Patients with a documented regimen of LDL or plasma apheresis were allowed to continue the regimen during the study with similar frequency and timing as baseline. When apheresis was performed on a study visit (dosing or non-dosing visit), blood samples for the measurement of LDL-C and other lipid levels were collected and laboratory assessments were undertaken before the apheresis. When apheresis was performed on a dosing visit, inclisiran was administered just after the completion of apheresis. No apheresis was performed within 72 hours after dosing of inclisiran. The subsequent study visits were planned to occur at least 2 weeks after apheresis to ensure LDL-C levels measured during a study visit were not confounded by apheresis. | PMC10815002 |
Genotyping | Genotyping was performed by a central laboratory or was available from the medical records of the study population. On the basis of this assessment, patients were categorized as homozygous | PMC10815002 | ||
Ethical Considerations | ORION-5 was conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E6 guideline for Good Clinical Practice, which has its origin from the Declaration of Helsinki. The study protocol and all amendments were approved by the independent ethics committee or institutional review board of all participating centers. All patients provided written informed consent. | PMC10815002 | ||
Data Sharing Statement | Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The availability of these trial data is according to the criteria and process described at | PMC10815002 | ||
Efficacy End Points | SECONDARY, HOFH | The primary end point was the percentage change in LDL-C level from baseline to day 150 (part 1 of the study). Key secondary end points were the absolute change in LDL-C level from baseline to day 150 and the percentage change in apoB (apolipoprotein B100), non–high-density lipoprotein cholesterol (non-HDL-C), and total cholesterol levels from baseline to day 150. Other secondary end points were the absolute and percentage changes in LDL-C, PCSK9, apoB, non–HDL-C, lipoprotein(a), and total cholesterol levels from baseline to day 720.An exploratory end point evaluated the response of LDL-C level reduction by underlying causal sequence variations of HoFH at day 150. A post hoc analysis was conducted to evaluate the placebo-corrected percentage change in LDL-C level from baseline, excluding patients with apheresis and double-null alleles for | PMC10815002 | |
Safety End Points | ADVERSE EVENTS | The safety and tolerability profile of inclisiran was measured by adverse events (AEs), serious AEs, and clinical laboratory values. In addition, an anti-inclisiran antibody analysis was performed. AEs were assessed from baseline to each assessment time up to day 720. Data captured during part 1 (up to day 180) were presented by the part 1 treatment group (inclisiran or placebo), whereas data captured during part 2 (after day 180 up to day 720) were presented by the part 2 treatment group (inclisiran–inclisiran or placebo–inclisiran). | PMC10815002 | |
Statistical Analysis | PMC10815002 | |||
Sample Size Calculation | It was calculated that a sample size of at least 45 patients (randomized 2:1 to inclisiran:placebo), with at least 30 patients in the inclisiran arm, would provide >80% power to detect a 20% reduction (assuming an SD of 20% in each arm) in placebo-corrected LDL-C levels from baseline to day 150 in the inclisiran group compared with the placebo group at a 1-sided significance level of 0.025 based on a 2-sample | PMC10815002 | ||
Missing Data Imputation | SECONDARY | Missing values in part 1 were imputed for the primary and key secondary end points using a prespecified multiple imputation (a total of 100 imputed data sets) washout model. The washout model can be thought of as a modified control-based pattern–mixture model. This was used to explore the possibility of data missing not at random for patients who discontinued the study early. For patients who discontinued the study early in the inclisiran group, their missing values for day 150 were imputed under the assumption that their outcome would be similar to those in the placebo group with similar background characteristics. For patients in the placebo group, their missing values over all visits after early termination were imputed based on the missing at random assumption. Multiple imputation was used to account for uncertainty in the imputation process and results from the imputed data sets were combined using the Rubin method. | PMC10815002 | |
Efficacy Analysis | SECONDARY | The primary analysis was conducted on the intent-to-treat population and based on an ANCOVA model on the percentage change in LDL-C level from baseline to day 150 on each multiply imputed data set (100 total). The model included the part 1 treatment group as a fixed effect and the baseline LDL-C level as a covariate. Treatment effects from these 100 ANCOVA analyses were combined using the Rubin method.The key secondary end points were analyzed from a similar ANCOVA model using the same multiply-imputed washout model as the primary efficacy end point. For the other secondary end points, descriptive and graphical summaries by treatment group were presented. The mixed-effects model for repeated measures was performed to analyze other secondary end points, such as the absolute or percentage change from baseline over time up to day 180 for LDL-C, PCSK9, and other lipid levels. The model included fixed effects of the part 1 treatment group, visit (day 90, day 150, and day 180), baseline value, and the interaction between treatment and visit. The restricted maximum likelihood estimation approach was used with the covariance structure set as “unstructured.” The least squares means were calculated for each treatment at each visit, and linear combinations of the estimated least squares mean were used to form The analysis of the exploratory end point was similar to that of the primary end point. The post hoc analysis was conducted similar to that of the other secondary end points.All end points were tested using a 2-sided significance level of 0.05. The | PMC10815002 | |
Safety Analysis | Safety variables were summarized descriptively by parts and treatment groups. Safety was analyzed in the safety population comprising all patients who received ≥1 dose of the study drug using the standard Medical Dictionary for Regulatory Activities nomenclature.All analyses were performed with SAS software (version 9.4). | PMC10815002 | ||
RESULTS | PMC10815002 | |||
Baseline Demographic Characteristics | death, ASCVD | ASCVD | Overall, 56 patients were enrolled, of whom 37 were randomized to the inclisiran group and 19 to the placebo group. A total of 53 patients (94.6%) completed part 1, 47 of whom (88.7%) also completed part 2. The reasons for discontinuation were death, withdrawal of consent, or “other” (Overall, the mean (SD) age of patients was 42.7 (12.9) years, and 60.7% were women. A total of 67.9% of patients had established ASCVD, and 32.1% had an ASCVD risk equivalent (Table Demographic and Baseline Characteristics (Intent-to-Treat Population) | PMC10815002 |
Key Secondary End Points | The placebo-corrected absolute change in LDL-C level from baseline to day 150 was 6.47 mg/dL, which was not statistically significant ( | PMC10815002 | ||
Other Secondary End Points | The placebo-corrected absolute and percentage changes from baseline by visit for LDL-C, apoB, non–HDL-C, lipoprotein(a), and total cholesterol levels were not statistically significant at any time point.The reductions in PCSK9 levels from baseline to days 90, 150, and 180 were consistently greater in the inclisiran group than in the placebo group and were statistically significant. The placebo-corrected absolute change in PCSK9 level from baseline to day 180 ranged between −304.4 µg/L (95% CI, −408.0 µg/L to −200.8 µg/L) and −390.4 µg/L (95% CI, −504.5 µg/L to −276.3 µg/L; | PMC10815002 | ||
Safety Evaluation | pyrexia, deaths, erythema, diarrhea | VIRAL RESPIRATORY TRACT INFECTION, ADVERSE EVENT, SUDDEN CARDIAC DEATH, CORONAVIRUS INFECTION, ERYTHEMA, VIRAL PNEUMONIA, MULTIPLE ORGAN DYSFUNCTION SYNDROME, EVENTS | A summary of the treatment-emergent AEs and the treatment-emergent serious AEs in part 1 and in part 2 is shown in Table Treatment-Emergent Adverse Events (Safety Population)The most commonly reported treatment-emergent AEs did not differ between treatment groups in either part of the study. In part 1, the most common treatment-emergent AEs were viral respiratory tract infection (n=2 [5.4%] inclisiran; n=2 [10.5%] placebo), diarrhea, and pyrexia (n=2 [5.4% inclisiran]; 0 placebo); in part 2, they were coronavirus infection (n=3 [8.8%] inclisiran–inclisiran; n=1 [5.3%] placebo–inclisiran) and an increased international normalized ratio (n=2 [5.9%] inclisiran–inclisiran; n=1 [5.3%] placebo–inclisiran). During the entire study, only one patient (2.9%) had an AE at the injection site (erythema); this was in the inclisiran–inclisiran group during part 2, and the AE was mild in severity, not persistent, and resolved rapidly.Although the AEs and serious AEs were based on a small number of events reported in a small data pool, the incidences of these did not differ between the inclisiran and placebo groups throughout the entire study or between the parts of the study. Three deaths were reported during the study, all during part 2. None of these deaths were related to inclisiran treatment, and all were attributed by the investigator to other factors (multiple organ dysfunction syndrome, sudden cardiac death, and viral pneumonia). No anti-inclisiran antibodies were detected in any of the samples during the study. | PMC10815002 |
DISCUSSION | SECONDARY, HOFH | ORION-5 did not meet its primary objective of detecting a statistically significant difference in the percentage change in LDL-C levels from baseline to day 150 between the inclisiran and placebo groups. Placebo-corrected changes in PCSK9 levels from baseline to day 150 were observed with inclisiran treatment and were sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant changes were observed in the levels of other lipids and lipoproteins (apoB, non–HDL-C, lipoprotein[a], and total cholesterol) between the inclisiran and placebo groups.In the ORION-2 proof-of-concept study, 3 of the 4 patients with HoFH showed a substantial reduction in LDL-C levels that was maintained for 180 days.Patients with HoFH often show high genetic variability, and the response to LDL-C–lowering therapies is affected by sequence variations mainly related to the A small study population with a heterogeneous set of genetic variants might have affected the treatment responses to inclisiran in the current study, leading to the study not meeting its primary end point and several secondary end points. There were 13 null/null patients with a homozygous or compound heterozygous In the real world, suboptimal adherence and persistence to daily LDL-C–lowering therapy is the most likely reason for not achieving the guideline-recommended LDL-C goals in many patients.Lipoprotein apheresis is often used as an adjunct therapy in patients with HoFH who do not achieve sufficient lowering of LDL-C level despite optimum LDL-C–lowering therapy.HoFH is difficult to treat, and patients often require treatment with multiple therapies. | PMC10815002 | |
Conclusions | HOFH | In this study, although inclisiran treatment did not result in a statistically significant reduction in LDL-C level compared with placebo, the sustained reduction in PCSK9 levels demonstrates target engagement with inclisiran even in patients with HoFH. Inclisiran was well-tolerated, and the safety findings are consistent with previously reported studies and the overall safety profile. No new safety signals were identified during the study. | PMC10815002 | |
ARTICLE INFORMATION | PMC10815002 | |||
Acknowledgments | The authors thank Ganesh Pedgaonkar, PhD, Vennila Dharman, MBBS, and Ritika Paul, MSc, MPhil, of Novartis Healthcare Pvt Ltd, for providing medical writing support in accordance with Good Publication Practice 2022 guidelines (Good Publication Practice Guidelines for Company-Sponsored Biomedical Research; 2022 Update; | PMC10815002 | ||
Sources of Funding | Novartis Pharma AG initiated and provided funding for this study and provided medical writing and editorial support in the development of the manuscript. The funder was also involved in study design and data collection, analysis, and interpretation, as well as review and feedback on the manuscript. The authors, who include both academic investigators and employees of the funder, had full editorial control of the manuscript and provided final approval of all content. All authors had access to the data and contributed to the review of and revisions to manuscript drafts. All authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. | PMC10815002 | ||
Disclosures | Dr Raal received consulting fees and honoraria from Amgen, Novartis Pharmaceuticals, Regeneron Pharmaceuticals, and LIB Therapeutics. Dr Durst received consulting fees and honoraria from Novartis and Sanofi, lecturing fees from Novartis, and honoraria from Medison. Drs Bi, Talloczy, Maheux, and Lesogor are full-time employees of Novartis and have Novartis stocks or stock options. Dr Kastelein received consulting fees from 89Bio, Esperion Therapeutics, Madrigal, CiVi Therapeutics, North Sea Therapeutics, CSL-Behring, Novartis, Inversago, Draupnir, CinCor, and Scribe Therapeutics; is a board member of North Sea and Staten Biotech; is Chief Scientific Officer of New Amsterdam Pharma; is acting Chief Medical Officer of Staten Biotech; and holds stock and stock options in New Amsterdam. | PMC10815002 | ||
Supplemental Material | AppendixTable S1Figures S1–S3 | PMC10815002 | ||
Supplementary Material | PMC10815002 | |||
REFERENCES | PMC10815002 | |||
Methods | An external rehearsal pilot cluster randomised controlled trial in four NHS Trusts (clusters) in England, UK. Clusters were randomised to intervention (where all eligible midwives received the intervention) or control (no intervention delivered) arms. A random sample of 100 midwives were invited to complete questionnaires pre- and post-intervention. UK guideline recommendations relating to midwives’ practice were categorised into: 1) communication-related behaviours (including weight- and risk-communication), and 2) support/intervention-related behaviours (including diet/nutrition, physical activity, weight management, referrals/signposting). Questionnaires were developed using SCT constructs (self-efficacy, outcome expectancies, intentions, behaviours) and 7-point Likert scale, converted to a 0–100 scale. Higher scores were more positive. Descriptive statistics compared intervention and control arms, pre- and post-intervention. | PMC9858407 | ||
Results | Seventy-four midwives consented and 68 returned questionnaires. Pre-intervention, self-efficacy for support/intervention-related behaviours scored lowest. In controls, there was limited difference between the pre- and post-intervention scores. Post-intervention, mean (SD) scores were consistently higher among intervention midwives than controls, particularly for support/intervention self-efficacy (71.4 (17.1) vs. 58.4 (20.1)). Mean (SD) self-efficacy was higher post-intervention than pre-intervention for all outcomes among intervention midwives, and consistently higher than controls. Mean differences pre- and post-intervention were greatest for support/intervention self-efficacy (17.92, 95% CI 7.78–28.07) and intentions (12.68, 95% CI 2.76–22.59). Self-efficacy was particularly increased for diet/nutrition and physical activity (MD 24.77, 95% CI 14.09–35.44) and weight management (18.88, 95% CI 7.88–29.88) behaviours, which showed the largest increase in scores. | PMC9858407 | ||
Conclusions | This study supports the theoretical models used to develop GLOWING, where low self-efficacy was a core implementation barrier. Results suggest that GLOWING successfully targets self-efficacy, potentially with a positive impact on guideline implementation. A definitive trial is required to determine effectiveness. | PMC9858407 | ||
Data Availability | Data cannot be shared publicly because ethical approval and consent did not specify this and some participants could potentially be identifiable from the data. Requests to access the data must be made to the approving Ethics Committee (Proportionate Review Sub-committee of the Yorkshire & The Humber—South Yorkshire Research Ethics Committee (ref: 15/YH/0565, 16/12/2015), contact via | PMC9858407 | ||
Introduction | Obesity, weight gain, weight retention | OBESITY | More than half of women enter pregnancy with a body mass index (BMI) in the overweight (BMI≥25kg/mWeight management interventions delivered during pregnancy can significantly improve women’s diet and physical activity (PA) behaviours, reduce GWG and postnatal weight retention, and reduce the risk of developing some adverse pregnancy outcomes [In the UK, national guidelines for weight management during pregnancy include recommendations relevant to health professionals’ routine practice [The GestationaL Obesity Weight management: Implementation of National Guidelines (GLOWING) intervention was developed using social cognitive theory (SCT) to address the evidence-based barriers to the implementation of guidelines regarding weight management in pregnancy [Materials and methodsThe aim of the GLOWING intervention was to support midwives’ implementation of UK guidelines for weight management during pregnancy into routine practice. The aim of the implementation of these guidelines is to improve pregnant women’s diet and physical activity behaviours and gestational weight gain. This paper reports the descriptive analysis of the midwives’ self-reported SCT constructs related to implementation of the UK guideline recommendations. | PMC9858407 |
Design, setting and participants | The details of the GLOWING intervention methods have been described elsewhere [ | PMC9858407 | ||
CONSORT 2010 flow diagram for cluster trials. | * Intervention arm: n = 33 midwives returned ≥1 questionnaire: n = 32 pre-intervention, n = 15 post-intervention, n = 14 both ** Control arm: n = 35 midwives returned ≥1 questionnaire: n = 34 pre-intervention, n = 34 post-intervention, n = 33 both. | PMC9858407 | ||
Intervention development and delivery | We followed a four-step approach for developing theory-informed implementation interventions [ | PMC9858407 | ||
SCT theoretical model for implementation of guideline recommendations for weight management in pregnancy: Communication-related behaviours. | SCT = social cognitive theory. Self-efficacy, outcome expectancies, goals/intentions and environment are SCT constructs relating to behaviours. Knowledge was identified as an important additional construct in the evidence base having an influence on self-efficacy. Bold and larger font size represent the key barriers to practice. Italics font represents facilitators to practice. | PMC9858407 | ||
SCT theoretical model for implementation of guideline recommendations for weight management in pregnancy: Support/intervention-related behaviours. | SCT = social cognitive theory. Self-efficacy, outcome expectancies, goals/intentions and environment are SCT constructs relating to behaviours. Knowledge and attitudes were identified as an important additional construct in the evidence base having an influence on self-efficacy and outcome expectancies. Bold and larger font size represent the key barriers to practice. Italics font represents facilitators to practice.There was consistency in the facilitators in both models relating to goals/intention, whereby health professionals were motivated to improve their communication and weight management skills (Figs The GLOWING intervention (content described in [ | PMC9858407 | ||
Data collection | obesity | OBESITY | Data reported in this paper are from the questionnaires that midwives completed pre- and post-intervention. There were no existing validated questionnaires that could be used to measure the SCT constructs as the questions had to be tailored to the guideline specific behaviours. The NICE guideline recommendations relevant to community midwives’ practice were used as the basis for the questionnaire development to define midwives’ behaviours and SCT constructs. As the guideline recommendations were not written as explicit behaviours, they were adapted to define the Target population, Action, Context and Time (TACT) [Health professionals’ attitudes were identified as evidence-based determinants of their behaviour. These were primarily related to negative obesity stereotypes and prejudices which are known to be informed, in part, by a lack of knowledge about the causes of obesity [ | PMC9858407 |
Data analysis | obesity | OBESITY | All data entry was carried out in duplicate. Two people entered the data independently, compared the data entered to identify potential data entry errors, and any discrepancies in data entry were validated against the original questionnaires. Descriptive analysis was carried out to compare the data with the theoretical models we had developed by pooling the data for all midwives pre-intervention for the SCT and BAOP questionnaires. A descriptive analysis was also carried out to explore midwives’ perception of their own weight status, and whether they felt this made it easier or harder to discuss pregnant women’s weight status and obesity risks. | PMC9858407 |
SCT questionnaires | The data for the behaviour items and SCT constructs were transformed to a 0–100 scale to enable comparisons across all constructs. The sum scores for the 7-point Likert scales were calculated by combining the individual questions within the two behaviour categories and for each SCT construct (The same process was carried out at the behaviour sub-category level to explore whether there were any specific areas of midwifery practice driving the overall category scores. Descriptive statistics were calculated to examine the mean and standard deviation (SD) of the scores at baseline and follow up, for the intervention and control arms. Mean difference in the change in pre- and post-intervention scores were estimated for midwives who returned both questionnaires, alongside 95% confidence intervals (CI).Internal consistency of the questionnaire was measured using Cronbach’s Alpha, pooling the intervention and control arm data at baseline. The analysis was applied to the data within the communication-related behaviours and support/intervention-related behaviours for each SCT construct to assess whether midwives who scored low or high on one question also scored similarly on other questions within that group. An overall Cronbach’s Alpha score of 0.8 or above, a corrected item total correlation of 0.4 or above, and if the Cronbach’s Alpha score for any deleted variable was lower than the overall value, was considered to represent good internal consistency [ | PMC9858407 | ||
Research ethics | The study was approved by the Proportionate Review Sub-committee of the Yorkshire & The Humber—South Yorkshire Research Ethics Committee (ref: 15/YH/0565, 16/12/2015). All midwives were provided with an information sheet explaining the study, and written informed consent was provided before completing the questionnaire. For midwives in the intervention arm, an additional information sheet was provided and written informed consent was provided before delivery of the GLOWING intervention. Midwives had a unique participant ID number to maintain anonymity and could request to withdraw from the study using this ID number as their reference. | PMC9858407 | ||
Results | PMC9858407 | |||
Participants | overweight, SD | One hundred midwives were randomly selected to complete the GLOWING questionnaires (n = 49 intervention, n = 51 control arm), 74 consented and 68 (92%) of those who consented returned questionnaires: 33 (87%) midwives in the intervention and 35 (97%) in the control arm. Of these, 47 (69%) returned both the pre- and post-intervention questionnaires (14 intervention and 33 control), 19 (28%) returned only the pre-intervention questionnaire (18 intervention and one control), and two (3%) returned only their post-intervention questionnaire (one intervention and one control). The key reason for loss to follow up in the intervention arm was related to the length of the questionnaires and time required to complete them, on top of attending the GLOWING intervention, completing evaluation form and participating in focus groups. When comparing the characteristics of midwives who returned both questionnaires compared with those who only returned one questionnaire, there was little difference in their age, sex, ethnic group, number of years practicing as a midwife, or their clinical speciality (The personal characteristics of midwives who completed pre-intervention questionnaires showed that all were female with a mean age of 46 years (SD 8.4), most were white (97%) and perceived their own weight to be slightly or very overweight (57.6%) ( | PMC9858407 | |
Personal and professional characteristics of midwives completing pre-intervention questionnaires. | obesity | OBESITY | SD = standard deviationWhen asked to consider whether their own weight made it easier, harder, or made no difference to having weight-related communication with pregnant women, the greatest proportion of midwives felt that their weight made it easier to discuss women’s weight status (43.1%) and obesity risks (50.0%) ( | PMC9858407 |
Questionnaire data | The Cronbach’s Alpha analysis demonstrated good internal consistency for communication-related behaviours and support/intervention-related behaviours for all SCT constructs (Cronbach’s Alpha ranging from 0.82–0.96; | PMC9858407 | ||
Comparing pre-intervention data with theoretical models | Pre-intervention, the midwives’ scores for the communication-related behaviours were generally higher overall than the scores for the support/intervention-related behaviours ( | PMC9858407 | ||
Comparing intervention and control arms | The descriptive statistics for pre- and post-intervention data are shown in | PMC9858407 | ||
Discussion | obesity, gestational diabetes | OBESITY, GESTATIONAL DIABETES | This paper reports the descriptive results of the GLOWING pilot trial relating to midwives reporting of their self-efficacy, outcome expectancies, intentions and routine behaviours in the context of UK guidelines for weight management during pregnancy. The data reported in this study provide some proof of concept for the evidence-based theoretical models that were developed to underpin the GLOWING intervention. Prior to GLOWING, the evidence-base suggested that health professionals’ low self-efficacy was central to the barriers and facilitators to the implementation of the UK guideline recommendations, and that the majority of barriers were related to the support/intervention-related behaviours. This is reflected in the GLOWING data which demonstrated that, pre-intervention, midwives’ self-efficacy was the lowest scoring construct across all behaviours, and the support/intervention-related behaviours tended to score lower than the communication-related behaviours. The GLOWING intervention was developed to address the evidence-based barriers incorporated in the SCT models. There was a particular emphasis on improving midwives’ self-efficacy for both communication- and support/intervention-related behaviours, but with more focus on the support/intervention related barriers to practice. The descriptive data reported by midwives in the GLOWING pilot trial suggests that there was limited change in self-efficacy for the control arm, whereas the self-efficacy scores increased in the intervention arm and were consistently higher than the control arm post-intervention. This was apparent for both communication- and support/intervention-related behaviours, but more so for the support/intervention-related behaviours. The pilot trial was not powered to be able to detect a significant difference between the intervention and control arms at follow-up or change in self-efficacy from pre- to post-intervention. However, the data are suggestive that the intervention may be impacting on the target construct of self-efficacy, particularly for the support/intervention-related behaviours.The data also suggested a potential ceiling effect for midwives reporting of intention and behaviour constructs for communication-related behaviours. Some of these behaviours (e.g. relating to measuring and discussing BMI at the booking appointment) are now embedded into routine care. The BMI measurement influences the further discussions and referrals required relating to clinical management of pregnancy, such as referral for routine screening for gestational diabetes or consultant obstetrician led care [This paper also reports data on midwives’ beliefs about people living with obesity using the BAOP scale. There was a similarity in pre-intervention BAOP data from midwives in this study (mean score 14.6 SD 5.7) to published data from a general population of UK adults (mean score 14.7 SD 6.7) [Despite the wealth of evidence of the multiple and complex barriers to practice for health professional guideline implementation relating to maternal obesity and weight management practice [There are strengths and limitations to this research. The intervention was developed following a rigorous approach using evidence-based theoretical models. A recent scoping review of implementation interventions in the maternity context identified that out of 158 published studies, only 14 reported the use of a theory, model and/or framework, and these typically guided data analysis or data collection rather than the design of the study [ | PMC9858407 |
Conclusions | The GLOWING pilot trial data provides proof of concept of the theoretical models used to inform its development. The descriptive data reported in this paper suggests that the intervention may be successfully targeting self-efficacy as it was designed to do. A definitive trial with adequate power is required to determine the effectiveness and cost-effectiveness of the GLOWING intervention. | PMC9858407 | ||
Supporting information | (DOCX)Click here for additional data file. | PMC9858407 | ||
Flowchart of NICE Guideline behaviours relevant to midwifery practice grouped into thematic behaviour categories and sub-categories for communication-related behaviours and behaviour support/intervention-related behaviours. | Note, Behaviour categories and sub-categories are: 1. Communication-related behaviours (sub-categories: weight communication and risk communication) 2. Support and intervention-related behaviours (sub-categories diet and nutrition, physical activity, weight management, referrals and signposting).(DOCX)Click here for additional data file. | PMC9858407 | ||
Standards for reporting implementation studies: The StaRI checklist. | (DOC)Click here for additional data file. | PMC9858407 | ||
Adapted NICE guideline recommended behaviours developed for the GLOWING questionnaire. | (DOCX)Click here for additional data file. | PMC9858407 | ||
Sum score behaviour categories derived from the questionnaire items for each SCT construct. | * Questions required reverse coding.(DOCX)Click here for additional data file. | PMC9858407 | ||
Midwife characteristics and scores for the behaviour categories and Social Cognitive Theory (SCT) constructs, comparing those who returned one or both questionnaires. | *Note, 21 midwives only returned one questionnaire, two of these only returned their post-intervention questionnaire therefore have missing pre-intervention data.(DOCX)Click here for additional data file. | PMC9858407 | ||
Midwives perceptions of the impact of their own weight on the level of difficulty the experience discussing weight status and risks of obesity with pregnant women. | HW = healthy weight, OW = slightly overweight/very overweight *HW in the intervention arm includes one midwife who perceived their own weight as slightly underweight.(DOCX)Click here for additional data file. | PMC9858407 | ||
Internal validity of the questionnaire items for each behaviour category and social cognitive theory construct. | *Communication-related behaviours include weight communication and risk communication; support/intervention-related behaviours include diet and nutrition, physical activity, weight management, and referrals and signposting.(DOCX)Click here for additional data file. | PMC9858407 | ||
A comparison of pre- and post-intervention scores for communication- and support/intervention-related behaviour sub-categories and social cognitive theory constructs. | SD = standard deviation * Due to the limited number of diet and nutrition questions for self-efficacy and outcome expectancies, these were combined with the physical activity questions when creating the sum scores for these constructs.(DOCX)Click here for additional data file.We would like to thank Anita Tibbs, Phoebe Orangu and Zoe Bell for contributing towards duplicate data entry and validation. We thank the research midwife teams at the participating NHS Trusts for facilitating the questionnaire distribution to midwives, Judith Ormonde, Gayle Gills, Helen Howlett, Christine Moller-Christensen and Caitlin Barry. We would like to thank Dr Lucia Rehackova for contributing to mapping the evidence-based barriers and facilitators to practice to the SCT models and intervention development. | PMC9858407 | ||
Abstract | PMC9825269 | |||
STUDY QUESTION | Does an estradiol-based combined oral contraceptive (COC) have a milder effect on the serum proteome than an ethinylestradiol (EE)-based COC or dienogest (DNG) only? | PMC9825269 | ||
SUMMARY ANSWER | The changes in serum proteome were multifold after the use of a synthetic EE-based COC compared to natural estrogen COC or progestin-only preparation. | PMC9825269 | ||
WHAT IS KNOWN ALREADY | blood coagulation | INFLAMMATION | EE-based COCs widely affect metabolism, inflammation, hepatic protein synthesis and blood coagulation. Studies comparing serum proteomes after the use of COCs containing EE and natural estrogens are lacking. | PMC9825269 |
STUDY DESIGN, SIZE, DURATION | This was a spin-off from a randomized, controlled, two-center clinical trial. Women (n = 59) were randomized to use either EE + DNG, estradiol valerate (EV) + DNG or DNG only continuously for 9 weeks. | PMC9825269 | ||
PARTICIPANTS/MATERIALS, SETTING, METHODS | Participants were healthy, young, white volunteer women. Serum samples were collected before and after 9 weeks of hormonal exposure. Samples from 44 women were available for analysis (EE + DNG n = 14, EV + DNG n = 16 and DNG only n = 14). Serum proteins were analyzed by quantitative, discovery-type label-free proteomics. | PMC9825269 | ||
MAIN RESULTS AND THE ROLE OF CHANCE | ACUTE PHASE RESPONSE | Altogether, 446 proteins/protein families with two or more unique peptides were detected and quantified. The number of proteins/families that altered over the 9-week period within the study groups was 121 for EE + DNG and 5 for EV + DNG, while no changes were detected for DNG only. When alterations were compared between the groups, significant differences were detected for 63 proteins/protein families, of which 58 were between the EE + DNG and EV + DNG groups. The most affected functions during the use of EE + DNG were the complement system, acute phase response signaling, metabolism and the coagulation system. The results were validated by fetuin-B and cortisol-binding globulin ELISA and sex hormone-binding globulin immunoassay. | PMC9825269 | |
LARGE SCALE DATA | Data are available via ProteomeXchange with identifiers PXD033617 (low abundance fraction) and PXD033618 (high abundance fraction). | PMC9825269 | ||
LIMITATIONS, REASONS FOR CAUTION | The power analysis of the trial was not based on the proteomic analysis of this spin-off study. In the future, targeted proteomic analysis with samples from another trial should be carried out in order to confirm the results. | PMC9825269 | ||
WIDER IMPLICATIONS OF THE FINDINGS | The EE-based COC exerted a broader effect on the serum proteome than the EV-based COC or the DNG-only preparation. These results demonstrate that the effects of EE in COCs go far beyond the established endpoint markers of estrogen action, while the EV combination is closer to the progestin-only preparation. The study indicates that EV could provide a preferable option to EE in COCs in the future and signals a need for further studies comparing the clinical health outcomes of COCs containing EE and natural estrogens. | PMC9825269 | ||
STUDY FUNDING/COMPETING INTEREST(S) | EVENTS | Funding for this researcher-initiated study was obtained from the Helsinki University Hospital research funds, the Hospital District of Helsinki and Uusimaa, the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Medical Association, the University of Oulu Graduate School, the Emil Aaltonen Foundation, the Swedish Cultural Foundation in Finland, the Novo Nordisk Foundation, Orion Research Foundation and the Northern Ostrobothnia Regional Fund. The funders had no role in study design, data collection and analysis, publishing decisions or manuscript preparation. T.P. has received honoraria for lectures, consultations and research grants from Exeltis, Gedeon Richter, MSD, Merck, Pfizer, Roche, Stragen and Mithra Pharmaceuticals. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. O.H. occasionally serves on advisory boards for Bayer AG and Gedeon Richter and has designed and lectured at educational events for these companies. The other authors have nothing to disclose. | PMC9825269 | |
TRIAL REGISTRATION NUMBER | ClinicalTrials.gov NCT02352090 | PMC9825269 | ||
TRIAL REGISTRATION DATE | 27 January 2015 | PMC9825269 | ||
DATE OF FIRST PATIENT’S ENROLMENT | 1 April 2015 | PMC9825269 | ||
Introduction | ADVERSE EVENTS | In addition to the contraceptive effect, combined oral contraceptives (COCs) have vast effects on female physiology. In the liver, COCs stimulate the synthesis of steroid-binding globulins, such as sex hormone-binding globulin (SHBG), thereby affecting circulating, free steroid levels (The net effect of COCs results from both estrogen and progestin action and their interplay (Recently, natural estrogens have been included in COCs to reduce EE-related adverse events. New combinations containing E2, its ester estradiol valerate (EV), and estetrol (E4) have proven effective in combined contraceptives. They induce good cycle control and provoke less marked changes in metabolic and endocrine parameters compared with EE (Serum proteomic analysis provides an option to investigate the broad pharmacodynamic effects during medication use. Instead of specific, planned targets, this shotgun method analyzes all proteins and enables a broad overview and novel findings. To our knowledge, this is the first study to utilize such discovery-type proteomic analysis on hormonal contraceptives.This study compared changes induced in the serum proteome during the use of COCs containing different estrogen components. A progestin-only preparation (containing the same progestin) was included as an active control. This study is a spin-off of a larger randomized controlled trial comparing the metabolic effects of EE + dienogest (DNG), EV + DNG and DNG only. We hypothesized that the EV + DNG preparation would have a milder impact on the serum proteome than that of EE + DNG and that the effect of DNG only would be neutral. | PMC9825269 | |
Materials and methods | This randomized, controlled, investigator-initiated clinical trial was conducted at Helsinki and Oulu University Hospitals, Finland, between April 2015 and January 2018. The study protocol has been described previously ( | PMC9825269 | ||
Subjects | Seventy-seven healthy women volunteered for the study (
| PMC9825269 | ||
Intervention | Participants were randomized to use either EE + DNG (Valette | PMC9825269 | ||
Serum proteomic analysis | Serum samples were stored at −70°C until analysis. High-abundance proteins and their protein complexes were affinity-purified from the samples, and the samples were divided into two pools: high- and low-abundance proteins. Human serum albumin was further removed from the high-abundance samples. Proteins were digested with trypsin and applied via a reverse-phase nano-liquid chromatograph column to a high-resolution mass spectrometer. Data were collected in a data-independent manner, and peptides were identified and quantified. | PMC9825269 | ||
Affinity chromatography | An Agilent Technologies (Santa Clara, CA, USA) Multiple Affinity Removal Column Human 14 (Cat No 5188-6557) was used in the affinity chromatography, according to the manufacturer’s instructions. Samples were diluted four-fold with buffer A. Fourteen proteins and their complexes (i.e. ‘high-abundance proteins’) were retained in the column: albumin, IgG, IgA, transferrin, haptoglobin, antitrypsin, fibrinogen, alpha2-macroglobulin, alpha1-acid glycoprotein, IgM, apolipoprotein AI, apolipoprotein AII, complement C3 and transthyretin. Low-abundance proteins were collected as a flow-through fraction. High-abundance proteins were eluted with buffer B and collected. | PMC9825269 | ||
Desalting and albumin removal from high-abundance samples | All samples were desalted using Thermo Fisher Scientific (Waltham, MA, USA) Zeba Spin desalting 96-well plates (Cat No 89808) to change the buffer to 25 mM Trizma BASE + 75 mM NaCl pH 7–8. The high-abundance samples were albumin-depleted with a Thermo Fisher Scientific Pierce Albumin Depletion Kit (Cat No 85160). Protein concentrations were measured in all samples using the Bradford method; 120 μg of proteins were aliquoted, dried, and stored at −70°C until digested. A SpeedVac vacuum concentrator (Model DNA120; Savant Systems LLC, MA, USA) was used for drying the samples. | PMC9825269 | ||
Trypsin digestion | Proteins in the samples were trypsin-digested with the aid of Waters Corporation (Milford, MA, USA) 0.2% surfactant RapiGest™ SF. Samples were boiled for 10 min, and proteins were reduced by adding 0.5 M 1,4-dithiothreitol to a final concentration of 5 mM, vortexed and incubated for 30 min in 60°C water bath. In the next step, the proteins were alkylated with a 15 mM final concentration of iodoacetamide and incubated for 30 min in the dark at room temperature. Sequence grade trypsin Promega Biotech AB (Madison, WI, USA) Trypsin Gold (Cat No V5280) was added to the samples in a 1:100 enzyme-to-protein ratio. Samples were incubated at 37°C overnight. Samples were acidified to a final concentration of 0.5% trifluoroacetic acid and incubated for 45 min at 37°C, after which cleaved RapiGest™ SF was removed by a 10-min centrifugation at 16 000 | PMC9825269 | ||
Mass spectrometry | Five hundred nanograms of the Hi3 spiked peptide mixture was injected to the Waters Corporation Synapt G2-Si HDMS and nanoACQUITY system. The system was equipped with Trap Column Symmetry C18, nanoACQUITY 10K 2G V/M Trap Column, 100 Å, 5 µm, 180 µm × 20 mm (Cat No 186006527) and analytical ultra-performance liquid chromatography (UPLC) column BEH C18 nanoACQUITY 10 K psi, 300 Å, 1.7 µm, 75 µm × 250 mm (Cat No 1886003815).Samples were loaded to trapping column 8 µl/min for 2 minutes with 2% B buffer. The analytical gradient used was as follows: 0–1 min 2% B buffer, 1–65 min 55% B buffer, 65–80 min 80% B buffer, 80–87 min 80% B buffer, 87–90 min 2% B buffer and 90–100 min 2% B buffer. The gradient curve between the time points was linear. Analytical gradient flow rate was 200 nl/min. Buffer A was 0.1% FA in water, and buffer B was 0.1% FA in ACN. The gradient curve between the time points was linear. Buffer A was 0.1% FA in water, and buffer B was 0.1% FA in ACN. All solvents were mass spectrometry–grade from Merck Life Science (Darmstadt, Germany).Data acquisition was performed with UPLC–ultra definition mass spectrometry (UPLC-UDMS | PMC9825269 | ||
Peptide identification and quantitation | The raw data were imported to Progenesis QI for proteomics (Nonlinear Dynamics, La Jolla, CA, USA), and simultaneously mass corrected with the leucine–enkephalin function. Proteinlynx Global Server (Waters Corporation) was used to identify peptides from the UDMS | PMC9825269 |
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