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Evaluation of the “check-up 45 +” in primary care | Access through the GP practice to apply for prevention or rehabilitation services is still under-used [A range of studies developed and evaluated screening instruments for needs assessment [The following research question will be explored: can the number of applications for prevention and rehabilitation services be increased through the “check-up 45 + ” in GP practices? | PMC10116757 | ||
Objectives | The aim of this study is to evaluate the effectiveness of the "check-up 45 + ". We will examine whether the "check-up 45 + " affects the number of applications for German Pension Insurance services through an early identification of needs of patients in primary care by a structured needs assessment, provision of information about German Pension Insurance services and a simplified application procedure.In addition, the practicability and acceptance of the implementation of the “check-up 45 + ” will be assessed among the stakeholders involved. | PMC10116757 | ||
Methods | PMC10116757 | |||
Study setting | The intervention is implemented in about 20 GP practices located in Berlin and Brandenburg. Practices in rural and urban areas, each with differing social structures, participate. The practices can have different specialisations (e.g. occupational medicine, naturopathy), but are all maintained by general practitioners or internists practising general medicine. In most practices, one physician and two medical assistants conduct the study; in some practices more persons are involved. | PMC10116757 | ||
Eligibility criteria | disability | All patients aged between 45 and 59 years and insured by the German Pension Insurance Berlin-Brandenburg or the German Federal Pension Insurance can participate in the study. Further inclusion criteria are residence in Berlin or Brandenburg, contribution to social insurance for at least 6 months within the last 24 months and sufficient knowledge of German. Excluded are patients who are currently applying for or receiving a prevention or rehabilitation service from the German Pension Insurance as well as those who receive a disability or old-age pension. | PMC10116757 | |
Treatment | PMC10116757 | |||
Control | The control group is recruited in the same way as the intervention group but is only handed a two-page questionnaire covering socio-economic and occupational variables. | PMC10116757 | ||
Primary outcome | The primary outcome is the proportion of applications for prevention and rehabilitation services of the German Pension Insurance within two months after study participation of each patient. | PMC10116757 | ||
Secondary outcomes | Secondary outcomes are (1) the proportion of approved applications for prevention interventions and medical rehabilitation services and (2) the proportion of completed prevention interventions and medical rehabilitation services. In addition, (3) the proportion of persons with a need for prevention and rehabilitation according to the "check-up 45 + " is examined (intervention group only). (4) The practicability, acceptance of and satisfaction with the implementation of the "check-up 45 + " under everyday conditions among participating patients, practice staff and employees of the German Pension Insurance involved in the study will be assessed by semi-structured interviews. | PMC10116757 | ||
Other measurements | Health-related and sociodemographic characteristics are assessed via the patient questionnaires and administrative data from the individual pension insurance account. Both groups receive a two-page questionnaire. These variables are collected for sample description, group comparison and to identify relevant covariates related to application for prevention or rehabilitation services. The intervention group additionally completes the two-page”screening 45 + ”. | PMC10116757 | ||
“Screening 45 + ” | PMC10116757 | |||
Dimension A—work ability | Work ability is assessed by adapted questions from the "Screening Instrument to Assess the Need for Medically and Occupationally Oriented Measures" (SIMBO) and the "Work Ability Index" (WAI). The SIMBO has already been used in numerous studies [ | PMC10116757 | ||
Dimension B—mental well-being | depressive, anxiety | Mental well-being is assessed via the short form of the Patient Health Questionnaire-4 (PHQ-4). The PHQ-4 is an ultra-short screening instrument with four items to identify depressive and anxiety symptoms [ | PMC10116757 | |
Dimension C—functional ability | Functional ability is assessed via adapted questions from the generic questionnaire "Indicators of Rehab Status, Version 3" (IRES-3) [ | PMC10116757 | ||
Dimension D—coping behaviour | The German Pension Insurance developed its own instrument consisting of four items to assess coping behaviour [ | PMC10116757 | ||
Dimension E—physical activity | The items on physical activity are adapted from the National Health Service's “German Practice Physical Activity Questionnaire” (GPPAQ). The GPPAQ is a short self-report questionnaire that can be used to measure physical performance [ | PMC10116757 | ||
Short questionnaire and administrative data | PMC10116757 | |||
Subjective health status | The subjective health status is assessed, according to a recommendation of the World Health Organization (WHO) [ | PMC10116757 | ||
Previous use of rehabilitation services | The previous use of rehabilitation services may influence application behaviour [ | PMC10116757 | ||
Further measurements of work ability | In the short questionnaire the current work ability compared with the lifetime best is measured by the “Work Ability Score” (WAS) [ | PMC10116757 | ||
Work-related data | The German Pension Insurance provides information on voluntary contributions on days with creditable periods due to unemployment in months and the occupational status. | PMC10116757 | ||
Sociodemographic data | Further data regarding gender, age, educational and professional qualifications, subjective socio-economic status as well as primary language spoken in the household will be assessed via the short questionnaire. | PMC10116757 | ||
Sample size estimation | The calculation of the sample size is based on a research project that evaluated the psychometric properties, reliability and criterion validity of the “screening 45 + ” [In order to detect a difference between the intervention and the control group of applications for prevention and medical rehabilitation services, the power calculation (two-sided test, type I error rate: 5%, power: 85%) resulted in a required minimum sample size of CONSORT flow diagram of the study | PMC10116757 | ||
Recruitment | RECRUITMENT | Before the recruitment phase, the study team visits the GP practices for an one-hour training session on the procedure of the study. The practice staff invite patients who visit the practice for standard care and meet the inclusion criteria (age, insured status) to participate in the study. Study information, consent form and questionnaires are handed out in envelopes for completion. To avoid selection bias, the practice staff is encouraged to address patients who fulfil the inclusion criteria, regardless of their health status and known need for rehabilitation. They should be approached in a neutral way without receiving information about potential prevention or rehabilitation services. | PMC10116757 | |
Allocation | RECRUITMENT | Block randomisation will be performed for each general practice, with the same number of patients per block. Allocation to the intervention or control group is randomised within each block (10 blocks of 10 per practice) to keep the number of case IDs balanced, even if the lists are not finished. The case IDs were generated with R version 4.2.2 and are reproducible. Only the German Pension Insurance is able to link the pseudonyms to the actual persons.The assignment of the participants included in the study to the intervention or control group is performed randomly, as the practice staff cannot influence the group affiliation of the invited participants during the recruitment process. The practice staff hand out the questionnaires and study documents in sealed, non-transparent envelopes on which the group affiliation is not indicated. The envelopes are only labelled with the questionnaire number (case ID) and are first opened by the participants. | PMC10116757 | |
Blinding | RECRUITMENT | The practice staff are blinded during the recruitment process while inviting patients to the study. Once patients return the completed questionnaires, the practice staff are no longer blinded.The patients are not aware of their group assignment, as they have no knowledge of the existence of two groups. Unblinding the control group is not intended. Participants in the intervention group are aware of the intervention when they are informed about the result of the "check-up 45 + " after evaluation of the "screening 45 + ". The project coordinators at the German Pension Insurance have no knowledge of the group assignment. The Charité study staff who perform the analyses know the group assignment. | PMC10116757 | |
Data collection | SECONDARY, RECRUITMENT | Primary and secondary outcomes are provided by the German Pension Insurance registers and the questionnaire “screening 45 + ” (Tab. After recruitment is completed, semi-structured interviews will be conducted by telephone or in person to investigate practicability and acceptance of the “check-up 45 + ”. Practice staff, participating patients and employees of the German Pension Insurance involved in the study will be interviewed. The interviews are recorded, transcribed, and analysed anonymously. | PMC10116757 | |
Data management | RECRUITMENT | A detailed data protection concept was developed with the data protection officer of the German Pension Insurance Berlin-Brandenburg, which clarifies the rights of participants as well as the organisational procedures for the collection, processing and storage of data. Pseudonymised administrative data of the participants are transferred from the German Pension Insurance Berlin-Brandenburg and German Federal Pension Insurance to the Charité based on the unique case ID for evaluation after completion of the recruitment process.Collected questionnaires are scanned and verified at the Charité with the data capture system evasys, to assign the pseudonymised questionnaire data to the corresponding case ID and to export them for the analyses. Data entry and data verification are carried out by trained research assistants. The questionnaires and administrative data can be linked via the unique case ID. The electronic data are stored on an internal server of the Charité. Only the study team has access to the data. | PMC10116757 | |
Statistical analysis | SECONDARY | All analyses are conducted according to the intention-to-treat principle. Both descriptive and analytical statistics will be used to compare differences between the two study groups. In order to determine the comparability of the two study groups, the distribution of the socio-demographic and health-related variables will be described. Frequencies, means and standard deviations will be calculated according to the scale level. For non-normally distributed data, medians and interquartile ranges will be presented. For the primary and secondary outcomes, absolute and relative frequencies and their 95% confidence intervals will be reported for both study groups. Fisher’s exact test will be applied to test for statistical significance between the intervention and control group. The results will be regarded as significant if the p-value is less than 0.05 (two-sided). Exploratory subgroup analyses will be performed in order to describe differences stratified by gender, age, GP practices and other possible confounders.The qualitative interview data will be analysed according to the Kuckartz method of qualitative analysis [ | PMC10116757 | |
Discussion | Needs assessment, information about and claiming of prevention and rehabilitation services to maintain work ability must take place earlier. Many studies are examining interventions to address patients with a prevention or rehabilitation need at an earlier stage. Our study uses a pragmatic approach to investigate the effectiveness and acceptance of a screening tool to assess prevention and rehabilitation needs in primary care. The aim is to examine whether the "check-up 45 + " affects the proportion of applications for German Pension Insurance services through an early identification of needs of patients by a structured needs assessment, by providing information about German Pension Insurance services and a simplified application procedure.The authors of this protocol will write the final study publications. The use of professional writers is not intended. The findings of our study will be published in articles, conference presentations and in a final report. The study protocol was developed in accordance to the protocol template of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) [39]. | PMC10116757 | ||
Trial status | RECRUITMENT | Recruitment has started and is currently ongoing. | PMC10116757 | |
Acknowledgements | We thank the involved persons of the GP practices and the German Pension Insurance for their cooperation and efforts in conducting the study, and Susanne Rossek and Christin Lissat for monitoring the practices and supporting data collection. We acknowledge financial support from the Open Access Publication Fund of Charité – Universitätsmedizin Berlin and the German Research Foundation (DFG). | PMC10116757 | ||
Authors’ contributions | MB conceived the study and has driven the funding acquisition together with KS. MB is in charge of the project. MB and JB developed and specified the study design and the intervention. JB is responsible for the implementation of the intervention and data collection in the general practices. JB prepared the first draft of the manuscript, MB revised the manuscript. All authors read and approved the final manuscript. All authors fulfil the authorship criteria of the International Committee of Medical Journal Editors. | PMC10116757 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. This study is funded by the German Pension Insurance Berlin-Brandenburg, 15228 Frankfurt (Oder), Germany (grant number: 10-R-40.07.05.07.023). Funding covers personnel, material, and travel costs. The study design, data collection, data analysis, data interpretation and writing of the study protocol are not influenced by the funding body. We acknowledge financial support from the Open Access Publication Fund of Charité – Universitätsmedizin Berlin and the German Research Foundation (DFG). | PMC10116757 | ||
Availability of data and materials | Primary data previously used for publications can be made available to researchers in anonymised form at the individual level after a justified and methodologically appropriate request to preha45@charite.de in accordance with data protection regulations for answering the questions formulated in the request. In accordance with data protection regulations, the study data will be retained for a maximum of 10 years after the end of the study. | PMC10116757 | ||
Declarations | PMC10116757 | |||
Ethics approval and consent to participate | The study is carried out in accordance with the Declaration of Helsinki. The study protocol has been approved by the Ethics Committee of the Charité – Universitätsmedizin Berlin, Berlin, Germany (number: EA4/215/21). No legal or ethical concerns were identified. Informed consent will be obtain from all subjects and/or their legal guardian(s). All participants will receive a written study information about the study objectives, participation, and their right to decline participation. On 03 March 2022, the study was prospectively registered in the German Clinical Trials Register (DRKS00028303, UTN U11111-1275–0063). The World Health Organization Trial Registration Data Set is available as Additional File | PMC10116757 | ||
Consent for publication | Not applicable. | PMC10116757 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10116757 | ||
References | PMC10116757 | |||
Subject terms | proven/probable IFDs, IFD, IFDs, proven/probable, ALL | ACUTE LYMPHOBLASTIC LEUKEMIA, REGRESSION, INVASIVE FUNGAL DISEASE, ADVERSE EVENT | In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 ( | PMC9883161 |
Introduction | malignancy, neutropenia, ALL | ACUTE LYMPHOBLASTIC LEUKEMIA, NEUTROPENIA | Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood and adolescence [Risk factors for IFD such as prolonged and profound neutropenia or extended periods of therapy with corticosteroids have been well established [ | PMC9883161 |
Patients and methods | PMC9883161 | |||
Study population | ALL | T(9;22) | A total of 6136 children enrolled as study patients in the international, multi-center prospective randomized Phase III clinical trial AIEOP-BFM ALL2009 (EudraCT 2007-004270-43) were included in the analysis. Patients were eligible if they were older than 1 year, younger than 18 years, and were not Ph-positive (BCR/ABL or t(9;22)). The study started June 1, 2010 and ended February 28, 2017 (manuscript submitted). The median time of follow-up was 6 years (1. and 3. quartile, 4.7 and 7.6). Whereas diagnostic procedures (e.g., evaluation of treatment response) and treatment for ALL was prescribed and monitored, supportive care including diagnostics of suspected IFD and antifungal prophylaxis and treatment was at the discretion of the responsible physician. The study was approved by the appropriate national and local review boards, and was conducted in accordance with the Declaration of Helsinki and national laws. Informed consent was obtained from the parents or guardians of each patient included in the study as required by ethical standards and national guidelines. | PMC9883161 |
Invasive fungal disease (IFD) | IFDs, IFD | ADVERSE EVENTS | Serious adverse events (SAEs) were prospectively captured and reported by the participating institutions. According to study guidelines, IFDs were considered as SAEs, thus, reporting was mandatory. All SAE reports were reviewed and classified by the safety desk of the clinical trial office in Germany (AM/JA), and all SAEs suggestive for IFD were independently reviewed by two experts (TL/AHG). Children were categorized with proven, probable, possible or no IFD according to the revised and updated consensus definitions elaborated by the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) [ | PMC9883161 |
Statistical analysis | death | MALIGNANT NEOPLASM, EVENT, REMISSION | Event-free survival (EFS) was calculated from diagnosis to first event, defined as death during induction therapy, resistance, relapse, death in complete remission, or development of a second malignant neoplasm. Overall survival rates were calculated according to Kaplan–Meier and compared by log-rank test [ | PMC9883161 |
Results | PMC9883161 | |||
Incidence and risk factors for IFD | AIEOP-BFM | In 6136 children treated as study patients in the clinical trial AIEOP-BFM ALL2009, a total of 419 SAEs reported on a suspected IFD. Out of these, 381 were identified as the first episode of a possible ( | PMC9883161 | |
Consort diagram of patients (pts) treated according to the clinical trial AIEOP-BFM 2017 and analyzed for possible, probable and proven invasive fungal disease (IFD). | infection, PcP | YEAST INFECTION, INFECTION, ADVERSE EVENT | *Yeast infection includes two patients with more than one yeast isolates. **Mold infection includes nine patients with more than one mold isolated. SAE severe adverse event, PcP Patient´s characteristics.The 2591 girls (42.3%) and 3536 boys (57.7%) with a median age (range) of 5.2 years (1-18) were treated in Germany (Univariate analysis of potential risk factors further revealed that insufficient treatment response in the early phase of therapy had a significant impact on the risk for IFD (Supplemental Table | PMC9883161 |
Invasive fungal disease (IFD) in the different treatment phases (protocol I, II, III and HR cycles, respectively) in standard (SR) and intermedium risk (MR) patients (above) and high risk (HR) patients (below). | proven/probable, IFDs, infections | REGRESSION, INFECTIONS | Shown are the absolute number of possible (blue), probable and proven yeast (orange) and probable/proven mold (grey) infections (Y axis). The percentages refer to the total number of IFDs in the respective risk groups (SR/MR and HR).Logistic regression revealed that the risk for proven/probable IFD was significantly increased in children ≥12 years of age [OR 1.4 (95% CI 1.3; 1.6)] and those with more than 10% blasts in the bone marrow on day 15 assessed by flow-cytometry [OR 2.3 (95% CI 1.7; 3.2)] ( | PMC9883161 |
Impact of IFD on duration of intensive chemotherapy | proven/probable, IFD | Compared to patients without IFD, patients with proven/probable and patients with possible IFD had a significantly longer duration of intensive chemotherapy (measured from start of intensive chemotherapy until start of maintenance therapy). The median duration (years; 1. and 3. quartile) of intensive chemotherapy was 0.69 (0.65; 0.73), 0.69 (0.65; 0.74) and 1.17 (1.09; 1.26) in SR, MR, and HR patients without IFD, 0.74 (0.69; 0.77), 0.72 (0.68; 0.82), and 1.26 (1.15; 1.35) in SR, MR and HR patients with possible IFD versus 0.77 (0.72; 0.86), 0.76 (0.71; 0.88) and 1.21 (1.14; 1.37) in SR, MR and HR patients with proven/probable IFD, respectively. The differences between patients with and without IFD were significant for each of the risk groups (SR and MR | PMC9883161 | |
Outcome | proven/probable, infection | INFECTION | A total of 24 and 25 patients suffering from proven/probable IFD did not survive the infection after 6 and 12 weeks, accounting for a 6-week and 12-week mortality rate of 10.7% and 11.2%, respectively (Fig. | PMC9883161 |
Cumulative incidence of death from possible (blue), probable (red) and proven (green) invasive fungal disease (IFD) in children treated for acute lymphoblastic leukemia. | proven/probable | MINIMAL RESIDUAL DISEASE | The In the multivariate analysis, the hazard ratio [95% confidence interval (CI)] for 5-year EFS was significant for proven/probable IFD (1.86, 1.42-2.45), age ≥12 years (1.14, 1.07–1.21), insufficient response to therapy [blast count on day 15 measured by flow- cytometry ≥10% (1.52, 1.26–1.82) or minimal residual disease measured by PCR on day 33 (2.08, 1.76–2.45); | PMC9883161 |
Discussion | IFD, neutropenia, proven/probable IFD, cancer, AML, ALL | ACUTE MYELOID LEUKEMIA, NEUTROPENIA, CANCER, PEDIATRIC ALL, AML, INVASIVE ASPERGILLOSIS | In the prospective, randomized multi-international clinical trial AIEOP-BFM ALL2009 enrolling 6136 children with ALL, the reported overall incidence of proven/probable IFD and proven/probable/possible IFD was 3.8% and 6.2%, respectively, but was significantly higher in various subgroups, e.g., in older children and adolescents or in patients with insufficient early treatment response. The reported incidence rates of IFD in children with ALL vary widely across previous studies with rates reaching from 3.8% to up to 24% [Unexpectedly, we found in a subgroup of patients a significant correlation between the number of neutrophils at the time of diagnosis of ALL and the risk for IFD. This is in contrast to children with acute myeloid leukemia (AML), in which neutropenia at the start of chemotherapy was independently associated with IFD [In an early report on invasive aspergillosis in 66 children with cancer published in the 1990ies, mortality after 1 month was 48%, and was 75% after 2 months [The strength of our study is the fact that the analysis is based on the data of a contemporary multi-centered international randomized controlled clinical trial. We included the largest dataset on IFD in pediatric ALL to date, and the data quality is extremely high due to the fact that SAEs were prospectively collected and monitored in a systematic way. In addition, all potentially relevant SAEs were independently evaluated by two experts, based on the revised and updated definitions of IFD from the EORTC/MSG consensus group, which added the widely used | PMC9883161 |
Conclusion | proven/probable IFD, ALL | PEDIATRIC ALL | In conclusion, our data show that the overall incidence rate of IFD in pediatric ALL is relatively low, but independent risk factors such as older age and treatment-response can define high risk groups for IFD. Based on this characterization of risk groups, randomized trials on antifungal prophylaxis can be designed, which may ultimately improve the overall outcome of ALL, as our data demonstrate that proven/probable IFD is an independent risk factor for both event-free and overall survival of children with ALL. | PMC9883161 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41375-022-01768-x. | PMC9883161 | ||
Acknowledgements | Cancer | CANCER | The clinical trial AIEOP-BFM ALL2009 has been supported by grant No. 108588 of the Deutsche Krebshilfe, Bonn, Germany. We also wish to thank the Israel Cancer Association and the Chaim Association for their support. | PMC9883161 |
Author contributions | SE, NB | TL designed the research, collected the data, analyzed the data, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. AHG designed the research, collected the data, analyzed the data, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. SC designed the research, collected the data, analyzed the data, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. JA collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. AA collected the data, analyzed the data, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. DB collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. NB collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. VC collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. SI collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. GM collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. AM designed the research, analyzed the data, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. FN collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. MS analyzed the data, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. JS collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. EZ collected the data, critically read and discussed the manuscript and approved the final version of the manuscript. MZ designed the research, analyzed the data, performed the statistical analysis, wrote the manuscript, critically read and discussed the manuscript and approved the final version of the manuscript. SE designed the research, analyzed the data, wrote the manuscript, critically read and discussed the manuscript, and approved the final version of the manuscript. | PMC9883161 | |
Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC9883161 | ||
Data availability | Under the permission that national data protection requirements are fully met, access to individual data may be made available upon reasonable request to the authors. | PMC9883161 | ||
COMPETING INTERESTS | TL has received grants from Gilead Sciences, has served as consultant to Gilead Sciences, Merck/MSD, Pfizer, Astellas, AstraZeneca and Roche, and served at the speaker´s bureau of Gilead Sciences, Merck/MSD, Astellas, Pfizer and GSK. AHG has received grants from Gilead, Merck, Sharp & Dohme and Pfizer and has served as consultant to Amplyx, Astellas, Basilea, F2G, Gilead. Merck, Sharp & Dohme, Pfizer, Scynexis, and Mundipharma. SC served at the speaker´s bureau of Gilead Sciences and Pfizer. AA has received honoraria for lectures, consultancy or advisory board participation from the following companies: Jazz Pharmaceuticals, Amgen, Novartis, MSD, Jazz Pharmaceuticals, Amgen, Novartis, MSD, and Gilead. He has received compensation for travel expenses from Jazz Pharmaceuticals. MS and/or study group have received research support from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis. MS has received honoraria from Servier, Novartis, and JazzPharma. | PMC9883161 | ||
References | PMC9883161 | |||
Background | Depression, diabetic, death | Depression is more common in diabetic patients, with a 1.5-fold increased risk of death. | PMC10152712 | |
Methods | depression, type 2 diabetes mellitus | TYPE 2 DIABETES MELLITUS | In this double-blind clinical trial, 60 volunteer patients (age range 20–65 years) with type 2 diabetes mellitus with symptoms of depression were randomized into the intervention (received 700 mg/day hydroalcoholic extract; | PMC10152712 |
Results | Sixty participants received | PMC10152712 | ||
Trial registration | All protocols in this study were followed in accordance with the Helsinki Declaration (1989 revision). Ethical approval for this study was obtained from the Iran University of Medical Sciences Ethics committee (IR.IUMS.FMD.REC 1396.9413468004; research.iums.ac.ir). The study was registered at the Iranian Registry of Clinical Trials (IRCT201709239472N16); Registration date: 09/10/2017.
| PMC10152712 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12906-023-03978-x. | PMC10152712 | ||
Keywords | PMC10152712 | |||
Materials and methods | PMC10152712 | |||
Preparation of plant extract | The In brief, to the determination of total flavonoids and the main component of Besides, the amount of rosmarinic acid in the extract capsule was quantified by HPLC according to previously detailed techniques [ | PMC10152712 | ||
Ethics approval and consent to participate | All protocols in this study were followed conducted in accordance with the Helsinki Declaration (1989 revision) and Ethical approval for this study was obtained from the Iran University of Medical Sciences Ethics committee (IR.IUMS.FMD.REC 1396.9413468004; research.iums.ac.ir). The study was registered at the Iranian Registry of Clinical Trials (IRCT201709239472N16;). All participants were informed of the study's purposes and signed written informed consent. | PMC10152712 | ||
Participants | depression, Depression, depressive | MAY, TYPE 2 DIABETES | Participants were 60 patients with type 2 diabetes combined with depression. The study was carried out at the Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences in Tehran, between May 2017 and May 2019. The Inclusion criteria were: type 2 diabetes patients with at least one year of DMT2 history, aged 20 to 65 years for both genders; the presence of depressive symptoms (depression score of more than ten based on Beck Depression Inventory) [ | PMC10152712 |
Study design | BLOOD | We conducted a single-center, randomized, and double-blind clinical trial. Participants, researchers, and statisticians were blinded. All subjects were initially randomly assigned by simple randomization procedures (computerized random numbers) to the intervention group (Patients in Furthermore, the validated Persian language version [Venous blood samples were collected after 12 to 14 h of overnight fasting before and after 12 weeks of intervention. The serum samples for measuring FBS and hs-CRP were frozen at -80 ˚C until measurement. Systolic and diastolic blood pressure were recorded after rest (at least 5 min), in the sitting position, using an OMRON M6 Comfort Automatic Blood Pressure Monitor (Tokyo, Japan) at baseline and after 12 weeks of study. Participants' weight and height were measured by using a standard calibrated scale (Seca, Hamburg, Germany) and Waist circumference (WC) were assessed by a practiced researcher. Body mass index (BMI) was calculated according to the following equation BMI = weight (kg)/length2 (m2). | PMC10152712 | |
Sample size | depression | A sample size of at least 25 patients per group was calculated, giving a power of 80% to detect the target difference in depression (as a critical variable obtained from a previous study) [Patients were assigned into two groups using permuted block randomization with two size blocks (case and control) and a random number table. To hide the treatment, the statistical advisor who was not involved in the study encoded the identical boxes of the capsules and generated the random sequence. Randomization and allocation were hidden from both the researchers and the patients until the final analyses were completed. The randomized allocation sequence, enrollment of patients, and allocation to interventions were operated by trained staff. | PMC10152712 | |
Laboratory analysis | FBS was calculated with a Cobas MIRA analyzer (Roche Diagnostic, Basel, Switzerland) by an enzymatic process (Pars Azmon Co., Tehran, Iran). The sensitivity of the assays for FBS was 5 mg/dL. hs-CRP was calculated by using the turbidimetric method the Pars Azmoon kit (Pars Azmoon Inc., Tehran, Iran) on Hitachi 917. The sensitivity of the assays for hs-CRP was 0.1 mg/L. | PMC10152712 | ||
Statistical analysis | The Kolmogorov–Smirnov test was done to investigate the normality of data. Between‐group comparisons of quantitative variables and their mean changes were made using independent samples t-test or Mann–Whitney U test for normally and non-normally distributed data, respectively. A Comparison of qualitative variables and their mean changes between the groups was done using the Chi‐square test and Fisher exact test. Within‐group comparisons were done using paired samples t-test or Wilcoxon signed‐ranks test for normally and non-normally distributed data, respectively. Results were expressed as mean ± standard deviation. All statistical analyses were assessed by Statistical Package for Social Science version 24 (SPSS Inc., Chicago, IL, USA).P-values equal or less than 0.05 were considered statistically significant. | PMC10152712 | ||
Results | PMC10152712 | |||
Extract analysis | The total flavonoid contents of | PMC10152712 | ||
Discussion | death, anxiety, diabetic, depression, diabetes | ADVERSE EVENTS, DISORDERS, DIABETES | The incidence of depression in diabetic patients significantly impacts glycemic control, adverse events, and quality of life in these patients. The combination of diabetes and depression increases the risk of death in these patients. We performed this study as the first clinical trial to reveal the clinical efficacy of 700 mg/bid. In line with our findings, Chehroudi et al. [Besides, Taiwo et al. [One of the main causes of depression that is nowadays highlighted is an increase in cortisol levels and a change in the cycle of cytokines such as gamma-aminobutyric acid and glutamate [Our results also exhibited that the study intervention did not significantly affect sleep disorders. This finding can be associated with the small sample size of the study. One of the main causes of anxiety is neurobiological disorders such as serotonin, gamma-aminobutyric acid and noradrenaline system disturbance [Supplementation had no significant effect on FBS in the lemon balm group. There are some controversial reports on the effects of In the present study, the reduction of hs-CRP in the Some components in There is also controversy about Nevertheless, a recent study revealed the antihypertensive effects of 700 mg of | PMC10152712 |
Strengths and limitations | Evaluation of dietary intakes and physical activity in the baseline, middle, and end of the study can be counted as the powers of our research; Nevertheless, inadequate | PMC10152712 | ||
Conclusions | The results of this study showed that the use of 700 mg of the hydroalcoholic extract of the aerial parts of | PMC10152712 | ||
Acknowledgements | The authors hereby appreciate all the volunteers who participated in this study. The authors would like to gratefully acknowledge the Institute of Medical PlantsJahadDaneshgahi and the nursing staff of the Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, for their assistance in providing the essential facilities for conducting this study. | PMC10152712 | ||
Authors' contributions | Conceptualization has conducted by Mostafa Safari, Akbar Asadi, NaheedAryaeian/. Methodology has conducted by Mostafa Safari, Akbar Asadi, NaheedAryaeian, Farzadshidfar, ShimaJazayeri, MojtabaMalek, Hasan FallahHuseini, AghaFateme Hosseini. Validation has conducted by NaheedAryaeian, Farzadshidfar, ShimaJazayeri, MojtabaMalek, Hasan FallahHuseini. Formal analysis has conducted by Mostafa Safari, NaheedAryaeian, AghaFateme Hosseini. Investigation has conducted by Mostafa Safari, Akbar Asadi, Zahra hamidi. Resources has conducted by MojtabaMalek, Hasan FallahHuseini. Writing—Original Draft has conducted by Mostafa Safari, NaheedAryaeian. All authors reviewed the manuscript. The author(s) read and approved the final manuscript. | PMC10152712 | ||
Funding | This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. | PMC10152712 | ||
Availability of data and materials | All data generated or analysed during this study are included in this published article [and its supplementary information files]. | PMC10152712 | ||
Declarations | PMC10152712 | |||
Ethics approval and consent to participate | All protocols in this study were followed conducted in accordance with the Helsinki Declaration (1989 revision)and Ethical approval for this study was obtained from the Iran University of Medical Sciences Ethics committee (IR.IUMS.FMD.REC 1396.9413468004; research.iums.ac.ir). The study was registered at the Iranian Registry of Clinical Trials (IRCT201709239472N16;) Registration date: 09/10/2017. All participants were informed of the purposes of the study, and theysigned a written informed consent.The Institute of Medicinal Plant Karaj Iran undertook the formal identification of the plant material used in our study. The authors have complied with all relevant institutional and national guidelines and legislation in experimental research and field studies on plants, including the collection of plant materials for this study. | PMC10152712 | ||
Consent for publication | We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. The manuscript has been read and approved by all the mentioned authors. All subjects gave informed consent and patient’s anonymity was preserved. | PMC10152712 | ||
Competing interests | The authors declared no conflict of interest. | PMC10152712 | ||
References | PMC10152712 | |||
Background | metabolic disease, diabetes mellitus, T2DM, metabolic anomaly | DIABETES MELLITUS | Edited by: Raffaella Maria Gadaleta, University of Bari Aldo Moro, ItalyReviewed by: Cosmin Mihai Vesa, University of Oradea, Romania; Ryan Russell, The University of Texas Rio Grande Valley, United StatesType 2 diabetes mellitus (T2DM) is a commonly observed metabolic anomaly globally, and as of the present time, there's no recognized solution. There is an increasing body of evidence from numerous observational studies indicating a significant correlation between gut flora and metabolic disease progression, particularly in relation to T2DM. Despite this, the direct impact of gut microbiota on T2DM isn't fully understood yet. | PMC10556527 |
Methods | MR, T2DM | The summary statistical figures for intestinal microbiota were sourced from the MiBioGen consortium, while the summary statistical data for T2DM were gathered from the Genome-Wide Association Studies (GWAS) database. These datasets were used to execute a two-sample Mendelian randomization (MR) investigation. The Inverse Variance Weighted (IVW), Maximum Likelihood, MR-Egger, Weighted Median, and Weighted Models strategies were employed to assess the impact of gut microbiota on T2DM. Findings were primarily obtained using the IVW technique. Techniques like MR-Egger were employed to identify the occurrence of horizontal pleiotropy among instrumental variables. Meanwhile, Cochran's Q statistical measures were utilized to assess the variability or heterogeneity within these instrumental variables. | PMC10556527 | |
Results | The outcomes from the IVW analysis demonstrated that the genus | PMC10556527 | ||
Conclusion | This MR study relies on genetic variation tools to confirm the causal effect of genus | PMC10556527 | ||
1. Introduction | obesity, MR, T2DM, intestinal flora disorders | OBESITY, DISEASE, DIABETES MELLITUS (DM), METABOLIC DISEASES, TYPE 2 DIABETES MELLITUS | As society progresses and living conditions improve, increased obesity rates, declining air quality, and an aging population are risk factors for a range of chronic metabolic diseases. One of such a globally prevalent disease is diabetes mellitus (DM), which includes type 2 diabetes mellitus (T2DM) (Gut flora, the collective term for the vast microbial ecosystem residing in our intestinal tract, boasts an impressive count of roughly 40 trillion bacteria and a gene count that exceeds the human's by approximately 150-fold (Recent studies have shown that in addition to poor dietary habits and impaired islet function, intestinal flora disorders may also contribute to T2DM (The Mendelian Randomization (MR) employed in this study serves as a tool for epidemiological scrutiny, which gauges the link between genetic variants and outcomes such as disease manifestation or mortality, based on genetic alterations tied to exposure elements. Essentially, it utilizes genetic information as a conduit to investigate the causal relationship between exposure and outcomes. MR is a potent instrument for making causal deductions, effectively circumventing the confounding bias often seen in traditional epidemiological research ( | PMC10556527 |
2. Methods | PMC10556527 | |||
2.1. Data sources | TYPE 2 DIABETES | In our research, we conducted two-sample MR analyses, designating gut microbiota as the exposure and type 2 diabetes as the outcome variable. The exposure data was sourced from MiBioGen ( | PMC10556527 | |
2.2. Experimental design | SE, MR, T2DM | In an effort to explore the cause-and-effect link between intestinal microflora and T2DM, a bi-sample Mendelian Randomization study was implemented, leveraging data from the MiBioGen consortium and the compiled dataset from GWAS. The instrumental variables (IVs) were initially subjected to a screening process. For an IV to be utilized in MR, it had to meet three primary assumptions: (1) Correlation: the SNPs were robustly linked to exposure; (2) Exclusivity: the SNPs did not correlate with the outcome; (3) Independence: the SNPs showed no association with confounding factors (where in β denotes the effect size of the SNP on exposure and SE represents β's standard error.An F statistic >10 was considered indicative of insignificant weak instrumental bias. Subsequently, data were extracted from both databases and compiled such that the impact values for exposure and outcome corresponded to the same effect allele. The identified SNPs linked with each genus underwent analysis via various statistical methods to deduce causal associations between gut flora and T2DM across the 6 families and 14 genera. Finally, to fulfill MR assumptions (2) and (3), SNPs directly linked to confounding factors and outcomes were excluded using the phenoscanner website (The flow chart outlines the study design and the process of Mendelian randomization (MR) analysis. SNP stands for single nucleotide polymorphism, which serves as the instrumental variables. IVW represents inverse-variance weighted, a method employed in the analysis. | PMC10556527 | |
2.3. Statistical analysis | WME, T2DM | REGRESSION | Within the framework of this research, a diverse array of methodologies was employed to explore the potential causal relationship between the gut microbiota and T2DM. These techniques encompassed an assortment of approaches, including but not limited to inverse variance weighted (IVW), Simple mode, MR-Egger regression, weighted median (WM), and weighted model (WME). The utilization of these multiple approaches allowed for a comprehensive investigation into the prospective causal linkages between the intestinal microflora and the occurrence of T2DM. Primarily, the IVW method was utilized as a leading causal effect estimator in MR research, demonstrating robust causal relationship detection and high testing efficacy ( | PMC10556527 |
2.4. Sensitivity analysis | To confirm the dependability of our outcomes, we performed sensitivity checks to gauge the sturdiness of the results, possible biases (like genetic pleiotropy and data diversity), and the impact of particular instrumental variables on the result variable ( | PMC10556527 |
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