المؤلفون: Grandt, Caine Lucas, Brackmann, Lara Kim, Foraita, Ronja, Schwarz, Heike, Hummel-Bartenschlager, Willempje, Hankeln, Thomas, Kraemer, Christiane, Zahnreich, Sebastian, Drees, Philipp, Mirsch, Johanna, Spix, Claudia, Blettner, Maria, Schmidberger, Heinz, Binder, Harald, Hess, Moritz, Galetzka, Danuta, Marini, Federico, Poplawski, Alicia, Marron, Manuela

المصدر: http://lobid.org/resources/991000067219706485Test#!, 29(1):41.

مصطلحات موضوعية: Kikme study, Pan-cancer, NGS, RNA-Seq, Radiation response, Childhood cancer, High dose, Low dose

الوصف: BACKGROUND: Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. METHODS: Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case–control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. RESULTS: We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. CONCLUSION: N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a ...

العلاقة: https://repository.publisso.de/resource/frl:6452805Test; https://doi.org/10.1186/s10020-023-00629-2Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061869Test/; https://molmed.biomedcentral.com/articles/10.1186/s10020-023-00629-2#Sec27Test

الإتاحة: https://doi.org/10.1186/s10020-023-00629-2Test
https://repository.publisso.de/resource/frl:6452805Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061869Test/

المؤلفون: Grandt, Caine Lucas, Brackmann, Lara Kim, Poplawski, Alicia, Schwarz, Heike, Marini, Federico, Hankeln, Thomas, Galetzka, Danuta, Zahnreich, Sebastian, Mirsch, Johanna, Spix, Claudia, Blettner, Maria, Schmidberger, Heinz, Marron, Manuela

المصدر: Frontiers in oncology, 13:1158176

مصطلحات موضوعية: weighted co-expression network analysis (WGCNA), radiation experiments, radiation response, differential gene expression analysis, RNA-Seq, NGS - next generation sequencing, KiKme Study

الوصف: INTRODUCTION: Long non-coding ribonucleic acids (lncRNAs) are involved in the cellular damage response following exposure to ionizing radiation as applied in radiotherapy. However, the role of lncRNAs in radiation response concerning intrinsic susceptibility to late effects of radiation exposure has not been examined in general or in long-term survivors of childhood cancer with and without potentially radiotherapy-related second primary cancers, in particular. METHODS: Primary skin fibroblasts (n=52 each) of long-term childhood cancer survivors with a first primary cancer only (N1), at least one second primary neoplasm (N2+), as well as tumor-free controls (N0) from the KiKme case-control study were matched by sex, age, and additionally by year of diagnosis and entity of the first primary cancer. Fibroblasts were exposed to 0.05 and 2 Gray (Gy) X-rays. Differentially expressed lncRNAs were identified with and without interaction terms for donor group and dose. Weighted co-expression networks of lncRNA and mRNA were constructed using WGCNA. Resulting gene sets (modules) were correlated to the radiation doses and analyzed for biological function. RESULTS: After irradiation with 0.05Gy, few lncRNAs were differentially expressed (N0: AC004801.4; N1: PCCA-DT, AF129075.3, LINC00691, AL158206.1; N2+: LINC02315). In reaction to 2 Gy, the number of differentially expressed lncRNAs was higher (N0: 152, N1: 169, N2+: 146). After 2 Gy, AL109976.1 and AL158206.1 were prominently upregulated in all donor groups. The co-expression analysis identified two modules containing lncRNAs that were associated with 2 Gy (module1: 102 mRNAs and 4 lncRNAs: AL158206.1, AL109976.1, AC092171.5, TYMSOS, associated with p53-mediated reaction to DNA damage; module2: 390 mRNAs, 7 lncRNAs: AC004943.2, AC012073.1, AC026401.3, AC092718.4, MIR31HG, STXBP5-AS1, TMPO-AS1, associated with cell cycle regulation). DISCUSSION: For the first time, we identified the lncRNAs AL158206.1 and AL109976.1 as involved in the radiation response in primary ...

العلاقة: https://repository.publisso.de/resource/frl:6453231Test; https://dx.doi.org/10.3389/fonc.2023.1158176Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174438Test/; https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1158176/full#h14Test

الإتاحة: https://doi.org/10.3389/fonc.2023.1158176Test
https://repository.publisso.de/resource/frl:6453231Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10174438Test/

المؤلفون: Brackmann, Lara Kim, Foraita, Ronja, Schwarz, Heike, Poplawski, Alicia, Hankeln, Thomas, Galetzka, Danuta, Zahnreich, Sebastian, Spix, Claudia, Blettner, Maria, Schmidberger, Heinz, Marron, Manuela

المساهمون: Bundesministerium für Bildung und Forschung

المصدر: Frontiers in Oncology ; volume 13 ; ISSN 2234-943X

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: Background Childhood cancer survivors (CCS) are at particularly high risk for therapy-related late sequelae, with secondary primary neoplasms (SPN) being the most detrimental. Since there is no standardized questionnaire for retrospective assessment of associations between prior cancer treatments and late health effects, we developed a self-administered questionnaire and validated it in a cohort of CCS. Methods CCS of a first primary neoplasm (FPN, N=340) only or with a subsequent SPN (N=101) were asked whether they had received cancer therapies. Self-reports were compared to participants’ medical records on cancer therapies from hospitals and clinical studies (N=242). Cohen’s Kappa (κ) was used to measure their agreement and logistic regression was used to identify factors influencing the concordance. Associations between exposure to cancer therapies and late health effects (overweight/obesity, diseases of the lipid metabolism and the thyroid gland, cardiovascular diseases, occurrence of SPN) were analyzed in all participants by applying generalized linear mixed models to calculate odds ratios (OR) and 95% confidence intervals (95%CI). Results For CCS of SPN, a perfect agreement was found between self-reports and medical records for chemotherapy (CT, κ=1.0) while the accordance for radiotherapy (RT) was lower but still substantial (κ=0.8). For the CCS of FPN the accordance was less precise (CT: κ=0.7, RT: κ=0.3). Cancer status, tumors of the central nervous system, sex, age at recruitment, vocational training, follow-up time, and comorbidities had no impact on agreement. CCS with exposure to CT were found to be less often overweight or obese compared to those without CT (OR=0.6 (95%CI 0.39; 0.91)). However, they were found to suffer more likely from thyroid diseases excluding thyroid cancers (OR=9.91 (95%CI 4.0; 24.57)) and hypercholesterolemia (OR=4.45 (95%CI 1.5; 13.23)). All other analyses did not show an association. Conclusion Our new questionnaire proved reliable for retrospective assessment of exposure ...

الإتاحة: https://doi.org/10.3389/fonc.2023.1150629Test

المؤلفون: Brackmann, Lara Kim, Foraita, Ronja, Schwarz, Heike, Galetzka, Danuta, Zahnreich, Sebastian, Hankeln, Thomas, Löbrich, Markus, Poplawski, Alicia, Grabow, Desiree, Blettner, Maria, Schmidberger, Heinz, Marron, Manuela

المصدر: Frontiers in oncology, 12:1037276

مصطلحات موضوعية: thyroid disease, body mass index - BMI, diet, smoking, childhood cancer survivors (CCS), lipid metabolism, alcohol, physical activity

الوصف: BACKGROUND: Improved treatments for childhood cancer result in a growing number of long-term childhood cancer survivors (CCS). The diagnosis and the prevalence of comorbidities may, however, influence their lifestyle later in life. Nonetheless, little is known about differences in late effects between CCS of a first primary neoplasm (FPN) in childhood and subsequent second primary neoplasms (SPN) and their impact on lifestyle. Therefore, we aim to investigate associations between the occurrence of FPN or SPN and various diseases and lifestyle in the later life of CCS. METHODS: CCS of SPN (n=101) or FPN (n=340) and cancer-free controls (n=150) were matched by age and sex, and CCS additionally by year and entity of FPN. All participants completed a self-administered questionnaire on anthropometric and socio-economic factors, medical history, health status, and lifestyle. Mean time between FPN diagnosis and interview was 27.3 years for SPN and 26.2 years for FPN CCS. To confirm results from others and to generate new hypotheses on late effects of childhood cancer as well as CCS´ lifestyles, generalized linear mixed models were applied. RESULTS: CCS were found to suffer more likely from diseases compared to cancer-free controls. In detail, associations with cancer status were observed for hypercholesterinemia and thyroid diseases. Moreover, CCS were more likely to take regular medication compared to controls. A similar association was observed for CCS of SPN compared to CCS of FPN. In contrast to controls, CCS rarely exercise more than 5 hours per week, consumed fewer soft and alcoholic drinks, and were less likely to be current, former, or passive smokers. Additionally, they were less likely overweight or obese. All other exploratory analyses performed on cardiovascular, chronic lung, inflammatory bone, allergic, and infectious diseases, as well as on a calculated health-score revealed no association with tumor status. CONCLUSION: CCS were more affected by pathologic conditions and may consequently take more ...

العلاقة: https://repository.publisso.de/resource/frl:6440298Test; https://doi.org/10.3389/fonc.2022.1037276Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618813Test/; https://www.frontiersin.org/articles/10.3389/fonc.2022.1037276/full#h13Test

الإتاحة: https://doi.org/10.3389/fonc.2022.1037276Test
https://repository.publisso.de/resource/frl:6440298Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618813Test/

المؤلفون: Grandt, Caine Lucas, Brackmann, Lara Kim, Poplawski, Alicia, Schwarz, Heike, Hummel-Bartenschlager, Willempje, Hankeln, Thomas, Kraemer, Christane, Marini, Federico, Zahnreich, Sebastian, Schmitt, Iris, Drees, Philipp, Mirsch, Johanna, Grabow, Desiree, Schmidberger, Heinz, Binder, Harald, Hess, Moritz, Galetzka, Danuta, Marron, Manuela

المصدر: Molecular medicine, 28(1):105

مصطلحات موضوعية: Radiation experiment, NGS, RNA-Seq, Radiation response, Diferential gene expression, High dose, Low dose, Pathway analysis

الوصف: BACKGROUND: The etiology and most risk factors for a sporadic first primary neoplasm in childhood or subsequent second primary neoplasms are still unknown. One established causal factor for therapy-associated second primary neoplasms is the exposure to ionizing radiation during radiation therapy as a mainstay of cancer treatment. Second primary neoplasms occur in 8% of all cancer survivors within 30 years after the first diagnosis in Germany, but the underlying factors for intrinsic susceptibilities have not yet been clarified. Thus, the purpose of this nested case–control study was the investigation and comparison of gene expression and affected pathways in primary fibroblasts of childhood cancer survivors with a first primary neoplasm only or with at least one subsequent second primary neoplasm, and controls without neoplasms after exposure to a low and a high dose of ionizing radiation. METHODS: Primary fibroblasts were obtained from skin biopsies from 52 adult donors with a first primary neoplasm in childhood (N1), 52 with at least one additional primary neoplasm (N2+), as well as 52 without cancer (N0) from the KiKme study. Cultured fibroblasts were exposed to a high [2 Gray (Gy)] and a low dose (0.05 Gy) of X-rays. Messenger ribonucleic acid was extracted 4 h after exposure and Illumina-sequenced. Differentially expressed genes (DEGs) were computed using limma for R, selected at a false discovery rate level of 0.05, and further analyzed for pathway enrichment (right-tailed Fisher’s Exact Test) and (in-) activation (z ≥|2|) using Ingenuity Pathway Analysis. RESULTS: After 0.05 Gy, least DEGs were found in N0 (n = 236), compared to N1 (n = 653) and N2+ (n = 694). The top DEGs with regard to the adjusted p-value were upregulated in fibroblasts across all donor groups (SESN1, MDM2, CDKN1A, TIGAR, BTG2, BLOC1S2, PPM1D, PHLDB3, FBXO22, AEN, TRIAP1, and POLH). Here, we observed activation of p53 Signaling in N0 and to a lesser extent in N1, but not in N2+. Only in N0, DNA (excision-) repair (involved genes: ...

العلاقة: https://repository.publisso.de/resource/frl:6438343Test; https://doi.org/10.1186/s10020-022-00520-6Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9450413Test/; https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00520-6#Sec22Test

الإتاحة: https://doi.org/10.1186/s10020-022-00520-6Test
https://repository.publisso.de/resource/frl:6438343Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9450413Test/

المؤلفون: Marron, Manuela, Brackmann, Lara Kim, Kuhse, Pia, Christianson, Lara, Langner, Ingo, Haug, Ulrike, Ahrens, Wolfgang

المصدر: Frontiers in oncology, 10:610843

مصطلحات موضوعية: Immunization, Immune system, Acute lymphoblastic leukemia, Leukemia death, Childhood leukemia

الوصف: INTRODUCTION: Infections may play a role in the etiology of childhood cancer and immunizations may be protective because vaccinations stimulate the immune system. Observational studies reported inconsistent associations between vaccination and risk of childhood cancer. Since a synthesis of the evidence is lacking, we conducted a meta-analysis stratified by histological and site-specific cancer. METHODS: We performed a systematic review (CRD42020148579) following PRISMA guidelines and searched for literature in MEDLINE, Embase, and the Science Citation Index databases. We identified in three literature databases 7,594 different articles of which 35 met the inclusion criteria allowing for 27 analyses of 11 cancer outcomes after exposure to nine different types of vaccinations. We calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) using random effects models. RESULTS: We observed four inverse associations between childhood leukemia and certain vaccines as well as the number of vaccinations: OR 0.49 (95% CI = 0.32 to 0.74) for leukemia death after bacillus Calmette–Guérin vaccination; OR 0.76 (95% CI = 0.65 to 0.90) for acute lymphoblastic leukemia after Haemophilus influenzae type b vaccination; OR 0.57 (95% CI = 0.36 to 0.88) for leukemia; and OR 0.62 (95% CI = 0.46 to 0.85) for acute lymphoblastic leukemia after three or more vaccinations of any type. All other conducted analyses did not show any associations. DISCUSSION: The results are consistent with the hypothesis that vaccinations reduce the risk of childhood leukemia. However, the robustness and validity of these results is limited due to the small number, substantial heterogeneity, and methodological limitations of available studies.

العلاقة: https://repository.publisso.de/resource/frl:6429044Test; https://doi.org/10.3389/fonc.2020.610843Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862764Test/; https://www.frontiersin.org/articles/10.3389/fonc.2020.610843/full#supplementary-materialTest

الإتاحة: https://doi.org/10.3389/fonc.2020.610843Test
https://repository.publisso.de/resource/frl:6429044Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862764Test/

المؤلفون: Marron, Manuela, Brackmann, Lara Kim, Hummel-Bartenschlager, Willempje, Zahnreich, Sebastian, Galetzka, Danuta, Schmitt, Iris, Grad, Christian, Hopf, Johannes, Mirsch, Johanna, Scholz-Kreisel, Peter, Kaatsch, Peter, Poplawski, Alicia, Hess, Moritz, Binder, Harald, Hankeln, Thomas, Blettner, Maria, Schmidberger, Heinz

المصدر: JMIR research protocols. - 10, 11 (2021) , e32395, ISSN: 1929-0748

الوصف: Background: Therapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development. Objective: Therefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls. Methods: We conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation). Results: Since 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510). Conclusions: This molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify ...

وصف الملف: pdf

العلاقة: https://freidok.uni-freiburg.de/data/222690Test

الإتاحة: https://doi.org/10.2196/32395Test
https://freidok.uni-freiburg.de/data/222690Test
https://nbn-resolving.org/urn:nbn:de:bsz:25-freidok-2226900Test
https://freidok.uni-freiburg.de/dnb/download/222690Test

المؤلفون: Brackmann, Lara Kim, Poplawski, Alicia, Grandt, Caine Lucas, Schwarz, Heike, Hankeln, Thomas, Rapp, Steffen, Zahnreich, Sebastian, Galetzka, Danuta, Schmitt, Iris, Grad, Christian, Eckhard, Lukas, Mirsch, Johanna, Blettner, Maria, Scholz-Kreisel, Peter, Hess, Moritz, Binder, Harald, Schmidberger, Heinz, Marron, Manuela

المصدر: Molecular medicine, 26:85

مصطلحات موضوعية: Gene-radiation interaction, RNA sequencing, Childhood cancer, High dose, Fibroblasts, Low dose, Second primary neoplasm, IPA, Ionizing radiation

الوصف: BACKGROUND: Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. METHODS: Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p-value < 0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. RESULTS: More genes were differentially expressed 4 h after exposure to low and high doses of radiation than after 2 h. In experiments with high dose irradiation and RNA sequencing after 4 h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I, glycolysis I, and prostanoid biosynthesis was observed taking p-value (< 0.05) and (in) activating z-score (≥2.00 or ≤ − 2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant (p < 0.05 and z-score ≥ 2.00 or ≤ − 2.00) activated or inactivated pathways for both time points. CONCLUSIONS: Compared to 2 h after irradiation, a higher number of differentially expressed genes were found 4 h ...

العلاقة: https://repository.publisso.de/resource/frl:6425806Test; https://doi.org/10.1186/s10020-020-00203-0Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488023Test/; https://molmed.biomedcentral.com/articles/10.1186/s10020-020-00203-0#Sec15Test

الإتاحة: https://doi.org/10.1186/s10020-020-00203-0Test
https://repository.publisso.de/resource/frl:6425806Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488023Test/

المؤلفون: Lubasch, Johanna Sophie, Thumann, Barbara, Bucksch, Jens, Brackmann, Lara Kim, Wirsik, Norman, Donnelly, Alan, Hayes, Grainne, Nimptsch, Katharina, Steinbrecher, Astrid, Pischon, Tobias, Brug, Johannes, Ahrens, Wolfgang, Hebestreit, Antje

المصدر: Frontiers in Sports and Active Living ; volume 2 ; ISSN 2624-9367

الإتاحة: https://doi.org/10.3389/fspor.2020.00093Test

المؤلفون: Brackmann, Lara Kim, Buck, Christoph, Nyangasa, Maria Adam, Kelm, Soerge, Sheikh, Mohammed, Hebestreit, Antje

المصدر: Frontiers in Public Health, 7:338

مصطلحات موضوعية: Body fat, Blood pressure, Body Mass Index, Sub-Sahara Africa, Waist circumference, Hypertension, Salt

الوصف: BACKGROUND: Aim of this study was to describe the proportion of hypertension among Zanzibari of different age-groups and to detect possible correlates of this non-communicable disease. METHODS: In 2013 a cross-sectional survey was conducted in Unguja Island, Zanzibar. A total of 235 randomly selected households, including 1,229 (2 to 95 years) eligible study participants, were examined. Association between objectively assessed obesity markers, salt intake and hypertension were investigated. Estimates of 24 h sodium and potassium excretion from a single morning spot urine specimen were calculated and used as surrogate for salt intake. The association between overweight/obesity and hypertension in different age-groups was assessed in multilevel logistic regression models. Further associations between salt intake and hypertension were analyzed. RESULTS: Measures of systolic and diastolic blood pressure as well as proportion of overweight/obesity and hypertension both increased with age. Overweight and obesity were significantly associated with hypertension in adults. Moreover, thinness seems to be associated with hypertension as well. We observed a significantly reduced chance of hypertension for higher urinary sodium-to-potassium compared to a lower ratio in children. CONCLUSION: Overweight/obesity and hypertension were highly prevalent (>47% of adults >40 years are overweight or obese and >69% are hypertensive in the same age group) in our sample. Weight status was confirmed as a correlate of high blood pressure in our sample from Zanzibar, Tanzania. To early and effectively prevent related severe cardiovascular outcomes, screening strategies but also monitoring strategies are required for this population.

العلاقة: https://repository.publisso.de/resource/frl:6417671Test; https://doi.org/10.3389/fpubh.2019.00338Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881248Test/; https://www.frontiersin.org/articles/10.3389/fpubh.2019.00338/full#h12Test

الإتاحة: https://doi.org/10.3389/fpubh.2019.00338Test
https://repository.publisso.de/resource/frl:6417671Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881248Test/