Genetically identification of endometriosis and cancers risk in women through a two-sample Mendelian randomization study.

Endometriosis is a prevalent and chronic inflammatory gynecologic disorder affecting approximately 6-10% of women globally, and has been associated with an increased risk of cancer. Nevertheless, previous studies have been hindered by methodological limitations that compromise the validity and robustness of their findings. In this study we conducted a comprehensive two-sample Mendelian randomization analysis to explore the genetically driven causal relationship between endometriosis and the risk of cancer. We conducted the analysis via the inverse variance weighted method, MR Egger method, and weighted median method utilizing publicly available genome-wide association study summary statistics. Furthermore, we implemented additional sensitivity analyses to assess the robustness and validity of the causal associations identified. We found strong evidence of a significant causal effect of endometriosis on a higher risk of ovarian cancer via inverse-variance weighted method (OR = 1.19, 95% CI 1.11-1.29, p < 0.0001), MR-Egger regression, and weighted median methodologies. Remarkably, our findings revealed a significant association between endometriosis and an increased risk of clear cell ovarian cancer (OR = 2.04, 95% CI 1.66-2.51, p < 0.0001) and endometrioid ovarian cancer (OR = 1.45, 95% CI 1.27-1.65, p < 0.0001). No association between endometriosis and other types of cancer was observed. We uncovered a causal relationship between endometriosis and an elevated risk of ovarian cancer, particularly clear cell ovarian cancer and endometrioid ovarian cancer. No significant associations between endometriosis and other types of cancer could be identified.

Genetic correlation between circulating cytokines and risk of three ophthalmic diseases: a bidirectional two-sample Mendelian randomization study.

PURPOSE: Pathogenesis and the associated risk factors of cataracts, glaucoma, and age-related macular degeneration (AMD) remain unclear. We aimed to investigate causal relationships between circulating cytokine levels and the development of these diseases. PATIENTS AND METHODS: Genetic instrumental variables for circulating cytokines were derived from a genome-wide association study of 8293 European participants. Summary-level data for AMD, glaucoma, and senile cataract were obtained from the FinnGen database. The inverse variance weighted (IVW) was the main Mendelian randomization (MR) analysis method. The Cochran's Q, MR-Egger regression, and MR pleiotropy residual sum and outlier test were used for sensitivity analysis. RESULTS: Based on the IVW method, MR analysis demonstrated five circulating cytokines suggestively associated with AMD (SCGF-ß, 1.099 [95%CI, 1.037-1.166], P = 0.002; SCF, 1.155 [95%CI, 1.015-1.315], P = 0.029; MCP-1, 1.103 [95%CI, 1.012-1.202], P = 0.026; IL-10, 1.102 [95%CI, 1.012-1.200], P = 0.025; eotaxin, 1.086 [95%CI, 1.002-1.176], P = 0.044), five suggestively linked with glaucoma (MCP-1, 0.945 [95%CI, 0.894-0.999], P = 0.047; IL1ra, 0.886 [95%CI, 0.809-0.969], P = 0.008; IL-1ß, 0.866 [95%CI, 0.762-0.983], P = 0.027; IL-9, 0.908 [95%CI, 0.841-0.980], P = 0.014; IL2ra, 1.065 [95%CI, 1.004-1.130], P = 0.035), and four suggestively associated with senile cataract (TRAIL, 1.043 [95%CI, 1.009-1.077], P = 0.011; IL-16, 1.032 [95%CI, 1.001-1.064], P = 0.046; IL1ra, 0.942 [95%CI, 0.887-0.999], P = 0.047; FGF-basic, 1.144 [95%CI, 1.052-1.244], P = 0.002). Furthermore, sensitivity analysis results supported the above associations. CONCLUSION: This study highlights the involvement of several circulating cytokines in the development ophthalmic diseases and holds potential as viable pharmacological targets for these diseases.

Blood cell parameters and risk of nonalcoholic fatty liver disease: a comprehensive Mendelian randomization study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is on the rise globally, and past research suggests a significant association with various blood cell components. Our goal is to explore the potential correlation between whole blood cell indices and NAFLD risk using Mendelian randomization (MR). METHODS: We analyzed data from 4,198 participants in the 2017-2018 National Health and Nutrition Examination Survey to investigate the link between blood cell indicators and NAFLD. Using various methods like weighted quantile sum and multivariate logistic regression, we assessed the association. Additionally, two-sample Mendelian randomization were employed to infer causality for 36 blood cell indicators and NAFLD. RESULTS: Multivariate logistic regression identified 10 NAFLD risk factors. Weighted quantile sum revealed a positive correlation (p = 6.03e-07) between total blood cell indices and NAFLD, with hemoglobin and lymphocyte counts as key contributors. Restricted cubic spline analysis found five indicators with significant nonlinear correlations to NAFLD. Mendelian randomization showed a notable association between reticulocyte counts and NAFLD using the inverse-variance weighted method. CONCLUSIONS: Hematological markers pose an independent NAFLD risk, with a positive causal link found for reticulocyte count. These results emphasize the importance of monitoring NAFLD and investigating specific underlying mechanisms further.

The genetic relationship between systemic lupus erythematosus and risk of primary ovarian failure from a mendelian randomization study.

Previous studies investigating the relationship between systemic lupus erythematosus (SLE) and primary ovarian failure (POF) generated conflicting results. To data, no mendelian randomization study has been applied to examine this association. In this study, genetic instruments for exposure (SLE) were selected from a GWAS study with 5201 cases and 9066 noncases. Outcome data for POF and three reproductive traits (age at menarche, age at menopause, and age at first live birth) were obtained from other eligible GWASs. To estimate causal association, the inverse-variance weighted (IVW) method (the main analyse), MR Egger test, weighted median, simple mode, and weighted mode were applied. Moreover, sensitivity analyses were conducted to ensure the robustness of the results. Estimated by the IVW method, SLE was suggested to be causally related to the risk of POF (OR = 1.166, 95% CI 1.055-1.289, P = 0.003) and delayed age at first live birth (OR = 1.006, 95% CI 1.002-1.010, P = 0.007), with no evidence of a causal association between SLE and age at menopause or menarche. The estimates were robust according to sensitivity analysis. In conclusion, the two-sample MR study supported a causal association between SLE and POF from a genetic aspect.

Causal effect of gut microbiota and diabetic nephropathy: a Mendelian randomization study.

BACKGROUND: The interaction of dysbiosis of gut microbiota (GM) with diabetic nephropathy (DN) drew our attention and a better understanding of GM on DN might provide potential therapeutic approaches. However, the exact causal effect of GM on DN remains unknown. METHODS: We applied two-sample Mendelian Randomization (MR) analysis, including inverse variance weighted (IVW), MR-Egger methods, etc., to screen the significant bacterial taxa based on the GWAS data. Sensitivity analysis was conducted to assess the robustness of MR results. To identify the most critical factor on DN, Mendelian randomization-Bayesian model averaging (MR-BMA) method was utilized. Then, whether the reverse causality existed was verified by reverse MR analysis. Finally, transcriptome MR analysis was performed to investigate the possible mechanism of GM on DN. RESULTS: At locus-wide significance levels, the results of IVW suggested that order Bacteroidales (odds ratio (OR) = 1.412, 95% confidence interval (CI): 1.025-1.945, P = 0.035), genus Akkermansia (OR = 1.449, 95% CI: 1.120-1.875, P = 0.005), genus Coprococcus 1 (OR = 1.328, 95% CI: 1.066-1.793, P = 0.015), genus Marvinbryantia (OR = 1.353, 95% CI: 1.037-1.777, P = 0.030) and genus Parasutterella (OR = 1.276, 95% CI: 1.022-1.593, P = 0.032) were risk factors for DN. Reversely, genus Eubacterium ventriosum (OR = 0.756, 95% CI: 0.594-0.963, P = 0.023), genus Ruminococcus gauvreauii (OR = 0.663, 95% CI: 0.506-0.870, P = 0.003) and genus Erysipelotrichaceae (UCG003) (OR = 0.801, 95% CI: 0.644-0.997, P = 0.047) were negatively associated with the risk of DN. Among these taxa, genus Ruminococcus gauvreauii played a crucial role in DN. No significant heterogeneity or pleiotropy in the MR result was found. Mapped genes (FDR < 0.05) related to GM had causal effects on DN, while FCGR2B and VNN2 might be potential therapeutic targets. CONCLUSIONS: This work provided new evidence for the causal effect of GM on DN occurrence and potential biomarkers for DN. The significant bacterial taxa in our study provided new insights for the 'gut-kidney' axis, as well as unconventional prevention and treatment strategies for DN.

Evaluation of Adverse Drug Events in Patients on Anti-Retroviral Therapy Regimen at Omdurman Voluntary Counselling and Testing and Anti-Retroviral Therapy Center in Sudan - A Cross-Sectional Study.

Background: Anti-retroviral therapy-related adverse drug events are accounted as a main cause of anti-retroviral therapy non-adherence. In Sudan, pharmacovigilance studies are relatively rare and obstructed by the problem of under-reporting. It is a well-defined issue worldwide and is highly reported in developing countries. This study aimed to evaluate the prevalence of adverse events associated with anti-retroviral therapy among adult patients with immunodeficiency virus at Omdurman Voluntary Counselling and Testing and Anti-retroviral Therapy Center. Methods: The study was a descriptive cross-sectional study conducted through direct interviews with 429 patients at the selected center using the Adverse Drug Events (ADEs) reporting form. The collected data were analyzed by The Statistical Package for Social Sciences. Results: More than half (55.5%) of the participants experienced adverse events, with 48.7% having experienced them at the beginning of treatment. Central nervous system manifestations were the most common adverse events. By using the Naranjo scale, most adverse events showed a "probable" relationship to anti-retroviral medicines. Based on the chi-square test, medication regimen was significantly associated with the presence of ADEs (namely abdominal pain and jaundice) (p values = 0.03 and 0.001), respectively. Conclusion: This study clearly stated that ART-related ADEs are common among Sudanese PLHIV and with central nervous system being the main adverse events. More pharmacovigilance studies and efforts by healthcare providers should be applied targeting ART-related ADEs under-reporting in Sudanese healthcare facilities.

Iron status and sarcopenia-related traits: a bi-directional Mendelian randomization study.

Although serum iron status and sarcopenia are closely linked, the presence of comprehensive evidence to establish a causal relationship between them remains insufficient. The objective of this study is to employ Mendelian randomization techniques to clarify the association between serum iron status and sarcopenia. We conducted a bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationship between iron status and sarcopenia. MR analyses were performed using inverse variance weighted (IVW), MR-Egger, and weighted median methods. Additionally, sensitivity analyses were conducted to verify the reliability of the causal association results. Then, we harvested a combination of SNPs as an integrated proxy for iron status to perform a MVMR analysis based on IVW MVMR model. UVMR analyses based on IVW method identified causal effect of ferritin on appendicular lean mass (ALM, ß = - 0.051, 95% CI - 0.072, - 0.031, p = 7.325 × 10-07). Sensitivity analyses did not detect pleiotropic effects or result fluctuation by outlying SNPs in the effect estimates of four iron status on sarcopenia-related traits. After adjusting for PA, the analysis still revealed that each standard deviation higher genetically predicted ferritin was associated with lower ALM (ß = - 0.054, 95% CI - 0.092, - 0.015, p = 0.006). Further, MVMR analyses determined a predominant role of ferritin (ß = - 0.068, 95% CI - 0.12, - 0.017, p = 9.658 × 10-03) in the associations of iron status with ALM. Our study revealed a causal association between serum iron status and sarcopenia, with ferritin playing a key role in this relationship. These findings contribute to our understanding of the complex interplay between iron metabolism and muscle health.

Human Leucocyte Antigen Genetics in Idiosyncratic Drug-Induced Liver Injury with Evidence Based on the Roussel Uclaf Causality Assessment Method.

The human leucocyte antigen (HLA) allele variability was studied in cohorts of patients with idiosyncratic drug-induced liver injury (iDILI). Some reports showed an association between HLA genetics and iDILI, proposing HLA alleles as a potential risk factor for the liver injury. However, the strength of such assumptions heavily depends on the quality of the iDILI diagnosis, calling for a thorough analysis. Using the PubMed database and Google Science, a total of 25 reports of case series or single cases were retrieved using the terms HLA genes and iDILI. It turned out that in 10/25 reports (40%), HLA genetics were determined in iDILI cases, for which no causality assessment method (CAM) was used or a non-validated tool was applied, meaning the findings were based on subjective opinion, providing disputable results and hence not scoring individual key elements. By contrast, in most iDILI reports (60%), the Roussel Uclaf Causality Assessment Method (RUCAM) was applied, which is the diagnostic algorithm preferred worldwide to assess causality in iDILI cases and represents a quantitative, objective tool that has been well validated by both internal and external DILI experts. The RUCAM provided evidence-based results concerning liver injury by 1 drug class (antituberculotics + antiretrovirals) and 19 different drugs, comprising 900 iDILI cases. Among the top-ranking drugs were amoxicillin-clavulanate (290 cases, HLA A*02:01 or HLA A*30:02), followed by flucloxacillin (255 cases, HLA B*57:01), trimethoprim-sulfamethoxazole (86 cases, HLA B*14:01 or HLA B*14:02), methimazole (40 cases, HLA C*03:02), carbamazepine (29 cases, HLA A*31:01), and nitrofurantoin (26 cases, HLA A*33:01). In conclusion, the HLA genetics in 900 idiosyncratic drug-induced liver injury cases with evidence based on the RUCAM are available for studying the mechanistic steps leading to the injury, including metabolic factors through cytochrome P450 isoforms and processes that activate the innate immune system to the adaptive immune system.

How causality impacts the renewable energy, carbon emissions, and economic growth nexus in the South Caucasus Countries?

Renewable energy is essential for boosting economic expansion and lowering carbon dioxide emission (CO2) to achieve carbon neutrality. This study's objective is to investigate the relationship between the use of renewable energy, economic growth, and CO2 for South Caucasus Countries. For analysis purposes, time series methods were applied on the panel data. Second-generation unit root and cointegration tests were used to test the cross-sectional dependence. Afterward, panel causality and panel VAR techniques were performed to examine the relationship between the variables. Based on feedback hypothesis, results of our causality analysis revealed a bidirectional causality relationship between growth and renewable energy consumption. Moreover, we revealed unidirectional causality from CO2 to renewable energy and from growth to CO2 emission. We also found that the effect of a shock in renewable energy on growth is increasing, and on CO2, it is decreasing implying that renewable energy consumption will trigger growth and have a reducing effect on CO2 emissions. We portrayed significant workable implications for policymakers, regulation bodies, companies, stakeholders, and managers. Results from this study should be extrapolated with caution since their applicability is limited to the South Caucasus Countries. In addition, the research heavily depends on summaries, which may obscure regional differences. In the future, researchers may want to dig deeper into the data and examine the subtle effect of renewable energy policy nationally. Moreover, including socio-economic aspects and technical improvements in the research might give a more thorough picture of the dynamics at play.

Causal interactions in brain networks predict pain levels in trigeminal neuralgia.

Trigeminal neuralgia (TN) is a highly debilitating facial pain condition. Magnetic resonance imaging (MRI) is the main method for generating insights into the central mechanisms of TN pain in humans. Studies have found both structural and functional abnormalities in various brain structures in TN patients as compared with healthy controls. Whereas studies have also examined aberrations in brain networks in TN, no studies have to date investigated causal interactions in these brain networks and related these causal interactions to the levels of TN pain. We recorded fMRI data from 39 TN patients who either rested comfortably in the scanner during the resting state session or tracked their pain levels during the pain tracking session. Applying Granger causality to analyze the data and requiring consistent findings across the two scanning sessions, we found 5 causal interactions, including: (1) Thalamus → dACC, (2) Caudate → Inferior temporal gyrus, (3) Precentral gyrus → Inferior temporal gyrus, (4) Supramarginal gyrus → Inferior temporal gyrus, and (5) Bankssts → Inferior temporal gyrus, that were consistently associated with the levels of pain experienced by the patients. Utilizing these 5 causal interactions as predictor variables and the pain score as the predicted variable in a linear multiple regression model, we found that in both pain tracking and resting state sessions, the model was able to explain ∼36 % of the variance in pain levels, and importantly, the model trained on the 5 causal interaction values from one session was able to predict pain levels using the 5 causal interaction values from the other session, thereby cross-validating the models. These results, obtained by applying novel analytical methods to neuroimaging data, provide important insights into the pathophysiology of TN and could inform future studies aimed at developing innovative therapies for treating TN.

Editorial: Are government early years learning and development frameworks evidence-based? A scientist's perspective.

Not all young children attend nurseries, childminders or other group settings before they start school, but many do. It is common for countries to set out a framework to guide practice for early years providers (such as nurseries) to follow. The conundrum regarding these frameworks for young children is that proving evidence of a causal link between early environments and later outcomes is very challenging scientifically. So how do governments choose what learning and development practices and goals to make mandatory for childcare providers? And is it realistic to expect early years providers to meet the legal requirements that these frameworks impose? We do not know which learning and development practices impact positively on later outcomes, and we certainly do not know if there is a one-size-fits-all approach for an early years framework that is guaranteed to work.

The impact of health on labour market outcomes: A rapid systematic review.

The relationship between an individual's health and their labour market outcomes has long been a subject of health economics research. This review aims to provide an up-to-date, global review of the substantive findings in the existing literature. We pay particular attention to causal effects, acknowledging the methodological complexities that have long challenged the research and emphasizing the importance of overcoming them to present robust, policy-relevant evidence. The recent literature shows a notable advancement in addressing these methodological issues compared to previous work. The evidence reviewed suggests that individuals with better health overwhelmingly exhibit higher earnings and often enhanced labour supply. These findings extend beyond geographical boundaries, as evidence from diverse regions underscores the global significance of this association. The review covers evidence from a wide range of health indicators and conditions - including e.g. self-reported health, chronic diseases, disability, nutritional health, infections, mental health, addictions and others. Within and across the different health domains, the health-related factors exert varying degrees of influence on labour market outcomes, highlighting the multifaceted nature of the health-labour relationship and its potentially profound implications for individuals, communities, and economies.

Mendelian randomization of chronic hepatitis B and cardiovascular disease.

Background: Evidence from observational studies suggests that chronic hepatitis B (CHB) is associated with cardiovascular disease (CVD). However, results have been inconsistent and causality remains to be established. We utilized two-sample Mendelian randomization (MR) to investigate potential causal associations between CHB and CVD, including atherosclerosis, coronary heart disease, hypertension, and ischemic stroke. Methods: The analysis was conducted through genome-wide association studies (GWAS), considering chronic hepatitis B as the exposure and cardiovascular disease as the endpoint. The primary method for evaluating causality in this analysis was the inverse-variance weighted (IVW) technique. Additionally, we employed the weighted median, MR-Egger regression, weighted mode, and simple mode methods for supplementary analyses. Finally, heterogeneity tests, sensitivity analyses, and multiple effects analyses were conducted. Results: In a random-effects IVW analysis, we found that genetic susceptibility to chronic hepatitis B was associated with an increased risk of atherosclerosis [OR = 1.048, 95% CI (1.022-1.075), P = 3.08E-04], as well as an increased risk of coronary heart disease [OR = 1.039, 95% CI (1.006-1.072), P = 0.020]. However, it was found to be inversely correlated with ischemic stroke risk [OR = 0.972, 95% CI (0.957-0.988), P = 4.13E-04]. There was no evidence that chronic hepatitis B was associated with hypertension [OR = 1.021, 95% CI (0.994-1.049), P = 0.121]. Conclusion: Our research indicates that chronic hepatitis B has a correlation with an elevated risk of developing atherosclerosis and coronary heart disease, while it is associated with a decreased risk of experiencing an ischemic stroke.

Causal effect of gut microbiota on the risk of prostatitis: a two-sample Mendelian randomization study.

BACKGROUND: Recent studies demonstrated that chronic prostatitis (CP) is closely related to the gut microbiota (GM). Nevertheless, the causal relationship between GM and CP has not been fully elucidated. Therefore, the two-sample Mendelian randomization (MR) analysis was employed to investigate this association. METHODS: The summary data of gut microbiota derived from a genome-wide association study (GWAS) involving 18,340 individuals in the MiBioGen study served as the exposure, and the corresponding summary statistics for CP risk, representing the outcome, were obtained from the FinnGen databases (R9). The causal effects between GM and CP were estimated using the inverse-variance weighted (IVW) method supplemented with MR-Egger, weighted median, weighted mode, and simple mode methods. Additionally, the false discovery rate (FDR) correction was performed to adjust results. The detection and quantification of heterogeneity and pleiotropy were accomplished through the MR pleiotropy residual sum and outlier method, Cochran's Q statistics, and MR-Egger regression. RESULTS: The IVW estimates indicated that a total of 11 GM taxa were related to the risk of CP. Seven of them was correlated with an increased risk of CP, while the remained linked with a decreased risk of CP. However, only Methanobacteria (OR 0.86; 95% CI 0.74-0.99), Methanobacteriales (OR 0.86; 95% CI 0.74-0.99), NB1n (OR 1.16; 95% CI 1.16-1.34), Methanobacteriaceae (OR 0.86; 95% CI 0.74-0.99), Odoribactergenus Odoribacter (OR 1.43; 95% CI 1.05-1.94), and Sutterellagenus Sutterella (OR 1.33; 95% CI 1.01-1.76) still maintain significant association with CP after FDR correction. Consistent directional effects for all analyses were observed in the supplementary methods. Subsequently, sensitivity analyses indicated the absence of heterogeneity, directional pleiotropy, or outliers concerning the causal effect of specific gut microbiota on CP (p > 0.05). CONCLUSION: Our study demonstrated a gut microbiota-prostate axis, offering crucial data supporting the promising use of the GM as a candidate target for CP prevention, diagnosis, and treatment. There is a necessity for randomized controlled trials to validate the protective effect of the linked GM against the risk of CP, and to further investigate the underlying mechanisms involved.

Avoidance of causality outside experiments: Hypotheses from cognitive dissonance reduction.

The avoidance of causality in the design, analysis and interpretation of non-experimental studies has often been criticised as an untenable scientific stance, because theories are based on causal relations (and not associations) and a rich set of methodological tools for causal analysis has been developed in recent decades. Psychology researchers (n = 106 with complete data) participated in an online study presenting a causal statement about the results of a fictitious paper on the potential effect of drinking clear water for years on the risk of dementia. Two randomised groups of participants were then asked to reflect on the conflict between the goal of approaching a causal answer and the prevailing norm of avoiding doing so. One of the two groups was also instructed to think about possible benefits of addressing causality. Both groups then responded to a list of 19 items about attitudes to causal questions in science. A control group did this without reflecting on conflict or benefits. Free-text assessments were also collected during reflection, giving some indication of how and why causality is avoided. We condense the exploratory findings of this study into five new hypotheses about the how and why, filtered through what can be explained by cognitive dissonance reduction theory. These concern the cost of addressing causality, the variety of ways in which dissonance can be reduced, the need for profound intervention through teaching and social aspects. Predictions are derived from the hypotheses for confirmation trials in future studies and recommendations for teaching causality. Open data are provided for researchers' own analyses.

Pseudo-time Series Structural MRI Revealing Progressive Gray Matter Changes with Elevated Intraocular Pressure in Primary Open-Angle Glaucoma: A Preliminary Study.

RATIONALE AND OBJECTIVES: Primary open-angle glaucoma (POAG) is accompanied with gray matter (GM) changes across the brain. However, causal relationships of the GM changes have not been fully understood. Our aim was to investigate the causality of GM progressive changes in POAG using Granger causality (GC) analysis and structural MRI. MATERIALS AND METHODS: Structural MRI from 20 healthy controls and 30 POAG patients with elevated intraocular pressure (IOP) were collected. We performed voxel-wise GM volume comparisons between control and POAG groups, and between control and four POAG subgroups (categorized by IOP). Then, we sequenced the structural MRI data of all POAG patients and conducted both voxel-wise and region of interest (ROI)-wise GC analysis to investigate the causality of GM volume changes in POAG brain. RESULTS: Compared to healthy controls, reduced GM volumes across the brain were found, GM volume enlargements in the thalamus, caudate nucleus and cuneus were also observed in POAG brain (false discovery rate (FDR) corrected at q< 0.05). As IOP elevated, the reductions of GM volume were more severe in the cerebellum and frontal lobe. GC analysis revealed that the bilateral cerebellum, visual cortices, and the frontal regions served independently as primary hubs of the directional causal network, and projected causal effects to the parietal and temporal regions of the brain (FDR corrected at q<0.05). CONCLUSION: POAG exhibits progressive GM alterations across the brain, with oculomotor regions and visual cortices as independent primary hubs. The current results may deepen our understanding of neuropathology of POAG.

Factors affecting the quality of life of patients with medication-related osteonecrosis of the jaw during treatment: A quality-of-life survey and causal analysis.

This prospective cohort study aimed to investigate the impact of medication-related osteonecrosis of the jaw (MRONJ) on health-related quality of life (HRQOL) and oral health-related QOL (OHRQOL) and the association between the downstaging of MRONJ and OHRQOL. The HRQOL and OHRQOL of 44 patients with MRONJ were assessed using the SF-36v2 and the General Oral Health Assessment Index (GOHAI), respectively. Treatment was performed in accordance with the AAOMS position paper (2014). The SF-36v2 and GOHAI scores at the beginning of the survey were used to evaluate the impact of MRONJ on QOL. Potential confounders affecting the association between downstaging and QOL improvement were selected using directed acyclic graphs. Multiple regression analysis was performed to evaluate causal inferences. HRQOL scale scores declined below the national average. The three-component summary score (3CS), comprising the physical component summary (PCS), mental component summary (MCS), and role/social component summary (RCS), revealed that performance status and primary disease significantly affected the PCS and RCS (P = 0.005 and P < 0.001, respectively) and PCS and MCS (P = 0.024 and P = 0.003, respectively). The MRONJ stage did not influence the 3CS; however, OHRQOL declined in a stage-dependent manner (P = 0.005). Downstaging of MRONJ was independently associated with the improvement rate of the total GOHAI scores after adjusting for variables (P = 0.045). The HRQOL of patients with MRONJ declined; however, this may depend on the underlying disease status rather than the MRONJ stage. Improvement of the disease status can potentially predict an improvement in OHRQOL, regardless of the treatment modality.

PM2.5, component cause of severe metabolically abnormal obesity: An in silico, observational and analytical study.

Obesity is currently one of the most alarming pathological conditions due to the progressive increase in its prevalence. In the last decade, it has been associated with fine particulate matter suspended in the air (PM2.5). The purpose of this study was to explore the mechanistic interaction of PM2.5 with a high-fat diet (HFD) through the differential regulation of transcriptional signatures, aiming to identify the association of these particles with metabolically abnormal obesity. The research design was observational, using bioinformatic methods and an explanatory approach based on Rothman's causal model. We propose three new transcriptional signatures in murine adipose tissue. The sum of transcriptional differences between the group exposed to an HFD and PM2.5, compared to the control group, were 0.851, 0.265, and -0.047 (p > 0.05). The HFD group increased body mass by 20% with two positive biomarkers of metabolic impact. The group exposed to PM2.5 maintained a similar weight to the control group but exhibited three positive biomarkers. Enriched biological pathways (p < 0.05) included PPAR signaling, small molecule transport, adipogenesis genes, cytokine-cytokine receptor interaction, and HIF-1 signaling. Transcriptional regulation predictions revealed CpG islands and common transcription factors. We propose three new transcriptional signatures: FAT-PM2.5-CEJUS, FAT-PM2.5-UP, and FAT-PM2.5-DN, whose transcriptional regulation profile in adipocytes was statistically similar by dietary intake and HFD and exposure to PM2.5 in mice; suggesting a mechanistic interaction between both factors. However, HFD-exposed murines developed moderate metabolically abnormal obesity, and PM2.5-exposed murines developed severe abnormal metabolism without obesity. Therefore, in Rothman's terms, it is concluded that HFD is a sufficient cause of the development of obesity, and PM2.5 is a component cause of severe abnormal metabolism of obesity. These signatures would be integrated into a systemic biological process that would induce transcriptional regulation in trans, activating obesogenic biological pathways, restricting lipid mobilization pathways, decreasing adaptive thermogenesis and angiogenesis, and altering vascular tone thus inducing a severe metabolically abnormal obesity.