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Purpose: Periprosthetic joint infection (PJI) is a leading cause of joint arthroplasty failure, potentially leading to critical complications like vertebral osteomyelitis (VO). The factors contributing to VO after PJI and the outcomes for these patients are not well understood. Our study aims to (1) identify risk factors for VO following PJI and (2) assess the clinical outcomes in these cases. Methods: We included PJI patients treated surgically at our centre from January 2006 to December 2020, excluding those with simultaneous VO post-PJI. Our focus was on patients with VO occurring after PJI, monitored for at least 5 years. Analysis included patient comorbidities, PJI treatment approaches, pathogen identification and clinical outcomes. Results: Of 1701 PJI cases, 21 (1.23%) developed VO. Key risk factors for VO post-PJI were identified: systemic inflammatory response syndrome, substance misuse, polymicrobial infection and undergoing at least three stages of resection arthroplasty (odds ratios: 1.86, 54.28, 52.33 and 31.88, respectively). Adverse outcomes were noted in VO patients, with recurrent VO in 6/21 and repeated PJIs in 18/21 cases. Conclusions: Patients with PJI, especially those with certain risk factors, have an increased likelihood of developing VO and encountering negative outcomes. The potential role of bacteremia in the development of VO after PJI needs further exploration. Level of Evidence: Level III.
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Purpose: This study investigates the outcomes of two-stage exchange arthroplasty (EA) for periprosthetic joint infection (PJI) following initial or unplanned repeat debridement antibiotics, and implant retention (DAIR). Methods: We retrospectively reviewed cases of knee arthroplasty infection treated with two-stage EA after DAIR, spanning from January 1994 to December 2010. A total of 138 patients were included, comprising 112 with initial DAIR and 26 with an unplanned second DAIR. Data on demographics, comorbidities, infection characteristics and causative organisms were analyzed. The primary outcome was implant failure or reinfection, observed over a minimum follow-up of 10 years. Results: The overall success rate for two-stage EA was 87% (119/138 patients). Factors identified for treatment failure included reinfection with the same pathogen for unplanned second DAIR (hazard ratio [HR] = 3.41; 95% confidence interval [CI] = 1.35-4.38; p = 0.004), higher reinfection rates in patients undergoing EA after an unplanned second DAIR, especially with a prior history of PJI within 2 years (HR = 4.23; 95% CI = 2.39-5.31; p = 0.002), pre-first DAIR C-reactive protein (CRP) levels over 100 mg/dL (HR = 2.52; 95% CI = 1.98-3.42; p = 0.003) and recurrence with the same pathogen (HR = 2.35; 95% CI = 1.32-4.24; p = 0.007). Additional factors such as male gender (HR = 3.92; 95% CI = 1.21-5.25; p = 0.007) and osteoporosis (T score < -2.5; HR = 3.27; 95% CI = 1.23-5.28; p = 0.005) were identified as risk factors for implant failure in all EA cases. Conclusions: This study identifies key risk factors for worse knee EA outcomes following DAIR, including a pre-first DAIR CRP level over 100 mg/L, same pathogen recurrence, and PJI history within 2 years. It shows implant failure rates remain constant across EA cases, regardless of DAIR sequence, particularly with risk factors like male gender and severe osteoporosis (T score < -2.5). These results underscore the need for careful evaluation before an unplanned second DAIR, given its significant impact on EA success. Level of Evidence: Level III.
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OBJECTIVE: Major adverse cardiovascular event (MACE) outcomes associated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies remain unclear in patients with type 2 diabetes and newly diagnosed diabetic foot complications (DFCs). This study examined the impact of SGLT2i and GLP-1 RA use on the rates of MACEs and amputations in patients with type 2 diabetes and without cardiovascular disease. METHODS: Data from the Taiwan National Health Insurance Research Database (2004-2017) were analyzed, focusing on patients with type 2 diabetes without previous MACE and newly diagnosed DFCs. The primary outcome was the first MACE occurrence, and the secondary outcomes included MACE components, all-cause mortality, and lower extremity amputation (LEA) rates. RESULTS: SGLT2i users showed a significant decrease in the MACE (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46-0.88) and hospitalization for heart failure (HR, 0.54; 95% CI, 0.35-0.83) rates compared with dipeptidyl peptidase-4 inhibitor users. The amputation rates were also lower in SGLT2i users without LEA at the first DFC diagnosis (HR, 0.28; 95% CI, 0.10-0.75) and did not increase in those with a history of peripheral artery disease or LEA. No significant differences were observed between dipeptidyl peptidase-4 inhibitor and GLP-1 RA users in terms of the primary or secondary outcomes. CONCLUSION: In patients with type 2 diabetes initially diagnosed with DFC, SGLT2i are effective in significantly reducing the hospitalization for heart failure and MACE rates. SGLT2i lower the amputation rates, especially in patients who have not previously had a LEA, than the dipeptidyl peptidase-4 inhibitor therapy.
Subject(s)
Amputation, Surgical , Diabetes Mellitus, Type 2 , Diabetic Foot , Heart Failure , Hospitalization , Incretins , Sodium-Glucose Transporter 2 Inhibitors , Humans , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Amputation, Surgical/statistics & numerical data , Male , Female , Middle Aged , Aged , Incretins/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetic Foot/epidemiology , Diabetic Foot/surgery , Heart Failure/epidemiology , Hospitalization/statistics & numerical data , Taiwan/epidemiology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucagon-Like Peptide-1 Receptor/agonists , Hypoglycemic Agents/therapeutic use , AdultABSTRACT
Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G-computation and inverse-probability-weighting, have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite-sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open-source R package "MedMR."
Subject(s)
Liver Neoplasms , Models, Statistical , Humans , Probability , Causality , TaiwanABSTRACT
Intrahepatic cholangiocarcinoma (iCCA) is a subtype of CCA and has a high mortality rate and a relatively poor prognosis. However, studies focusing on increased cell motility and loss of epithelial integrity during iCCA progression remain relatively scarce. We collected seven fresh tumor samples from four patients to perform RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to determine the transcriptome profile and chromatin accessibility of iCCA. The increased expression of cell cycle regulators, including PLK1 and its substrate MISP, was identified. Ninety-one iCCA patients were used to validate the clinical significance of PLK1 and MISP. The upregulation of PLK1 and MISP was determined in iCCA tissues. Increased expression of PLK1 and MISP was significantly correlated with tumor number, N stage, and lymphatic invasion in an iCCA cohort. Knockdown of PLK1 or MISP reduced trans-lymphatic endothelial migration and wound healing and affected focal adhesions in vitro. In cellâcell junctions, MISP localized to adherens junctions and suppressed E-cadherin dimerization. PLK1 disrupted adherens junctions in a myosin-dependent manner. Furthermore, PLK1 and MISP promoted cell proliferation in vitro and tumorigenesis in vivo. In iCCA, PLK1 and MISP promote aggressiveness by increasing lymphatic invasion, tumor growth, and motility through the repression of E-cadherin adherens junctions.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Adherens Junctions/genetics , Adherens Junctions/metabolism , Adherens Junctions/pathology , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/metabolism , Bile Ducts, Intrahepatic/metabolism , Cadherins/genetics , Cadherins/metabolism , Cholangiocarcinoma/genetics , Cholangiocarcinoma/metabolismABSTRACT
Background: Despite the early demonstrated safety and effectiveness of COVID-19 vaccines in children, uptake was slow throughout the pandemic and remains low globally. Understanding vaccine refusal could provide insights to improving vaccine uptake in future pandemics. Methods: In a population-wide registry of all COVID-19 paediatric vaccination appointments, we used interrupted time series analysis to evaluate the impact of public policies. In a population-based cohort of adults, we used population attributable fractions to assess the individual and joint contributions of potential determinants to paediatric COVID-19 vaccination, and used mediation analysis to identify modifiable mediators between political views and paediatric vaccination. Findings: School vaccination requirements were associated with an increase in vaccination appointments by 278.7% (95% CI 85.3-673.9) in adolescents aged 12-17 and 112.8% (27.6-255.0) in children aged 5-11. Government-mandated vaccine pass, required for entry into restaurants, shopping malls and supermarkets, was associated with increased vaccination appointments by 108.7% (26.6-244.0) in adolescents. The following four determinants may explain 82.5% (63.5-100.0) of the reasons why children were unvaccinated: familial political views, vaccine hesitancy for children, mistrust in doctors and academics, and vaccine misconceptions. The influence of political views may be mitigated since 95.9% (76.4-100.0) of its association with vaccine reluctance for adolescents was mediated by modifiable factors such as mistrust in health authorities and low vaccine confidence. Interpretation: School vaccination requirements and vaccine passes were associated with increased vaccine uptake. Clinicians should recognise that factors beyond health, such as political views, can influence paediatric vaccine uptake to a significant extent. Nonetheless, such influences could be mitigated by targeted interventions and public policies. Funding: Hong Kong Jockey Club Charities Trust, Research Grants Council, University Grants Committee, and Health Bureau.
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Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Pancreatic Neoplasms , Humans , Afatinib/therapeutic use , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/metabolism , Cell Line, Tumor , Cholangiocarcinoma/metabolism , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Drug Resistance, Neoplasm/genetics , ErbB Receptors , Gemcitabine , Mucin-4/genetics , Pancreatic Neoplasms/pathology , Proto-Oncogene Proteins c-aktABSTRACT
Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.
Subject(s)
Malnutrition , Skin Diseases , Zinc , Humans , Protein Kinase Inhibitors/adverse effects , Skin/pathology , Vascular Endothelial Growth Factor A , Zinc/deficiency , Skin Diseases/chemically inducedABSTRACT
OBJECTIVE: Chronic subdural hematoma (CSDH) is a common neurological disease among elderly adults. The progression of CSDH is an angiogenic process, involving inflammatory mediators that affect vascular permeability, microvascular leakage, and hematoma thickness. The authors aimed to identify biomarkers associated with angiogenesis and vascular permeability that might influence midline shift and hematoma thickness. METHODS: Medical records and laboratory data of consecutive patients who underwent surgery for CSDH were analyzed. Collected data were basic demographic data, CSDH classification, CSDH thickness, midline shift, heme oxygenase-1 (HO-1) levels in hematomas, and common laboratory markers. Linear regression analysis was used to evaluate the relationship of CSDH thickness with characteristic variables. The chick chorioallantoic membrane (CAM) assay was used to test the angiogenic potency of identified variables in ex ovo culture of chick embryos. RESULTS: In total, 93 patients with CSDH (71.0% male) with a mean age of 71.0 years were included. The mean CSDH thickness and midline shift were 19.7 and 9.8 mm, respectively. The mean levels of HO-1, ferritin, total bilirubin, white blood cells, segmented neutrophils, lymphocytes, platelets, international normalized ratio, and partial thromboplastin time were 36 ng/mL, 14.8 µg/mL, 10.5 mg/dL, 10.3 × 103 cells/µL, 69%, 21.7%, 221.1 × 109 cells/µL, 1.0, and 27.8 seconds, respectively. Pearson correlation analysis revealed that CSDH thickness was positively correlated with midline shift distance (r = 0.218, p < 0.05) but negatively correlated with HO-1 concentration (r = -0.364, p < 0.01) and ferritin level (r = -0.222, p < 0.05). Multivariate linear regression analysis revealed that HO-1 was an independent predictor of CSDH thickness (ß = -0.084, p = 0.006). The angiogenic potency of HO-1 in hematoma fluid was tested with the chick CAM assay; topical addition of CSDH fluid with low HO-1 levels promoted neovascularization and microvascular leakage. Addition of HO-1 in a rescue experiment inhibited CSDH fluid-mediated angiogenesis and microvascular leakage. CONCLUSIONS: HO-1 is an independent risk factor in CSDH hematomas and is negatively correlated with CSDH thickness. HO-1 may play a role in the pathophysiology and development of CSDH, possibly by preventing neovascularization and reducing capillary fragility and hyperpermeability.
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BACKGROUND: This study aimed to investigate (1) the mental health impacts (i.e., insomnia and suicide ideas) of the COVID-19 pandemic and (2) the mediation effects of stay-at-home levels on those impacts. METHODS: This study investigated monthly national COVID-19 deaths, stay-at-home levels, and internet searches for words for "insomnia" and "suicide" across 45 countries during the first year of the COVID-19 pandemic (March 1, 2020, to February 28, 2021). We used the changes of internet search volumes for "insomnia" and "suicide" (from the Google Trends database) to represent the mental health impacts, and the time of cell phone activity at the residence (from Google Location History) to estimate the stay-at-home effects. We computed the proportion mediated (PM) caused by stay-at-home levels in the COVID-19 impacts on insomnia and suicide ideas, respectively. RESULTS: Throughout the first year of the COVID-19 pandemic, national COVID-19 deaths significantly correlated to increased internet searches for "insomnia" but decreased searches for "suicide". In addition, the mediation effect was significant in the first six-month of COVID-19-related increases in insomnia (PM = 42.6 %, p = 0.016), but this effect was not significant (PM = 13.1 %, p = 0.270) in the second six-month. By contrast, the mediation effect was not significant in the first six-month of COVID-19-related decrease in suicide ideation (PM = 8.1 %, p = 0.180), but this effect was significant (PM = 39.6 %, p = 0.014) in the second six-month. CONCLUSIONS: Stay-at-home levels significantly mediated both increased insomnia and decreased suicide ideas, but within different time frames.
Subject(s)
COVID-19 , Sleep Initiation and Maintenance Disorders , Humans , Pandemics , Sleep Initiation and Maintenance Disorders/epidemiology , Mental Health , Suicidal Ideation , InternetABSTRACT
In longitudinal studies with time-varying exposures and mediators, the mediational g-formula is an important method for the assessment of direct and indirect effects. However, current methodologies based on the mediational g-formula can deal with only one mediator. This limitation makes these methodologies inapplicable to many scenarios. Hence, we develop a novel methodology by extending the mediational g-formula to cover cases with multiple time-varying mediators. We formulate two variants of our approach that are each suited to a distinct set of assumptions and effect definitions and present nonparametric identification results of each variant. We further show how complex causal mechanisms (whose complexity derives from the presence of multiple time-varying mediators) can be untangled. We implemented a parametric method, along with a user-friendly algorithm, in R software. We illustrate our method by investigating the complex causal mechanism underlying the progression of chronic obstructive pulmonary disease. We found that the effects of lung function impairment mediated by dyspnea symptoms accounted for 14.6% of the total effect and that mediated by physical activity accounted for 11.9%. Our analyses thus illustrate the power of this approach, providing evidence for the mediating role of dyspnea and physical activity on the causal pathway from lung function impairment to health status. See video abstract at, http://links.lww.com/EDE/B988 .
Subject(s)
Dyspnea , Mediation Analysis , Humans , Algorithms , Exercise , Health StatusABSTRACT
Causal mediation analysis is advantageous for mechanism investigation. In settings with multiple causally ordered mediators, path-specific effects have been introduced to specify the effects of certain combinations of mediators. However, most path-specific effects are unidentifiable. An interventional analog of path-specific effects is adapted to address the non-identifiability problem. Moreover, previous studies only focused on cases with two or three mediators due to the complexity of the mediation formula in a large number of mediators. In this study, we provide a generalized definition of traditional path-specific effects and interventional path-specific effects with a recursive formula, along with the required assumptions for nonparametric identification. Subsequently, a general approach is developed with an arbitrary number of multiple ordered mediators and with time-varying confounders. All methods and software proposed in this study contribute to comprehensively decomposing a causal effect confirmed by data science and help disentangling causal mechanisms in the presence of complicated causal structures among multiple mediators.
Subject(s)
Mediation Analysis , Models, Statistical , CausalityABSTRACT
BACKGROUND: Increasing evidence suggests that glucagon-like peptide 1 (GLP-1) receptor agonists (RA) can stabilize glycemic variability (GV) and interfere with eating behavior. This study compared the impact of insulin, GLP-1 RA, and dietary components on GV using professional continuous glucose monitoring (CGM). METHODS: Patients with type 2 diabetes underwent CGM before and after switching from a twice-daily pre-mixed insulin treatment regimen to a GLP-1 RA (liraglutide) plus basal insulin regimen. The dietary components were recorded and analyzed by a certified dietitian. The interactions between the medical regimen, GV indices, and nutrient components were analyzed. RESULTS: Sixteen patients with type 2 diabetes were enrolled in this study. No significant differences in the diet components and total calorie intake between the two regimens were found. Under the pre-mixed insulin regimen, for increase in carbohydrate intake ratio, mean amplitude of glucose excursion (MAGE) and standard deviation (SD) increased; in contrast, under the new regimen, for increase in fat intake ratio, MAGE and SD decreased, while when the protein intake ratio increased, the coefficient of variation (CV) decreased. The impact of the food intake ratio on GV indices disappeared under the GLP-1 RA regimen. After switching to the GLP-1 RA regimen, the median MAGE, SD, and CV values decreased significantly. However, the significant difference in GV between the two regimens decreased during the daytime. CONCLUSION: A GLP-1 RA plus basal insulin regimen can stabilize GV better than a regimen of twice-daily pre-mixed insulin, especially in the daytime, and can diminish the effect of food components on GV.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin , Humans , Blood Glucose , Biphasic Insulins , Glucagon-Like Peptide-1 Receptor , Diabetes Mellitus, Type 2/drug therapy , Blood Glucose Self-Monitoring , Glucose , Glucagon-Like Peptide 1ABSTRACT
BACKGROUND: Treatment protocols for two-stage revision arthroplasty with diabetes mellitus (DM) have not yet been established. The control of glycated hemoglobin (HbA1c) in two-stage revision arthroplasty is still debated. This study aimed to clarify the importance of preoperative HbA1c levels before each stage of revision arthroplasty and to analyze the risk factors for reinfection. METHODS: Five hundred eighty-eight patients suffered from first-time PJI and was treated in our institute from January 1994 to December 2010 were reviewed. The mean follow-up time was 13.8 (range, 10.2-24.8) years. Patients underwent two-stage revision arthroplasty with DM at presentation were included. The endpoint of the study was reinfection of the revision arthroplasty. Demographic, survivorship, and surgical variables were also analyzed. RESULTS: Eighty-eight patients were identified and grouped by HbA1c level before the first stage surgery: Groups 1 and 2 had HbA1c levels < 7% and ≥ 7%, respectively. Reinfection was identified in 4.55% (2/44) and 18.18% (8/44) of the patients in Groups 1 and 2, respectively. Survivorship analysis revealed correction of the HbA1c before the final stage of revision arthroplasty as an independent factor (p < 0.001). The identified risks for reinfection were HbA1c levels ≥ 7% before final-stage surgery, ≥ 3 stages of revision arthroplasty, and extended-spectrum beta-lactamase (ESBL)-Escherichia coli PJI. CONCLUSION: The HbA1c level before the final stage of revision arthroplasty could affect staged revision arthroplasty outcomes. Therefore, the necessity of postponing the elective final-stage revision arthroplasty procedure for HbA1c control should be further investigated in the future.
Subject(s)
Arthroplasty, Replacement, Knee , Diabetes Mellitus , Prosthesis-Related Infections , Humans , Retrospective Studies , Prosthesis-Related Infections/etiology , Follow-Up Studies , Reoperation/methods , Reinfection , Glycated Hemoglobin , Arthroplasty, Replacement, Knee/adverse effects , Diabetes Mellitus/epidemiology , Diabetes Mellitus/surgeryABSTRACT
Path-specific effects are a critical measure for assessing mediation in the presence of multiple mediators. However, the conventional definition of path-specific effects has generated controversy because it often causes misinterpretation of the results of multiple mediator analysis. For in-depth analysis of this issue, we propose the concept of decomposing fully mediated interaction from the average causal effect. We show that misclassification of fully mediated interaction is the main cause of misinterpretation of path-specific effects. We propose two strategies for specifying fully mediated interaction: isolating and reclassifying fully mediated interaction. The choice of strategy depends on the objective. Isolating fully mediated interaction is the superior strategy when the main objective is elucidating the mediation mechanism, whereas reclassifying it is superior when the main objective is precisely interpreting the mediation analysis results. To compare performance, this study used the two proposed strategies and the conventional decomposition strategy to analyze the mediating roles of dyspnea and anxiety in the effect of impaired lung function on poor health status in a population of patients with chronic obstructive pulmonary disease. The estimation result showed that the conventional decomposition strategy underestimates the importance of dyspnea as a mechanism of this disease. Specifically, the strategy of reclassifying fully mediated interaction revealed that 50% of the average causal effect is attributable to mediating effects, particularly the mediating effect of dyspnea.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Causality , Dyspnea , Humans , Pulmonary Disease, Chronic Obstructive/epidemiologyABSTRACT
Triple-negative breast cancer (TNBC) is treated with neoadjuvant chemotherapy (NAC). The response to NAC, particularly the probability of a complete pathological response (pCR), guides the surgical approach and adjuvant therapy. We developed a prediction model using a nomogram integrating blood tests and pre-treatment ultrasound findings for predicting pCR in patients with stage II or III operable TNBC receiving NAC. Clinical data before and after the first cycle of NAC collected from patients between 2012 and 2019 were analyzed using univariate and multivariate analyses to identify correlations with pCR. The coefficients of the significant parameters were calculated using logistic regression, and a nomogram was developed based on the logistic model to predict the probability of pCR. Eighty-eight patients were included. Five parameters correlated with the probability of pCR, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte (PLR) ratio, percentage change in PLR, presence of echogenic halo, and tumor height-to-width ratio. The discrimination performance of the nomogram was indicated by an area under the curve of 87.7%, and internal validation showed that the chi-square value of the Hosmer-Lemeshow test was 7.67 (p = 0.363). Thus, the integrative prediction model using clinical data can predict the probability of pCR in patients with TNBC receiving NAC.
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PURPOSE: Population attributable fraction (PAF), defined as the proportion of the occurrence of a disease which will be reduced by eliminating risk factors in a population, is one of the most common measurements for evaluating the benefit of a health-related policy in epidemiologic study. In this article, we propose an alternative PAF defined based on sufficient cause framework, which decompose the occurrence of a disease into several pathways including mediation and mechanistic interaction. METHODS: We propose a formal statistical definition and regression-based estimator for PAF based on sufficient cause framework within mediation settings. Under monotonicity assumption, the proposed method can decompose the occurrence of a disease into nine PAFs corresponding to all types of mechanisms attributing to exposure and the mediator, including the portion attributing to exposure directly, to mediator, to indirect effect through mediator, to the mechanistic interaction, to both of mediation and interaction, and to none of exposure or mediator. RESULTS: We apply the proposed method to explore the mechanism of a hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) mediated by and/or interacted with alanine aminotransferase (ALT) and hepatitis B virus (HBV). When treating ALT as mediator, 56.77% of diseased subjects can be attributable to either HCV or abnormal ALT. When treating HBV as mediator, HCC is mainly induced by an exogenous high HBV viral load directly. CONCLUSIONS: The proposed method can identify the impact of exposure and pathway effects, and benefit to allocate the resources on intervention strategies.
Subject(s)
Carcinoma, Hepatocellular , Hepatitis B , Hepatitis C , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/epidemiology , Carcinoma, Hepatocellular/etiology , Liver Neoplasms/epidemiology , Hepatitis B/epidemiology , Hepatitis B/complications , Hepatitis C/epidemiology , Hepatitis B virus , HepacivirusABSTRACT
Background and Aims: Parkinson's disease (PD) is a worldwide neurodegenerative disease with an increasing global burden, while constipation is an important risk factor for PD. The gastrointestinal tract had been proposed as the origin of PD in Braak's gut-brain axis hypothesis, and there is increasing evidence indicating that intestinal microbial alteration has a role in the pathogenesis of PD. In this study, we aim to investigate the role of intestinal microbial alteration in the mechanism of constipation-related PD. Methods: We adapted our data from Hill-Burns et al., in which 324 participants were enrolled in the study. The 16S rRNA gene sequence data were processed, aligned, and categorized using DADA2. Mediation analysis was used to test and quantify the extent by which the intestinal microbial alteration explains the causal effect of constipation on PD incidence. Results: We found 18 bacterial genera and 7 species significantly different between groups of constipated and non-constipated subjects. Among these bacteria, nine genera and four species had a significant mediation effect between constipation and PD. All of them were short-chain fatty acid (SCFA)-producing bacteria that were substantially related to PD. Results from the mediation analysis showed that up to 76.56% of the effect of constipation on PD was mediated through intestinal microbial alteration. Conclusion: Our findings support that gut dysbiosis plays a critical role in the pathogenesis of constipation-related PD, mostly through the decreasing of SCFA-producing bacteria, indicating that probiotics with SCFA-producing bacteria may be promising in the prevention and treatment of constipation-related PD. Limitations: 1) Several potential confounders that should be adjusted were not provided in the original dataset. 2) Our study was conducted based on the assumption of constipation being the etiology of PD; however, constipation and PD may mutually affect each other. 3) Further studies are necessary to explain the remaining 23.44% effect leading to PD by constipation.
Subject(s)
Gastrointestinal Microbiome , Neurodegenerative Diseases , Parkinson Disease , Bacteria/genetics , Constipation/etiology , Fatty Acids, Volatile , Gastrointestinal Microbiome/genetics , Humans , Mediation Analysis , Parkinson Disease/complications , RNA, Ribosomal, 16S/geneticsABSTRACT
STUDY QUESTION: Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? SUMMARY ANSWER: Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. WHAT IS KNOWN ALREADY: Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. STUDY DESIGN, SIZE, DURATION: In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69â552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200â000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148â291 individuals as of May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited individuals in two cohorts, with 13â899 females in TWB1 and 55â653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646â973 TWB1 single-nucleotide polymorphisms (SNPs) and 686â439 TWB2 SNPs were assessed in our analysis. There were 99â939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547â034 TWB1 array-specific SNPs and 586â500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. MAIN RESULTS AND THE ROLE OF CHANCE: In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P < 10-10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P < 10-10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche. LIMITATIONS, REASONS FOR CAUTION: A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.