Histopathologic image-based deep learning classifier for predicting platinum-based treatment responses in high-grade serous ovarian cancer.

Platinum-based chemotherapy is the cornerstone treatment for female high-grade serous ovarian carcinoma (HGSOC), but choosing an appropriate treatment for patients hinges on their responsiveness to it. Currently, no available biomarkers can promptly predict responses to platinum-based treatment. Therefore, we developed the Pathologic Risk Classifier for HGSOC (PathoRiCH), a histopathologic image-based classifier. PathoRiCH was trained on an in-house cohort (n = 394) and validated on two independent external cohorts (n = 284 and n = 136). The PathoRiCH-predicted favorable and poor response groups show significantly different platinum-free intervals in all three cohorts. Combining PathoRiCH with molecular biomarkers provides an even more powerful tool for the risk stratification of patients. The decisions of PathoRiCH are explained through visualization and a transcriptomic analysis, which bolster the reliability of our model's decisions. PathoRiCH exhibits better predictive performance than current molecular biomarkers. PathoRiCH will provide a solid foundation for developing an innovative tool to transform the current diagnostic pipeline for HGSOC.

Unveiling nurses' end-of-life care experiences: Moral distress and impacts.

BACKGROUND: Nurses providing care to patients with end-of-life or terminal illnesses often encounter ethically challenging situations leading to moral distress. However, existing quantitative studies have examined moral distress using instruments that address general clinical situations rather than those specific to end-of-life care. Furthermore, qualitative studies have often been limited to participants from a single unit or those experiencing moral distress-induced circumstances. A comprehensive and integrated understanding of the overarching process of moral distress is vital to discern the unique circumstances surrounding end-of-life care and its consequential impacts. RESEARCH OBJECTIVES: To explore the moral distress experiences of nurses who are frequently involved in caring for patients with end-of-life or terminal illnesses and apply it to two existing theories: the model of moral distress and the ecological model. RESEARCH DESIGN: A qualitative descriptive approach was employed. PARTICIPANTS AND RESEARCH CONTEXT: Seven focus group interviews involving 30 nurses were performed. The subsequent transcriptions underwent rigorous content analysis. ETHICAL CONSIDERATIONS: We obtained Institutional Review Board approval from a university. Focus group interviews were conducted with nurses who agreed to participate and signed the consent form. FINDINGS: The moral distress-inducing factors and nurses' perceived impact of moral distress were identified and categorized based on moral distress theories and ecological models. A total of 15 categories and 30 subcategories across the following 4 domains were derived: (1) intrapersonal, (2) interpersonal, (3) organizational, and (4) structural factors. CONCLUSIONS: End-of-life-specific circumstances induced moral distress among nurses, with both negative and positive impacts identified. Effective organizational and policy support is essential to manage conflicts, form a healthy organizational culture, provide training, and prevent unnecessary expenses due to the negative consequences of moral distress.

Reliability Exercise of Ultrasound Salivary Glands in Sjögren's Disease: An International Web Training Initiative.

INTRODUCTION: Major salivary gland ultrasonography (SGUS) demonstrated its good metric properties as an outcome measure for diagnosing primary Sjögren's disease (SD). The objective was to assess SGUS reliability among sonographers with different levels of experience, using web training. METHODS: Sonographers from expert centers participated in the reliability exercise. Before exercises, training was done by videoconferencing. Reliability of the two most experienced sonographers (MES) was assessed and then compared to other sonographers. Intra-reader and inter-reader reliability of SGUS items were assessed by computing Cohen's κ coefficients. RESULTS: All sets were read twice by all 14 sonographers within a 4-month interval. Intra-reader reliability of MES was almost perfect for homogeneity, substantial for Outcome Measures in Rheumatology (OMERACT) scoring system (OMERACTss). Among LES (less experienced sonographers), reliability was moderate to almost perfect for homogeneity, fair to moderate for OMERACTss, and fair to almost perfect for binary OMERACTss. Inter-reader reliability between MES was almost perfect for homogeneity, substantial for diagnosis, moderate for OMERACTss, and substantial for binary OMERACTss. Compared to MES, reliabilities of LES were moderate to almost perfect for both homogeneity and diagnosis, only fair to moderate for OMERACTss, but increased in binary OMERACTss. CONCLUSIONS: Videoconferencing training sessions in an international reliability exercise could be an excellent tool to train experienced and less-experienced sonographers. SGUS homogeneity items is useful to distinguish normal from abnormal salivary glands parenchyma independently of diagnosis. Structural damage evaluations by OMERACT scoring system is a new comprehensive score to diagnose patients with SD and could be easily used by sonographers in a binary method.

The goal of this project was to evaluate the reliability of salivary gland ultrasonography in patients with Sjögren's disease using online training in an international study. Currently, salivary gland ultrasonography is routinely used only by European expert sonographers but few studies have studied intra-reader and inter-reader reliability, among less experienced international sonographers. Many salivary gland ultrasonography scoring systems are used today, but it is difficult to know how to put them into practice. Online training on an international level allows a significant number of practitioners to use the different scoring systems including the latest OMERACT (Outcome Measures in Rheumatology) score, which is simple and comprehensive. There were two phases to this project: A first step consisted in a training session by videoconferencing to all sonographers, the second step was an inter and intra-reader reliability exercises. The results of our study showed satisfactory results, especially for parenchyma homogeneity. Regarding the comprehensive OMERACT score, the results are quite disparate, notably for less experienced sonographers and could be explained by this new comprehensive scoring system. However, when binary OMERACT score (minor damage versus major damage of salivary gland parenchyma (OMERACT score 0­1 vs. 2­3) was employed, reliability increased and can be very useful for novice sonographers in routine practice because it does not require scoring of all the pathological features in Sjögren's disease. This study highlights the need to train non-experts interested in this field and demonstrates the potential for beginners to quickly become experts.

Quality Measure Adherence and Oral Health Outcomes in Children.

Importance: Process-based quality measures are generally intended to promote evidence-based practices that have been proven to improve outcomes. However, due to lack of standardized implementation of diagnostic codes in dentistry, assessing the association between process and oral health outcomes has been challenging. Objective: To estimate the association of adhering to dental quality measures with patient oral health outcomes. Design, Setting, and Participants: Using a target trial emulation, a causal inference framework, this retrospective cohort study estimated the difference in the risk of developing tooth decay between US children who adhered to process-based dental quality measures (receiving topical fluoride and sealant [treated groups]) and those who did not (control groups). Electronic health records of US children and adolescents aged 0 to 18 years from January 1, 2014, to December 31, 2020, were used. To emulate random treatment assignment based on baseline confounders, coarsened exact matching was used to produce covariate balance between the treated and control groups. A time-to-event regression model produced effect estimates, adjusting for time-varying covariates. Near-far matching was used to account for unmeasured confounders as a sensitivity analysis. Data were analyzed from May 1 to August 7, 2023. Exposures: Adherence to dental quality measures. Main Outcomes and Measures: Incidence of tooth decay. Results: Among 69 212 US children aged between 0 and 18 years (mean [SD] age, 10.2 [5.0] years; 49.5% male, 50.4% female, and 0.1% unknown or transgender), 1930 (2.8%) were Asian, 2038 (2.9%) were Black, 8667 (12.5%) were Hispanic, 33 632 (48.6%) were White, and 22 945 (33.2%) were multiracial, other, or missing racial and ethnic group identification. Relative to control individuals, treated individuals were more likely to be at elevated risk of caries (fluoride measure: 16 453 [76.5%] vs 15 236 [39.8%]; sealant measure: 2264 [54.6%] vs 997 [44.0%]) and have regular dental visits (fluoride measure: 21 498 [100%] vs 13 741 [35.9%]; sealant measure: 1623 [39.2%] vs 871 [38.4%]). Adherence to quality measures was associated with reduced risk of tooth decay with adjusted hazard ratios of 0.82 (95% CI, 0.78- 0.86) for fluoride and 0.86 (95% CI, 0.76-0.97) for sealant in the matched cohort. Benefits of adhering to quality measures were greater among children at elevated vs low risk and with public vs commercial insurance for both measures. Conclusions: In this cohort study, adhering to dental quality measures was associated with reduced risk of tooth decay, and benefits were greater among children at elevated risk and with public insurance. These findings provide insights in facilitating targeted application of quality measures or developing more tailored quality improvement initiatives.

Subtherapeutic hydroxychloroquine concentration is associated with increased disease activity and greater organ damage in lupus.

OBJECTIVE: To investigate the effects of the serum HCQ concentration on clinical manifestations, disease activity and organ damage in a longitudinal cohort of SLE patients. METHODS: The 338 SLE patients were assessed with respect to their demographic data, clinical and laboratory findings, Physician's Global Assessment (PGA), adjusted mean SLEDAI-2000 (AMS) and SLICC Damage Index (SDI) annually for 5 consecutive years. Patients were divided into two groups according to their serum HCQ concentration at baseline: subtherapeutic (<500 ng/ml) and therapeutic (≥500 ng/ml) groups. The impact of the HCQ concentration on the clinical outcomes was evaluated in a longitudinal analysis using a generalized estimating equation (GEE). RESULTS: Of the 338 patients, 287 (84.9%) were in the subtherapeutic group at baseline. This group had a higher incidence of newly developed LN (P = 0.036) and had been prescribed higher mean and cumulative doses of prednisolone (P = 0.003 and P = 0.013, respectively) than the therapeutic group. In multivariable analyses based on GEE, the subtherapeutic group had a higher AMS score (ß = 1.398, 95% CI 0.607, 2.189; P < 0.001), higher PGA score (ß = 0.328, 95% CI 0.215, 0.441; P < 0.001) and higher SDI score (ß = 0.366, 95% CI 0.061, 0.671; P = 0.019) across all 5 years. CONCLUSION: The subtherapeutic HCQ concentration was associated with the development of new-onset LN, and had significant associations with disease activity and cumulative organ damage in SLE patients over time.

How different are accuracies of clinicians' prediction of survival by assessment methods?

BACKGROUND: No standardized method has been established for evaluating the accuracy of a clinicians' prediction of survival (CPS). Till now, no study has compared the accuracy of CPS according to the evaluation methods using the same dataset. We aimed to examine the accuracy of CPS by different statistical approaches in patients with far-advanced cancer. METHODS: The current study was a secondary analysis of an international multicenter prospective cohort study. Newly admitted patients with advanced cancer were enrolled in palliative care units (PCUs) in Japan, Korea, and Taiwan. We obtained the temporal CPS at enrollment. The patients were classified into groups of days (≤7 days) and weeks (≤30 days) based on CPS and actual survival (AS). We evaluated the accuracy of CPS by the distribution, area under the receiver operating characteristics curve (AUROCs), and an estimate ±33% of AS. RESULTS: A total of 2,571 patients were assessed and admitted in 37 PCUs between January 2017 and September 2018. As for the "days" category, the distribution of AS is larger than that of CPS, however, the results are reversed in the "weeks" category. The AUROCs showed over 80% discrimination for both the "days" and "weeks" categories. Accurate CPS within ±33% of AS was approximately 30% in both "days" and "weeks" categories. CONCLUSIONS: We showed a discrepancy of approximately 30-80% in the accuracy of CPS among three different analysis methods: distribution, AUROC, and AS comparison. Considering the low accuracy of AS comparisons, clinicians should provide a wide range of survival time. CPS was able to effectively discriminate and may be useful for risk stratification.

Renal histopathological predictors of end-stage kidney disease in ANCA-associated vasculitis with glomerulonephritis: a single-centre study in Korea.

This study investigated whether histopathological classification and histologic lesion scores could significantly and independently predict the progression to end-stage kidney disease (ESKD) in Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-glomerulonephritis (AAV-GN). This study included 113 patients with AAV-GN confirmed by kidney biopsy. The glomerular, tubulointerstitial, and vascular lesions were systematically assessed using a scoring system. The scoring system was adopted from the Banff scoring system but also the Oxford study and the revision of the ISN/RPS. For comparison, the scores were classified into two groups; the low, and the high, and the difference was investigated between ESKD and non-ESKD groups using Cox proportional analysis. At diagnosis, the median age was 59.0 years and 33.6% were males. Of 113 patients, 44.2% had ESKD progression during follow-up. There were significant differences in several kidney-, inflammation-, and AAV-pathogenesis-related variables between AAV-GN patients with ESKD and those without. The sclerotic class exhibited the worst renal prognosis among the four histopathological classes. Among histopathological features, high interstitial fibrosis, tubular atrophy and global glomerulitis scores were significantly associated with ESKD progression. Whereas multivariable Cox analysis revealed only a high global glomerulitis score which means global endocapillary hypercellularity in a larger number of glomeruli is an independent predictor of ESKD progression. Moreover, among clinical and histopathological features, a high global glomerulitis score could also predict ESKD progression in addition to serum blood urea nitrogen and creatinine. This study demonstrated the worst renal prognosis for the sclerotic class and first discovered that a high global glomerulitis score was an independent predictor of ESKD in patients with AAV-GN.

Imaging Findings of Adenocarcinoma Arising from Lingual Foregut Duplication Cyst.

Lingual foregut duplication cysts are rare developmental anomalies with varied symptoms, and adenocarcinomas may develop from them. Radiological evaluations, including computed tomography and magnetic resonance imaging, can help diagnose these lesions and determine their extent. Abnormal enhancement should raise the suspicion of malignancy of a lingual foregut duplication cyst. Early detection and complete surgical resection of lingual foregut duplication cysts are necessary to prevent malignant transformations. Complete tumor resection with adjuvant radiotherapy or radiochemotherapy is recommended. The teaching point is that mucinous adenocarcinoma can develop from a lingual foregut duplication cyst, and radiological studies may aid in the diagnosis. Teaching Point: Adenocarcinomas can develop from lingual foregut duplication cysts, which are rare developmental anomalies, and radiologic studies may aid in the diagnosis.

xCT-mediated glutamate excretion in white adipocytes stimulates interferon-γ production by natural killer cells in obesity.

Obesity-mediated hypoxic stress underlies inflammation, including interferon (IFN)-γ production by natural killer (NK) cells in white adipose tissue. However, the effects of obesity on NK cell IFN-γ production remain obscure. Here, we show that hypoxia promotes xCT-mediated glutamate excretion and C-X-C motif chemokine ligand 12 (CXCL12) expression in white adipocytes, resulting in CXCR4+ NK cell recruitment. Interestingly, this spatial proximity between adipocytes and NK cells induces IFN-γ production in NK cells by stimulating metabotropic glutamate receptor 5 (mGluR5). IFN-γ then triggers inflammatory activation of macrophages and augments xCT and CXCL12 expression in adipocytes, forming a bidirectional pathway. Genetic or pharmacological inhibition of xCT, mGluR5, or IFN-γ receptor in adipocytes or NK cells alleviates obesity-related metabolic disorders in mice. Consistently, patients with obesity showed elevated levels of glutamate/mGluR5 and CXCL12/CXCR4 axes, suggesting that a bidirectional pathway between adipocytes and NK cells could be a viable therapeutic target in obesity-related metabolic disorders.

Analysis of Race and Ethnicity, Socioeconomic Factors, and Tooth Decay Among US Children.

Importance: While large oral health disparities remain by race and ethnicity among children, the associations of race, ethnicity, and mediating factors with oral health outcomes are poorly characterized. Identifying the pathways that explain these disparities would be critical to inform policies to effectively reduce them. Objective: To measure racial and ethnic disparities in the risk of developing tooth decay and quantify relative contributions of factors mediating the observed disparities among US children. Design, Setting, and Participants: This retrospective cohort study used electronic health records of US children from 2014 to 2020 to measure racial and ethnic disparities in the risk of tooth decay. Elastic net regularization was used to select variables to be included in the model among medical conditions, dental procedure types, and individual- and community-level socioeconomic factors. Data were analyzed from January 9 to April 28, 2023. Exposures: Race and ethnicity of children. Main Outcomes and Measures: The main outcome was diagnosis of tooth decay in either deciduous or permanent teeth, defined as at least 1 decayed, filled, or missing tooth due to caries. An Anderson-Gill model, a time-to-event model for recurrent tooth decay events with time-varying covariates, stratified by age groups (0-5, 6-10, and 11-18 years) was estimated. A nonlinear multiple additive regression tree-based mediation analysis quantified the relative contributions of factors underlying the observed racial and ethnic disparities. Results: Among 61 083 children and adolescents aged 0 to 18 years at baseline (mean [SD] age, 9.9 [4.6] years; 30 773 [50.4%] female), 2654 Black individuals (4.3%), 11 213 Hispanic individuals (18.4%), 42 815 White individuals (70.1%), and 4401 individuals who identified as another race (eg, American Indian, Asian, and Hawaiian and Pacific Islander) (7.2%) were identified. Larger racial and ethnic disparities were observed among children aged 0 to 5 years compared with other age groups (Hispanic children: adjusted hazard ratio [aHR], 1.47; 95% CI, 1.40-1.54; Black children: aHR, 1.30; 95% CI, 1.19-1.42; other race children: aHR, 1.39; 95% CI, 1.29-1.49), compared with White children. For children aged 6 to 10 years, higher risk of tooth decay was observed for Black children (aHR, 1.09; 95% CI, 1.01-1.19) and Hispanic children (aHR, 1.12; 95% CI, 1.07-1.18) compared with White children. For adolescents aged 11 to 18 years, a higher risk of tooth decay was observed only in Black adolescents (aHR, 1.17; 95% CI, 1.06-1.30). A mediation analysis revealed that the association of race and ethnicity with time to first tooth decay became negligible, except for Hispanic and children of other race aged 0 to 5 years, suggesting that mediators explained most of the observed disparities. Insurance type explained the largest proportion of the disparity, ranging from 23.4% (95% CI, 19.8%-30.2%) to 78.9% (95% CI, 59.0%-114.1%), followed by dental procedures (receipt of topical fluoride and restorative procedures) and community-level factors (education attainment and Area Deprivation Index). Conclusions: In this retrospective cohort study, large proportions of disparities in time to first tooth decay associated with race and ethnicity were explained by insurance type and dental procedure types among children and adolescents. These findings can be applied to develop targeted strategies to reduce oral health disparities.

Validation of Modified Models of Objective Prognostic Score in Patients With Advanced Cancer.

Background: The objective prognostic score (OPS) needs to be modified to reflect practical palliative care circumstances. Objectives: We aimed to validate modified models of OPS with few or no laboratory tests for patients with advanced cancer. Design: An observational study was performed. Setting/Subjects: A secondary analysis of an international, multicenter cohort study of patients in East Asia was performed. The subjects were inpatients with advanced cancer in the palliative care unit. Measurements: We developed two modified OPS (mOPS) models to predict two-week survival: mOPS-A consisted of two symptoms, two objective signs, and three laboratory results, while mOPS-B consisted of three symptoms, two signs, and no laboratory data. We compared the accuracy of the prognostic models using sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). Calibration plots for two-week survival and net reclassification indices (NRIs) were compared for the two models. Survival differences between higher and lower score groups of each model were identified by the log-rank test. Results: We included a total of 1796 subjects having median survival of 19.0 days. We found that mOPS-A had higher specificity (0.805-0.836) and higher AUROCs (0.791-0.797). In contrast, mOPS-B showed higher sensitivity (0.721-0.725) and acceptable AUROCs (0.740-0.751) for prediction of two-week survival. Two mOPSs showed good concordance in calibration plots. Considering NRIs, replacing the original OPS with mOPSs improved overall reclassification (absolute NRI: 0.47-4.15%). Higher score groups of mOPS-A and mOPS-B showed poorer survival than those of lower score groups (p < 0.001). Conclusions: mOPSs used reduced laboratory data and had relatively good accuracy for predicting survival in advanced cancer patients receiving palliative care.

Histologic evaluation of activity and chronicity of lupus nephritis and its clinical significance.

The National Institutes of Health (NIH) lupus nephritis activity and chronicity indices, which comprise six activity scores and four chronicity scores, have a long development history. The 2018 revised International Society of Nephrology/Renal Pathology Society classification for lupus nephritis adopted the most recent NIH indices to replace subclasses A, C, and A/C. Although an evidence-based approach should further evaluate the clinical significance of the modified NIH indices, recent validation studies demonstrated that the modified chronicity indices have a strong correlation with kidney outcome of lupus nephritis.

Significance of co-positivity for anti-dsDNA, -nucleosome, and -histone antibodies in patients with lupus nephritis.

OBJECTIVE: The aim of this study was to define the clinical, histopathologic, and prognostic features associated with simultaneous positivity for anti-dsDNA, -nucleosome, and -histone antibodies (3-pos) in Korean patients with biopsy-proven lupus nephritis (LN). METHODS: The 102 patients included in the study had undergone kidney biopsy prior to the start of induction treatment, were treated with immunosuppressives, and followed-up for >12 months. RESULTS: In total, 44 (43.1%) of the 102 LN patients were 3-pos. Patients with 3-pos had a higher SLEDAI-2K score (p = .002), lower lymphocyte count (p = .004), and higher rates of proteinuria > 3.5 g/24 h (p = .039) and positivity for urinary sediments (p = .005) at the time of renal biopsy than non-3-pos patients. 3-pos patients had a more proliferative form of LN (p = .045) in the renal histopathologic findings, and as co-positivity gradually increased from 0 to 3, the total activity score in the renal biopsy findings increased significantly (p = .033). In addition, 3-pos patients had a more rapid eGFR decline than non-3-pos patients after a follow-up of 83.2 months (p = .016). CONCLUSIONS: Our findings suggest that 3-pos is related to severe LN and that 3-pos patients are more likely to experience a rapid decline of renal function than non-3-pos patients.KEY MESSAGEPatients with co-positivity for anti-dsDNA, -nucleosome, and -histone antibodies (3-pos) had higher disease activity and a worse renal histopathology than those without co-positivity.3-pos patients had a more rapid decline of renal function than non-3-pos patients.

Clinicians' Prediction of Survival and Prognostic Confidence in Patients with Advanced Cancer in Three East Asian Countries.

Background: Little is known about accuracy and confidence of clinicians' prediction of survival (CPS) in East-Asian countries. Objective: We aimed to examine accuracy of CPS for 7-, 21-, and 42-day survival in palliative inpatients and its association with prognostic confidence. Design: An international prospective cohort study in Japan (JP), Korea (KR), and Taiwan (TW). Setting/Subjects: Subjects were inpatients with advanced cancer admitted to 37 palliative care units in three countries. Measurements: Discrimination of CPS was investigated through sensitivity, specificity, overall accuracy, and area under the receiver operating characteristics curves (AUROCs) according to 7-, 21-, and 42-day survival. The accuracies of CPS were compared with those of Performance Status-based Palliative Prognostic Index (PS-PPI). Clinicians were instructed to rate confidence level on a 0-10-point scale. Results: A total of 2571 patients were analyzed. The specificity was highest at 93.2-100.0% for the 7-day CPS, and sensitivity was highest at 71.5-86.8% for the 42-day CPS. The AUROCs of the seven-day CPS were 0.88, 0.94, and 0.89, while those of PS-PPI were 0.77, 0.69, and 0.69 for JP, KR, and TW, respectively. As for 42-day prediction, sensitivities of PS-PPI were higher than those of CPS. Clinicians' confidence was strongly associated with the accuracy of prediction in all three countries (all p-values <0.01). Conclusions: CPS accuracies were highest (0.88-0.94) for the seven-day survival prediction. CPS was more accurate than PS-PPI in all timeframe prediction except 42-day prediction in KR. Prognostic confidence was significantly associated with the accuracy of CPS.

Cost-effectiveness of Dental Workforce Expansion Through the National Health Service Corps and Its Association With Oral Health Outcomes Among US Children.

Importance: Despite considerable efforts to improve oral health for all, large disparities remain among US children. A dental professional shortage is thought to be among the determinants associated with oral health disparities, particularly for those residing in underserved communities. Objective: To evaluate the cost-effectiveness of expanding the dental workforce through the National Health Service Corps (NHSC) and associations with oral health outcomes among US children. Design, Setting, and Participants: A cost-effectiveness analysis was conducted to estimate changes in total costs and quality-adjusted life years (QALYs) produced by increasing the NHSC funding for dental practitioners by 5% to 30% during a 10-year period. A microsimulation model of oral health outcomes using a decision analytic framework was constructed based on oral health and dental care utilization data of US children from 0 to 19 years old. Data from the nationally representative National Health and Nutrition Examination Survey (NHANES, 2011-2016) were linked to county-level dentist supply and oral health professional shortage areas (HPSAs) information. Changes in prevalence and cumulative incidence of dental caries were also estimated. Sensitivity analyses were conducted to assess the robustness of results to variation in model input parameters. Data analysis was conducted from August 1, 2021, to November 1, 2022. Exposures: Expanding dental workforce through the NHSC program. Main Outcomes and Measures: Changes in total QALYs, costs, and dental caries prevalence and cumulative incidence. Results: This simulation model informed by NHANES data of 10 780 participants (mean [SD] age, 9.6 [0.1] years; 5326 [48.8%] female; 3337 [weighted percentage, 57.9%] non-Hispanic White individuals) found that when funding for the NHSC program increased by 10%, dental caries prevalence and total number of decayed teeth were estimated to decrease by 0.91 (95% CI, 0.82-1.00) percentage points and by 0.70 (95% CI, 0.62-0.79) million cases, respectively. When funding for the NHSC program increased between 5% and 30%, the estimated decreases in number of decayed teeth ranged from 0.35 (95% CI, 0.27-0.44) to 2.11 (95% CI, 2.03-2.20) million cases, total QALY gains ranged from 75.76 (95% CI, 59.44-92.08) to 450.50 (95% CI, 434.30-466.69) thousand QALYs, and total cost savings ranged from $105.53 (95% CI, $70.14-$140.83) to $508.23 (95% CI, $598.91-$669.22) million among children residing in dental HPSAs from a health care perspective. Benefits of the intervention accrued most substantially among Hispanic children and children in low-income households. Conclusions and Relevance: This cost-effectiveness analysis using a decision analytic model suggests that expanding the dental workforce through the NHSC program would be associated with cost savings and a reduced risk of dental caries among children living in HPSAs.

Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice.

Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) instigates nuclear factor-κB (NF-κB)-mediated inflammatory responses in alcohol-associated liver diseases (ALD). Here, we utilized a novel optogenetically engineered exosome technology called 'exosomes for protein loading via optically reversible protein-protein interactions (EXPLOR)' to efficiently deliver the super-repressor IκB-loaded exosomes (Exo-srIκB) to the liver and examined its therapeutic potential in acute-on-chronic alcohol-associated liver injury. We detected enhanced uptake of DiI-labeled Exo-srIκB by LPS-treated inflammatory KCs, which suppressed LPS-induced inflammatory gene expression levels. In animal experiments, a single intravenous injection of Exo-srIκB prior to alcohol binge drinking significantly attenuated alcohol-associated hepatic steatosis and infiltration of neutrophils and macrophages but not a liver injury. Notably, three consecutive days of Exo-srIκB injection remarkably reduced alcohol-associated liver injury, steatosis, apoptosis of hepatocytes, fibrosis-related gene expression levels in hepatic stellate cells, infiltration of neutrophils and macrophages, and inflammatory gene expression levels in hepatocytes and KCs. In particular, the above effects occurred with inhibition of nuclear translocation of NF-κB in liver tissues, and these beneficial effects of Exo-srIκB on ALD were shown regardless of doses. Our results suggest an exosome-based modulation of NF-κB activity in KCs by Exo-srIκB as a novel and efficient therapeutic approach in ALD.

Ethnic differences in attitudes, beliefs, and patterns of meat consumption among American young women meat eaters.

BACKGROUND/OBJECTIVES: Meat eaters face conflicts over meat consumption due to recent increasing demands for reduced-meat diets to promote human and environmental health. Attitudes toward consuming meat have been shown to be culture-specific. Thus, this study was performed to examine cultural differences in attitudes, beliefs, and patterns of meat consumption among meat eaters in a group homogeneous in terms of age and sex but with diverse ethnicities. SUBJECTS/METHODS: In this cross-sectional study conducted in New York City in 2014, 520 female meat eaters (Whites = 25%; Blacks = 20%; East Asians = 35%; Hispanics = 20%) aged 20-29 completed a questionnaire consisting of a series of questions on meat consumption behaviors, which addressed amounts of consumption, cooking methods, past and future changes in meat consumption, and attitudes and beliefs regarding relationships between health and meat consumption. Logistic and multiple regression analyses were used to assess the effects of variables on meat consumption. RESULTS: Blacks had the highest annual total meat consumption (64.2 kg), followed by East Asians (53.6 kg), Whites (46.9 kg), and Hispanics (35.8 kg). Blacks ate significantly more chicken than the other ethnic groups (P < 0.001), and East Asians ate significantly more pork and processed meat (P < 0.001). Regardless of ethnicity, grilling/roasting/broiling were the preferred cooking methods, and vegetables were most consumed as a side dish. More than half of the participants expressed an intention to decrease future meat consumption. East Asians more strongly perceived meat as a festive food (P < 0.001) and were less guilty about the slaughtering animals (P = 0.11) than other groups. No differences were found between the ethnic groups regarding negative attitudes to meat consumption. CONCLUSIONS: The results show that ethnicities differ in terms of attitudes, beliefs, and patterns of meat consumption. Irrespective of ethnicity, the meat-eating participants almost unanimously demonstrated a willingness to reduce future meat consumption. It is hoped these findings aid the formulation of culturally-tailored interventions that effectively reduce meat consumption.

Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease.

Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the ß2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.

Folate deficiency is associated with increased radiographic severity of osteoarthritis in knee joints but not in hand joints.

OBJECTIVES: No previous studies have explored the effect of folate deficiency on the severity of osteoarthritis (OA). Therefore, we investigated the relationship between folate level and features on knee and hand radiographs in a large, population-based OA cohort. METHODS: Among 9,260 subjects enrolled in the Dong-gu study, 2,489 who had knee and hand joint radiographs were included. Of these, subjects with a history of amputation or total knee replacement were excluded. Serum folate levels were measured using blood samples collected at the time of enrolment and stored. A semi-quantitative system was used to grade the severity of hand and knee x-ray changes. Linear regression was performed to assess relationships between serum folate levels and knee and hand radiographic scores after adjusting for age, sex, body mass index, smoking, alcohol consumption, education, physical activity, occupation, vitamin D, and ferritin. RESULTS: A total of 2,322 subjects were recruited. After adjusting for confounders, participants with folate deficiency (<4 ng/mL) had higher total (p<0.001), osteophyte (p<0.001), joint space narrowing (p=0.002), tibial attrition (p<0.001), and sclerosis (p=0.005) scores for knee joint radiographs compared to participants with a normal folate level. After adjusting for confounders, the radiographic scores for hand joints did not differ between the groups. CONCLUSIONS: Folate deficiency is associated with increased radiographic severity of OA in knee joints, but not in hand joints. Further studies are needed to explore the differential effects of folate on the severity of knee and hand OA.