Prognostic score-based model averaging approach for propensity score estimation.

BACKGROUND: Propensity scores (PS) are typically evaluated using balance metrics that focus on covariate balance, often without considering their predictive power for the outcome. This approach may not always result in optimal bias reduction in the treatment effect estimate. To address this issue, evaluating covariate balance through prognostic scores, which account for the relationship between covariates and the outcome, has been proposed. Similarly, using a typical model averaging approach for PS estimation that minimizes prediction error for treatment status and covariate imbalance does not necessarily optimize PS-based confounding adjustment. As an alternative approach, using the averaged PS model that minimizes inter-group differences in the prognostic score may further reduce bias in the treatment effect estimate. Moreover, since the prognostic score is also an estimated quantity, model averaging in the prognostic scores can help identify a better prognostic score model. Utilizing the model-averaged prognostic scores as the balance metric for constructing the averaged PS model can contribute to further decreasing bias in treatment effect estimates. This paper demonstrates the effectiveness of the PS model averaging approach based on prognostic score balance and proposes a method that uses the model-averaged prognostic score as a balance metric, evaluating its performance through simulations and empirical analysis. METHODS: We conduct a series of simulations alongside an analysis of empirical observational data to compare the performances of weighted treatment effect estimates using the proposed and existing approaches. In our examination, we separately provid four candidate estimates for the PS and prognostic score models using traditional regression and machine learning methods. The model averaging of PS based on these candidate estimators is performed to either maximize the prediction accuracy of the treatment or to minimize intergroup differences in covariate distributions or prognostic scores. We also utilize not only the prognostic scores from each candidate model but also an averaged score that best predicted the outcome, for the balance assessment. RESULTS: The simulation and empirical data analysis reveal that our proposed model-averaging approaches for PS estimation consistently yield lower bias and less variability in treatment effect estimates across various scenarios compared to existing methods. Specifically, using the optimally averaged prognostic scores as a balance metric significantly improves the robustness of the weighted treatment effect estimates. DISCUSSION: The prognostic score-based model averaging approach for estimating PS can outperform existing model averaging methods. In particular, the estimator using the model averaging prognostic score as a balance metric can produce more robust estimates. Since our results are obtained under relatively simple conditions, applying them to real data analysis requires adjustments to obtain accurate estimates according to the complexity and dimensionality of the data. CONCLUSIONS: Using the prognostic score as the balance metric for the PS model averaging enhances the performance of the treatment effect estimator, which can be recommended for a wide variety of situations. When applying the proposed method to real-world data, it is important to use it in conjunction with techniques that mitigate issues arising from the complexity and high dimensionality of the data.

Burosumab treatment of X-linked hypophosphatemia patients: interim analysis of the SUNFLOWER longitudinal, observational cohort study.

X-linked hypophosphatemia (XLH) is a genetic disease that results in excessive FGF23, chronic hypophosphatemia, and musculoskeletal abnormalities, with affected patients experiencing symptoms such as bone pain, bone deformity, fracture, and pseudofracture. Burosumab is a fully human monoclonal antibody that binds to FGF23, improving lowered serum 1,25(OH)2D and phosphate levels in patients with XLH. There are insufficient data on the use of burosumab, its safety, and the outcomes of treated patients in a real-world setting. The SUNFLOWER (Study of longitUdinal observatioN For patients with X-Linked hypOphosphatemic rickets/osteomalacia in collaboration With Asian partnERs) study is an ongoing longitudinal, observational cohort study of patients with XLH in Japan and South Korea. Enrollment occurred between April 2018 and December 2020. This interim analysis compared the background characteristics of patients who received burosumab with those who did not, and assessed improvements in biomarkers, physical and motor function, health-related quality-of-life (HRQOL) and other patient-reported outcome (PRO) measures, as well as the safety of burosumab treatment in 143 Japanese patients from 15 institutions over 6 mo. The patients had a median [interquartile range] age of 17.5 [11.0, 38.8] yr and 98 (68.5%) were female. Among patients aged <18 and ≥18 yr, 40/73 (54.8%) and 25/70 (35.7%) received burosumab, respectively. More patients aged ≥18 who received burosumab had bone pain at baseline vs those not treated with burosumab (6/25, 24.0% vs 2/45, 4.4%, p=.021). Patients treated with burosumab had improved serum phosphate and 1,25(OH)2D levels; moreover, rickets severity and HRQOL/PRO measures, such as pain, appeared to improve over 6 mo of burosumab treatment, and no new safety concerns were identified. This study identified trends in the background characteristics of patients with XLH who receive burosumab in real-world clinical practice. Furthermore, the results support the use of burosumab therapy in real-world settings.

Health guidance intervention mitigates the escalation of predicted comprehensive cardiovascular disease risk: Interrupted time series design.

INTRODUCTION: Metabolic syndrome increases the risk of cardiovascular events. Despite the Japanese healthcare system's efforts in early detection and intervention, particularly through Specific Health Checkup and Guidance programs, research on their effectiveness is limited. This study evaluated the impact of Specific Health Guidance on the predicted risk of atherosclerotic cardiovascular disease (ASCVD) in working-age Japanese individuals. METHODS: Employing an Interrupted Time Series (ITS) design, this study compared the trends in predicted ASCVD risk and each individual risk factor used for the prediction of ASCVD risk before and after intervention in individuals participating in the guidance. RESULTS: Analyses based on the ITS design indicated that participation in Specific Health Guidance programs, specifically the intensive level program, mitigates the increase trend of the predicted ASCVD risk. On the other hand, the impact on the trends of individual cardiovascular risk factors was minimal. CONCLUSIONS: The intensive level Specific Health Guidance appeared to reduce the increasing trend in ASCVD risk, emphasizing the importance of comprehensive risk assessment in evaluating health interventions. However, the results are limited owing to the specific demographics and short evaluation period. Further research is necessary to understand the long-term impacts and broader applicability.

Changes in FeNO, d-ROMs, and BH4 by Intravenous L-Arginine in Children and Its Putative Role in Asthma Treatment.

Purpose: Pteridines are metabolites of tetrahydrobiopterin (BH4), being coenzymes for nitric oxide synthase (NOS). No study has clarified the relationship among pteridines and NOS, fractional exhaled nitric oxide (FeNO) generated by pteridines, and reactive oxygen species. In this study, we administered arginine, a precursor of NO, and confirmed changes in the levels of pteridines, FeNO, and reactive oxygen species and their relationship to clarify the pathogenesis of airway inflammation in which oxidative stress is involved, such as bronchial asthma. Patients and Methods: This is a prospective, randomized open-label study. Children, aged 2 to 15 years, who were scheduled for growth hormone stimulation tests and were able to undergo a respiratory function test were recruited. They were randomly divided into two groups: arginine-administered and control groups. In the former, L-arginine hydrochloride was intravenously administered. After administration, the levels of diacron-reactive oxygen metabolites (d-ROMs), serum pteridines, serum amino acids, and fractional exhaled NO (FeNO) were measured. Results: We analyzed 15 children aged 4 to 14 years. In the arginine-administered group, there was an increase in the FeNO level and a decrease in the d-ROMs level, reaching a peak 30 min after administration, compared with the control group. In addition, there was a decrease in the serum biopterin level and an increase in the d-ROMs level, reaching peak 60 min after administration. Conclusion: The administration of L-arginine increased the NO level and decreased the d-ROMs level. Due to this, biopterin may be consumed and decreased, leading to an increase in the d-ROMs level. As a reduction in reactive oxygen species leads to the relief of inflammation, arginine and biopterin may be useful for inhibiting inflammation.

Amino acids to prevent cardiac surgery-associated acute kidney injury: a randomized controlled trial.

BACKGROUND: This study aimed to examine the preventive effect of amino acids on postoperative acute kidney injury (AKI). METHODS: This was single-center, patient- and assessor-blinded, randomized controlled trial. Patients who underwent aortic surgery with cardiopulmonary bypass were included. The intervention group received 60 g/day of amino acids for up to 3 days. The control group received standard care. The primary outcome was the incidence of AKI. We assessed the effect of amino acids on AKI using a Cox proportional hazards regression model. RESULTS: Sixty-six patients were randomly assigned to the control or intervention group. One patient in the control group withdrew consent after randomization. The incidence of AKI was 10 patients (30.3%) in the intervention group versus 18 patients (56.2%) in the control group (adjusted hazard ratio, 0.44; 95% confidence interval, 0.20-0.95; P = 0.04). CONCLUSIONS: This trial demonstrated a significant reduction in AKI incidence with amino acid supplementation. TRIAL REGISTRATION: jRCT, jRCTs051210154. Registered 31 December 2021, https://jrct.niph.go.jp/re/reports/detail/69916.

Japanese Study of the Effects of AMG (α1-Microglobulin) Reduction Rates on Survival (JAMREDS): A Protocol of a Multicenter Prospective Observational Cohort Study.

INTRODUCTION: Recent advances in dialysis therapy have made it possible to remove middle molecules. Removal of small-middle molecules, such as ß2-microglobulin, can now be achieved with conventional hemodialysis (HD), and removal of large-middle molecules has become a target, particularly for α1-microglobulin (AMG, 33 kD). The AMG reduction rate has emerged as a target for improvement of various clinical symptoms, but the effects on prognosis have yet to be determined. The "Japanese study of the effects of AMG (α1-microglobulin) reduction rates on survival" (JAMREDS) was started in April 2020, with the goal of determining if the AMG reduction rate associates with the risk of mortality and cardiovascular disease (CVD) events. METHODS: JAMREDS is a prospective observational study in patients on HD to examine the effects of: (1) AMG reduction rate on survival outcome and CVD events; (2) dialysis treatment modalities (HD, intermittent infusion hemodiafiltration(iHDF), pre/post-dilution online HDF) on survival and CVD events (based on AMG reduction rates with treatment mode); and (3) AMG reduction rates on survival and CVD events in patients undergoing each therapy (iHDF, pre/post-dilution online HDF). The number of planned subjects was 4,000 in preplanning. Data are collected using RED-Cap, which is an EDC system. A total of 9,930 patients were enrolled at the beginning of the study at 59 registered facilities. The JAMREDS observation period will continue until the end of 2023, after which the data will be cleaned and confirmed before analysis. CONCLUSION: This study may provide new evidence for the relationship between the amount of removed large-middle molecules (such as AMG) and the mortality and CVD risk. Comparisons with convection volumes will also be of interest.

Laparoscopic and open minor liver resection for hepatocellular carcinoma with clinically significant portal hypertension: a multicenter study using inverse probability weighting approach.

BACKGROUND: Liver resection offers substantial advantages over open liver resection (OLR) for patients with hepatocellular carcinoma (HCC) in terms of reduced intraoperative blood loss and morbidity. However, there is limited evidence comparing the indications and perioperative outcomes with the open versus laparoscopic approach for resection. This study aimed to compare postoperative outcomes between patients undergoing laparoscopic liver resection (LLR) and OLR for HCC with clinically significant portal hypertension (CSPH). METHODS: A total of 316 HCC patients with CSPH (the presence of gastroesophageal varices or platelet count < 100,000/ml and spleen diameter > 12 cm) undergoing minor liver resection at eight centers were included in this study. To adjust for confounding factors between the LLR and OLR groups, an inverse probability weighting method analysis was performed. RESULTS: Overall, 193 patients underwent LLR and 123 underwent OLR. After weighting, LLR was associated with a lower volume of intraoperative blood loss and the incidence of postoperative complications (including pulmonary complications, incisional surgical site infection, and paralytic ileus) compared to the OLR group. The 3-, 5-, and 7-year postoperative recurrence-free survival rates were 39%, 26%, and 22% in the LLR group and 49%, 18%, and 18% in the OLR group, respectively (p = 0.18). And, the 3-, 5-, and 7-year postoperative overall survival rates were 71%, 56%, and 44% in the LLR group and 76%, 51%, 44% in the OLR group, respectively (p = 0.87). CONCLUSIONS: LLR for HCC patients with CSPH is clinically advantageous by lowering the volume of intraoperative blood loss and incidence of postoperative complications, thereby offering feasible long-term survival.

Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

OBJECTIVE: Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. METHODS: Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. RESULTS: The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). CONCLUSIONS: This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

Relationship between Full-Thickness Macular Hole Onset and Posterior Vitreous Detachment: A Temporal Onset Theory.

Purpose: To evaluate the relationship between full-thickness macular hole (FTMH) onset and perifoveal posterior vitreous detachment using OCT data. Design: Retrospective study. Participants: A total of 742 patients with FTMH or impending macular hole (MH) in ≥ 1 eye, as determined by ophthalmoscopy and OCT. Methods: Macular holes were staged using OCT results. Patients with the posterior vitreous membrane clearly detected in the OCT images and vitreoretinal adhesion size ≤ 1500 µm-eyes with MH stages 1-3-were included in the study. The contralateral eyes were also included in the analyses if they showed the focal type of vitreomacular adhesion (VMA) (i.e., vitreoretinal adhesion ≤ 1500 µm). The distance between the posterior vitreous membrane and the surface of the retina was defined as the posterior vitreous separation height (PVSH). Using the OCT images, PVSHs of each eye in 4 directions (nasal, temporal, superior, and inferior) at 1 mm from the center of the MH or fovea were calculated. Main Outcome Measures: The main outcome measures were PVSHs according to the MH stage and VMA, the relationship of the foveal inner tear with PVSH, and the likelihood of a foveal inner tear based on the direction. Results: The PVSH trends in each of the 4 directions were as follows: VMA < MH stage 1 = MH stage 2 < MH stage 3. Initial MH stage 2 (onset of FTMH) was defined as the presence of a gap in only 1 of the 4 directions from the center of the MH. With increased PVSH, the likelihood of a gap increased (P = 0.002), and a temporal gap was more likely to occur than a nasal gap (P = 0.002). Conclusions: At FTMH onset, a foveal inner tear likely appears on the temporal side or the side showing a high PVSH value. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Evaluation of tetracycline and fluoroquinolone therapy against Japanese spotted fever: Analysis based on individual data from case reports and case series.

OBJECTIVES: Although approximately 40 years have passed since Japanese spotted fever (JSF) was first reported in Japan, its treatment has not yet been standardised. As in other rickettsial infections, tetracycline (TC) is the first-line treatment, but successful instances of fluoroquinolone (FQ) combination therapy in severe cases have been reported. However, the effectiveness of TC plus FQ combined treatment (TC+FQ) remains controversial. Therefore, the antipyretic effect of TC+FQ was evaluated in this study. METHODS: A comprehensive search of published JSF case reports was conducted to extract individual patient data. In cases where it was possible to extract temperature data, after homogenising patient characteristics, time-dependent changes in fever type from the date of the first visit was evaluated for the TC and TC+FQ groups. RESULTS: The primary search yielded 182 cases, with individual data evaluations resulting in a final analysis of 102 cases (84 in the TC group and 18 in the TC+FQ group) that included temperature data. The TC+FQ group had significantly lower body temperature compared with the TC group from Days 3 to 4. CONCLUSIONS: Although TC monotherapy for JSF can eventually result in defervescence, the duration of fever is longer compared with other rickettsial infections such as scrub typhus. The results suggest that the antipyretic effect of TC+FQ was more effective, with a potential shortening of the duration that patients suffer from febrile symptoms.

Clinical features and risk factors for interstitial lung disease spreading in low-dose irradiated areas after definitive radiotherapy with or without durvalumab consolidation therapy for patients with non-small cell lung cancer.

BACKGROUND: The current standard of care for patients with unresectable locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) combined with durvalumab consolidation therapy. However, radiotherapy (RT) always carries the risk of radiation pneumonitis (RP), which can preclude durvalumab continuation. In particular, the spread of interstitial lung disease (ILD) in low-dose areas or extending beyond the RT field often makes it difficult to determine the safety of continuation or rechallenging of durvalumab. Thus, we retrospectively analyzed ILD/RP after definitive RT with and without durvalumab, with assessment of radiologic features and dose distribution in RT. METHODS: We retrospectively evaluated the clinical records, CT imaging, and radiotherapy planning data of 74 patients with NSCLC who underwent definitive RT at our institution between July 2016 and July 2020. We assessed the risk factors for recurrence within one year and occurrence of ILD/RP. RESULTS: Kaplan-Meier method showed that ≥ 7 cycles of durvalumab significantly improved 1-year progression free survival (PFS) (p < 0.001). Nineteen patients (26%) were diagnosed with ≥ Grade 2 and 7 (9.5%) with ≥ Grade 3 ILD/RP after completing RT. There was no significant correlation between durvalumab administration and ≥ Grade 2 ILD/RP. Twelve patients (16%) developed ILD/RP that spread outside the high-dose (> 40 Gy) area, of whom 8 (67%) had ≥ Grade 2 and 3 (25%) had Grade 3 symptoms. In unadjusted and multivariate Cox proportional-hazards models adjusted for V20 (proportion of the lung volume receiving ≥ 20 Gy), high HbA1c level was significantly correlated with ILD/RP pattern spreading outside the high-dose area (hazard ratio, 1.842; 95% confidence interval, 1.35-2.51). CONCLUSIONS: Durvalumab improved 1-year PFS without increasing the risk of ILD/RP. Diabetic factors were associated with ILD/RP distribution pattern spreading in the lower dose area or outside RT fields, with a high rate of symptoms. Further study of the clinical background of patients including diabetes is needed to safely increase the number of durvalumab doses after CRT.

Reduced incidence of cardiovascular disease in patients with type 2 diabetes through the integrated improvement of diabetes care by comparing two prospective observational cohorts in real-world clinical practice (JDDM 72).

AIM: To investigate whether any reduction in all-cause mortality and cardiovascular disease morbidity was found over the decade in type 2 diabetes on real-world practice. METHODS: A prospective observational study was performed by following two independent cohorts recruited in 2004 (n = 3286, Cohort 1) and 2014 (n = 3919, Cohort 2). The primary outcome was a composite of onset of cardiovascular disease and death. Cox proportional hazards analysis was used to explore any difference between Cohort 2 and Cohort 1 for the composite endpoints and cardiovascular disease after adjustment for covariates and accumulation of five risks (smoking, HbA1c, blood pressure, lipids, and albuminuria) outside target ranges. RESULTS: During the 8-year follow-up, 391 (11.9%) and 270 (6.9%) primary outcomes, and 270 (8.2%) and 161 (4.1%) cardiovascular diseases occurred in Cohort 1 and Cohort 2, respectively. Cohort 2 (vs. Cohort 1) exhibited a significant risk reduction for composite endpoints (HR 0.73, 95% CI 0.62 to 0.86) and cardiovascular disease (HR 0.64, 95% CI 0.52 to 0.79), and similarly exhibited a significant reduction independent of the accumulation of the five risks. CONCLUSIONS: The significant reduction of Cohort 2 for cardiovascular disease independent of the baseline covariates suggests an integrated effect delivered by the recent treatment advances.

Association of Serum Levels of Cholesterol Absorption and Synthesis Markers with the Presence of Cardiovascular Disease: The CACHE Study CVD Analysis.

AIM: Serum levels of cholesterol absorption and synthesis markers have been associated with cardiovascular risk in the United States and European countries. In this study, we examined the relevance of these biomarkers and the presence of cardiovascular disease (CVD) in Japanese individuals. METHODS: The CACHE consortium, comprising of 13 research groups in Japan possessing data on campesterol, an absorption marker, and lathosterol, a synthesis marker measured by gas chromatography, compiled the clinical data using the REDCap system. RESULTS: Among the 2,944 individuals in the CACHE population, those with missing campesterol or lathosterol data were excluded. This cross-sectional study was able to analyze data from 2,895 individuals, including 339 coronary artery disease (CAD) patients, 108 cerebrovascular disease (CeVD) patients, and 88 peripheral artery disease (PAD) patients. The median age was 57 years, 43% were female, and the median low-density lipoprotein cholesterol and triglyceride levels were 118 mg/dL and 98 mg/dL, respectively. We assessed the associations of campesterol, lathosterol, and the ratio of campesterol to lathosterol (Campe/Latho ratio) with the odds of CVD using multivariable-adjusted nonlinear regression models. The prevalence of CVD, especially CAD, showed positive, inverse, and positive associations with campesterol, lathosterol, and the Campe/Latho ratio, respectively. These associations remained significant even after excluding individuals using statins and/or ezetimibe. The associations of the cholesterol biomarkers with PAD were determined weaker than those with CAD. Contrarily, no significant association was noted between cholesterol metabolism biomarkers and CeVD. CONCLUSION: This study showed that both high cholesterol absorption and low cholesterol synthesis biomarker levels were associated with high odds of CVD, especially CAD.

Sepsis-related coagulopathy treatment based on the disseminated intravascular coagulation diagnostic criteria: a post-hoc analysis of a prospective multicenter observational study.

BACKGROUND: The development of disseminated intravascular coagulation (DIC) in patients with sepsis has been repeatedly confirmed as a factor associated with poor prognosis. Anticoagulant therapy has been expected to improve sepsis patient outcomes, whereas no randomized controlled trials have demonstrated the survival benefit of anticoagulant therapies in non-specific overall sepsis. Patient selection based on the component of "high disease severity" in addition to "sepsis with DIC" has recently proved important in identifying appropriate targets for anticoagulant therapy. The aims of this study were to characterize "severe" sepsis DIC patients and to identify the patient population benefiting from anticoagulant therapy. METHODS: This retrospective sub-analysis of a prospective multicenter study included 1,178 adult patients with severe sepsis from 59 intensive care units in Japan from January 2016 to March 2017. We examined the association of patient outcomes, including organ dysfunction and in-hospital mortality, with the DIC score and prothrombin time-international normalized ratio (PT-INR), one of the components of the DIC score, using multivariable regression models including the cross-product term between these indicators. Multivariate Cox proportional hazard regression analysis with non-linear restricted cubic spline including a three-way interaction term (anticoagulant therapy × the DIC score × PT-INR) was also performed. Anticoagulant therapy was defined as the administration of antithrombin, recombinant human thrombomodulin, or their combination. RESULTS: In total, we analyzed 1013 patients. The regression model showed that organ dysfunction and in-hospital mortality deteriorated with higher PT-INR values in the range of < 1.5 and that this trend was more pronounced with higher DIC scores. Three-way interaction analysis demonstrated that anticoagulant therapy was associated with better survival outcome in patients with a high DIC score and high PT-INR. Furthermore, we identified a DIC score ≥ 5 and PT-INR ≥ 1.5 as the clinical threshold for identification of optimal targets for anticoagulant therapy. CONCLUSIONS: The combined use of the DIC score and PT-INR helps in selecting the optimal patient population for anticoagulant therapy in sepsis-induced DIC. The results obtained from this study will provide valuable information regarding the study design of randomized controlled trials examining the effects of anticoagulant therapy for sepsis. TRIAL REGISTRATION: UMIN-CTR, UMIN000019742. Registered on November 16, 2015.

Serum Values of Cholesterol Absorption and Synthesis Biomarkers in Japanese Healthy Subjects: The CACHE Study HEALTHY Analysis.

AIM: Blood cholesterol absorption and synthesis biomarkers predict cardiovascular risk. This study aimed to determine the values of serum non-cholesterol sterol markers [lathosterol (Latho), campesterol (Campe), and sitosterol (Sito)] in healthy individuals and factors affecting these markers. METHODS: The CACHE Consortium compiled clinical data, including serum Latho (cholesterol synthesis marker), and Campe and Sito (cholesterol absorption markers), by a gas chromatography method in 2944 individuals. Healthy subjects were selected by excluding those with prior cardiovascular disease, diabetes mellitus, hypertension, chronic kidney disease, familial hypercholesterolemia, sitosterolemia, current smokers, those with low (＜17 kg/m2) or high (≥ 30 kg/m2) body mass index (BMI), and those with treatment for dyslipidemia or hyperuricemia. Nonlinear regression stratified by sex was used to examine the associations of cholesterol metabolism markers with age, BMI, and serum lipid levels. RESULTS: Of 479 individuals selected, 59.4% were female; the median age was 48 years in females and 50 years in males. The three markers showed positively skewed distributions, and sex differences were present. Age was associated positively with Latho, inversely with Campe, but not significantly with Sito. BMI was associated positively with Latho, but not significantly with Campe or Sito. High-density lipoprotein cholesterol (HDL-C) was positively associated with Campe and Sito, but not significantly with Latho. Non-HDL-C was positively associated with the three markers. CONCLUSION: Our study results in the healthy subjects help to interpret the non-cholesterol sterol markers for cardiovascular risk assessment in patients with cardiovascular risk factors.

Decreased thymic output predicts progression of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is age-related disease, and decreased renal function is associated with the premature aging of T cells and increased incidence of other age-related diseases. However, the relationship between T cell senescence and CKD progression remains unclear. Here, we investigated the relationship between T cell senescence, as indicated by decreased thymic output and increased proportion of highly differentiated CD28- T cells, and CKD progression. RESULTS: A total of 175 patients with non-dialysis-dependent CKD were enrolled in this study. Thymic output was assessed based on the CD45RA+CD31+CD4+ cell (recent thymic emigrant [RTE]) counts (RTEs) (/mm3) and the proportion of RTE among CD4+ T cells (RTE%). Highly differentiated T cells were assessed based on the proportion of CD28- cells among CD4+ T cells (CD28-/CD4+) and CD28- cells among CD8+ T cells (CD28-/CD8+). The primary outcome was estimated glomerular filtration rate (eGFR) decline of ≥40% or initiation of renal replacement therapy. The association between T cell senescence and renal outcomes was examined using Cox proportional hazards models and restricted cubic splines. The median age was 73 years, 33% were women, and the median eGFR was 26 mL/min/1.73 m2. The median RTEs, RTE%, CD28-/CD4+, and CD28-/CD8+ were 97.5/mm3, 16.2, 5.3, and 49.7%, respectively. After a median follow-up of 1.78 years, renal outcomes were observed in 71 patients. After adjusting for age, sex, eGFR, proteinuria, diabetes, and cytomegalovirus seropositivity, decreased RTEs, which corresponded to decreased thymic output, significantly and monotonically increased the risk of poor renal outcome (p = 0.04), and decreased RTE% and increased highly differentiated CD28-/CD4+ T cells also tended to monotonically increase the risk (p = 0.074 and p = 0.056, respectively), but not CD28-/CD8+ T cells. CONCLUSIONS: Decreased thymic output in CKD patients, as well as increased highly differentiated CD4+ T cells, predicted renal outcomes. Thus, the identification of patients prone to CKD progression using T cell senescence, particularly decreased RTE as a biomarker, may help to prevent progression to end-stage kidney disease.

Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis.

AIM: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. METHODS: In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. RESULTS: In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. CONCLUSION: FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.

Relationship between Diabetes Mellitus and Serum Lathosterol and Campesterol Levels: The CACHE Study DM Analysis.

AIM: Risk of cardiovascular disease is increased in patients with diabetes mellitus (DM). Cholesterol metabolism (hepatic synthesis and intestinal absorption) is known to be associated with cardiovascular risk. Next, we examined the association of DM with cholesterol absorption/synthesis. METHODS: The CACHE Consortium, which is comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured by gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were used for several analyses including this study. RESULTS: This study analyzed data from eligible 2182 individuals including 830 patients with DM; 42.2% were female, median age was 59 years, and median HbA1c of patients with DM was 7.0%. There was no difference in Latho between DM and non-DM individuals. Campe and Campe/Latho ratio were significantly lower in DM individuals than in non-DM individuals. When the associations of glycemic control markers with these markers were analyzed with multivariable-adjusted regression model using restricted cubic splines, Campe and Campe/Latho ratio showed inverse associations with glucose levels and HbA1c. However, Latho showed an inverted U-shaped association with plasma glucose, whereas Latho showed a U-shaped association with HbA1c. These associations remained even after excluding statin and/or ezetimibe users. CONCLUSION: We demonstrated that DM and hyperglycemia were independent factors for lower cholesterol absorption marker levels regardless of statin/ezetimibe use.