Lipoprotein-subclass particle numbers in children with abdominal obesity.

BACKGROUND: The lipoprotein particle number (PN) profile may be a better marker of cardiovascular risks than standard serum lipid measurements. The aim of this study was to analyze the lipoprotein PNs in Japanese children with abdominal obesity and to determine the subclass profile. METHODS: The participants included 164 Japanese children (79 boys and 85 girls) aged 9-13 years. We obtained waist-to-height ratios (WHtR) and serum lipids for all participants. The lipoprotein PNs in 12 subclasses were analyzed using high performance liquid chromatography (HPLC). RESULTS: Both boys and girls with abdominal obesity (WHtR ≧ 0.5) had significantly higher triglyceride (TG), very-low-density lipoprotein (VLDL)-PN, and all VLDL-subclass PNs compared to those without abdominal obesity. In boys with abdominal obesity, low-density lipoprotein (LDL)-PN was higher, but lipoprotein cholesterol (LDL-C) was not, and high-density lipoprotein cholesterol (HDL-C) was lower, but HDL-PN was not compared to those without abdominal obesity. In girls with abdominal obesity, LDL-C and LDL-PN were not significantly different and both HDL-C and HDL-PN were lower compared to those without abdominal obesity. Subclass analyses demonstrated that boys and girls with abdominal obesity had significantly lower very large and large HDL-PNs than those without abdominal obesity. In addition, medium, small, and very small LDL-PNs were higher in boys with abdominal obesity than those without abdominal obesity. CONCLUSIONS: This study found that Japanese children with abdominal obesity are affected by the lipoprotein-subclass PN profile, with sex differences in the LDL- and HDL-subclasses, which is different from results obtained by standard serum lipid measurements.

Control of cell migration by the novel protein phosphatase-2A interacting protein inka2.

Cell migration is essential for many physiological and pathological processes, including embryonic development, wound healing, immune response and cancer metastasis. Inka2 transcripts are observed in migrating cells during embryonic development, suggesting the involvement of inka2 in cell migration. However, its precise role remains unclear. Here, we found that inka2 controlled focal adhesion dynamics and cell migration, likely by regulating protein phosphatase-2A (PP2A) function. A scratch assay revealed that inka2 shRNA-transfected NIH3T3 cells showed rapid wound closure, indicating an inhibitory effect by inka2 on cell migration. Live-cell imaging of NIH3T3 cells expressing EGFP-paxillin using total internal reflection fluorescence microscopy revealed that inka2 knockdown increased the turnover rate of focal adhesions. Given that PP2A, which consists of catalytic (C), regulatory (B) and scaffolding (A) subunits, is known to regulate focal adhesions, we examined the inka2-PP2A interaction. Immunoprecipitation revealed an association between inka2 and the PP2A C subunit. Binding of Inka2 to the C subunit prevented the association between the A and C subunits, suggesting that inka2 can inhibit PP2A function. Furthermore, both inka2 expression and PP2A inhibition decreased focal adhesion kinase-paxillin interaction, resulting in reduced formation of focal adhesions. We assessed the effect of pharmacological PP2A inhibition on the inka2 knockdown-induced increase in cell migration speed and found that treatment with a PP2A inhibitor negated the accelerated migration of inka2 knockdown cells. These results suggest that inka2 knockdown exerts its effects through PP2A-dependent regulation of focal adhesions. Our findings contribute to a better understanding of the molecular mechanisms underlying cell migration.

Molecular mechanisms for enhancement of stromal cell-derived factor 1-induced chemotaxis by platelet endothelial cell adhesion molecule 1 (PECAM-1).

Platelet endothelial cell adhesion molecule 1 (PECAM-1) is a cell adhesion protein involved in the regulation of cell adhesion and migration. Interestingly, several PECAM-1-deficient hematopoietic cells exhibit impaired chemotactic responses to stromal cell-derived factor 1 (SDF-1), a chemokine essential for B lymphopoiesis and bone marrow myelopoiesis. However, whether PECAM-1 is involved in SDF-1-regulated chemotaxis is unknown. We report here that SDF-1 induces tyrosine phosphorylation of PECAM-1 at its immunoreceptor tyrosine-based inhibition motifs in several hematopoietic cell lines via the Src family kinase Lyn, Bruton's tyrosine kinase, and JAK2 and that inhibition of these kinases reduced chemotaxis. Overexpression and knockdown of PECAM-1 enhanced and down-regulated, respectively, SDF-1-induced Gαi-dependent activation of the PI3K/Akt/mTORC1 pathway and small GTPase Rap1 in hematopoietic 32Dcl3 cells, and these changes in activation correlated with chemotaxis. Furthermore, pharmacological or genetic inhibition of the PI3K/Akt/mTORC1 pathway or Rap1, respectively, revealed that these pathways are independently activated and required for SDF-1-induced chemotaxis. When coexpressed in 293T cells, PECAM-1 physically associated with the SDF-1 receptor CXCR4. Moreover, PECAM-1 overexpression and knockdown reduced and enhanced SDF-1-induced endocytosis of CXCR4, respectively. Furthermore, when expressed in 32Dcl3 cells, an endocytosis-defective CXCR4 mutant, CXCR4-S324A/S325A, could activate the PI3K/Akt/mTORC1 pathway as well as Rap1 and induce chemotaxis in a manner similar to PECAM-1 overexpression. These findings suggest that PECAM-1 enhances SDF-1-induced chemotaxis by augmenting and prolonging activation of the PI3K/Akt/mTORC1 pathway and Rap1 and that PECAM-1, at least partly, exerts its activity by inhibiting SDF-1-induced internalization of CXCR4.

Cyclic Nucleotide Control of Microtubule Dynamics for Axon Guidance.

UNLABELLED: Graded distribution of intracellular second messengers, such as Ca(2+) and cyclic nucleotides, mediates directional cell migration, including axon navigational responses to extracellular guidance cues, in the developing nervous system. Elevated concentrations of cAMP or cGMP on one side of the neuronal growth cone induce its attractive or repulsive turning, respectively. Although effector processes downstream of Ca(2+) have been extensively studied, very little is known about the mechanisms that enable cyclic nucleotides to steer migrating cells. Here, we show that asymmetric cyclic nucleotide signaling across the growth cone mediates axon guidance via modulating microtubule dynamics and membrane organelle transport. In embryonic chick dorsal root ganglion neurons in culture, contact of an extending microtubule with the growth cone leading edge induces localized membrane protrusion at the site of microtubule contact. Such a contact-induced protrusion requires exocytosis of vesicle-associated membrane protein 7 (VAMP7)-positive vesicles that have been transported centrifugally along the microtubule. We found that the two cyclic nucleotides counteractively regulate the frequency of microtubule contacts and targeted delivery of VAMP7 vesicles: cAMP stimulates and cGMP inhibits these events, thereby steering the growth cone in the opposite directions. By contrast, Ca(2+) signals elicit no detectable change in either microtubule contacts or VAMP7 vesicle delivery during Ca(2+)-induced growth cone turning. Our findings clearly demonstrate growth cone steering machinery downstream of cyclic nucleotide signaling and highlight a crucial role of dynamic microtubules in leading-edge protrusion for cell chemotaxis. SIGNIFICANCE STATEMENT: Developing neurons can extend long axons toward their postsynaptic targets. The tip of each axon, called the growth cone, recognizes extracellular guidance cues and navigates the axon along the correct path. Here we show that asymmetric cyclic nucleotide signaling across the growth cone mediates axon guidance through localized regulation of microtubule dynamics and resulting recruitment of specific populations of membrane vesicles to the growth cone's leading edge. Remarkably, cAMP stimulates microtubule growth and membrane protrusion, whereas cGMP promotes microtubule retraction and membrane senescence, explaining the opposite directional polarities of growth cone turning induced by these cyclic nucleotides. This study reveals a novel microtubule-based mechanism through which cyclic nucleotides polarize the growth cone steering machinery for bidirectional axon guidance.

High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma.

In order to prevent central nervous system (CNS) involvement and improve the prognosis of primary intraocular lymphoma (PIOL), we prospectively evaluated the efficacy of combined therapy using intravitreal methotrexate (MTX) and systemic high-dose MTX on treatment-naïve PIOL. Patients with newly diagnosed PIOL whose lymphoma was limited to the eyes were enrolled. The patients were treated with weekly intravitreal MTX until the ocular lesions were resolved, followed by five cycles of systemic high-dose MTX (3.5 g/m2 ) every other week. Ten patients were enrolled in this study and completed the treatment. All patients achieved complete response for their ocular lesions with rapid decrease of intravitreal interleukin-10 concentration. Adverse events of intravitreal and systemic high-dose MTX were mild and tolerable. With a median follow-up of 29.5 months, four patients (40%) experienced the CNS disease development and the mean CNS lymphoma-free survival (CLFS) time was 51.1 months. Two-year CLFS, which was the primary end-point of the study, was 58.3% (95% confidence interval, 23.0-82.1%). In contrast, eight patients were treated with intravitreal MTX alone in our institute, and their 2-year CLFS was 37.5% (95% confidence interval, 8.7-67.4%). In conclusion, systemic high-dose MTX following intravitreal MTX is feasible and might be effective in preventing CNS involvement of PIOL. Further arrangements are worth considering in order to improve the effects. This study was registered with UMIN Clinical Trials Registry (UMIN000003921).

High-resolution genomic copy number profiling of primary intraocular lymphoma by single nucleotide polymorphism microarrays.

Primary intraocular lymphoma (PIOL) is a rare lymphoma. Because of difficulties in obtaining tissue samples, little is known about the disease's genetic features. In order to clarify these features, we carried out single nucleotide polymorphism array karyotyping of IOL using genomic DNA extracted from vitreous fluid. We analyzed 33 samples of IOLs consisting of 16 PIOLs, 12 IOLs with a central nervous system (CNS) lesion at diagnosis (IOCNSL), and five secondary IOLs following systemic lymphoma. All were B-cell type. We identified recurrent copy number (CN) gain regions in PIOLs, most frequently on chromosome 1q followed by 18q and 19q. Chromosome 6q was the most frequent loss region. Although these CN gain regions of PIOL were in common with those of IOCNSL, loss of 6q22.33 containing PTPRK and 9p21.3 containing CDKN2A were more frequently deleted in IOCNSL. Large CN loss in 6q was detected in three of four PIOL patients who had early CNS development and short survival periods, whereas long-term survivors did not have such deletions. There was a correlation between gain of the IL-10 gene located on 1q and intravitreal interleukin-10 concentration, which was higher in IOL than in benign uveitis. The results suggest that IOCNSL is a highly malignant form of PIOL that infiltrates into the CNS at an early stage. They also indicate that genetic differences between PIOL and primary CNS lymphoma need to be clarified.

Kidney outcomes of SGLT2 inhibitors among older patients with diabetic kidney disease in real-world clinical practice: the Japan Chronic Kidney Disease Database Ex.

INTRODUCTION: We compared the kidney outcomes between patients with diabetic kidney disease (DKD) aged ≥75 years initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors versus other glucose-lowering drugs, additionally presenting with or without proteinuria. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database, we developed propensity scores, implementing a 1:1 matching protocol. The primary outcome included the decline rate in estimated glomerular filtration rate (eGFR), and secondary outcomes incorporated a composite of a 40% reduction in eGFR or progression to end-stage kidney disease. RESULTS: At baseline, the mean age at initiation of SGLT2 inhibitors (n=348) or other glucose-lowering medications (n=348) was 77.7 years. The mean eGFR was 59.3 mL/min/1.73m2 and proteinuria was 230 (33.0%) patients. Throughout the follow-up period, the mean annual rate of eGFR change was -0.80 mL/min/1.73 m2/year (95% CI -1.05 to -0.54) among SGLT2 inhibitors group and -1.78 mL/min/1.73 m2/year (95% CI -2.08 to -1.49) in other glucose-lowering drugs group (difference in the rate of eGFR decline between the groups was 0.99 mL/min/1.73 m2/year (95% CI 0.5 to 1.38)), favoring SGLT2 inhibitors (p<0.001). Composite renal outcomes were observed 38 in the SGLT2 inhibitors group and 57 in the other glucose-lowering medications group (HR 0.64, 95% CI 0.42 to 0.97). There was no evidence of an interaction between SGLT2 inhibitors initiation and proteinuria. CONCLUSIONS: The benefits of SGLT2 inhibitors on renal outcomes are also applicable to older patients with DKD aged≥75 years.

Population characteristics and diagnosis rate of chronic kidney disease by eGFR and proteinuria in Japanese clinical practice: an observational database study.

Chronic kidney disease (CKD) guidelines recommend early identification and intervention to delay the progression of CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) heatmap is widely used for risk evaluation in CKD management; however, real-world evidence on clinical characteristics based on the KDIGO heatmap remains limited worldwide including Japan. In order to understand the management of CKD including its diagnostic rates in a Japanese clinical setting on the basis of KDIGO heatmap, we utilized a medical record database that contains estimated glomerular filtration rate (eGFR) and urine protein data. Adult individuals (≥ 18 years) with two eGFR results of < 90 mL/min/1.73 m2, 90-360 days apart, were included. Approximately half of patients (452,996/788,059) had proteinuria test results and 6.9% (54,073) had quantitative results. CKD diagnosis rate in patients without proteinuria data was 5.9%, with a lower rate (2.9%) in stage G2; the corresponding rates with quantitative test results were 43.5% and 31.3%, respectively. The most frequent comorbidities were hypertension, diabetes, and cardiovascular disease, and their prevalence increased as the eGFR and proteinuria stages progressed. This study revealed a low rate of proteinuria assessment, especially using quantitative methods, and diagnosis in individuals with suspected CKD. With emerging treatment options to prevent CKD progression and complication onset, there is a need for early evaluation and diagnosis of CKD.

Radiological findings associated with postoperative wound infection after extraction of impacted mandibular third molar: A retrospective study.

INTRODUCTION: Studies directly relating radiological findings to the risk of postoperative wound infection (PWI) in impacted mandibular third molars (M3) are limited and poorly understood. This study aimed to clarify the radiological risk of PWI. MATERIALS AND METHODS: Twenty-six patients who developed PWI after M3 extraction were retrospectively analyzed using orthopantomography (OPG) and computed tomography (CT) before M3 extraction to determine the association between M3 impaction status and PWI. These were compared with an equal number of non-infected groups. Moreover, the possibility of assessing the same risk in OPG as in CT imaging was examined. RESULTS: Multivariate analysis identified class III and position B of the Pell and Gregory classification system as independent risk factors for PWI. On CT, an axial overlap distance (AOD) >3.5 mm was significantly associated with PWI. Furthermore, the sagittal overlap distance (SOD) and AOD of the OPG were significantly greater in group III-B. A strong positive correlation was observed between SOD and AOD. CONCLUSION: These results indicate that class III, position B, and an AOD >3.5 mm may be novel risk factors for M3 PWI. The strong correlation between SOD and AOD suggests that the risk assessment for PWI can be performed by evaluating OPG alone.

Outcome of 3q26.2/MECOM rearrangements in chronic myeloid leukemia.

STUDY AIMS: To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML). METHODS: We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015. RESULTS: We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89 months, median survival was 14 months. The 5-year survival rate was 19% overall, 23% in CML-CP/AP, and 15% in CML-BP. In the 6-month landmark analysis, the 5-year survival rate was 41% for allogeneic stem cell transplantation (allo-SCT) recipients versus 17% for non-recipients (P = 0.050). Multivariate analysis showed that the percentage of marrow blasts and achievement of MCyR or deeper could predict survival. CONCLUSION: Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.

Treatment patterns and trajectories in patients after acute heart failure hospitalization.

AIMS: The trajectories of systolic function after admission for acute heart failure (HF) and their effect on clinical outcomes have not been fully elucidated. We aimed to assess changes in left ventricular ejection fraction (LVEF) between the index and 1 year after discharge and to examine their prognostic implications. METHODS AND RESULTS: We extracted data from a prospective multicentre registry of patients hospitalized for acute HF and identified 1636 patients with LVEF data at admission and 1 year after discharge. We categorized them into five groups based on LVEF changes: HF with unchanged-preserved EF [HFunc-pEF (EF ≥ 50%); N = 527, 32.2%], unchanged-mildly reduced EF [HFunc-mrEF (EF 41-49%); N = 86, 5.3%], unchanged-reduced EF [HFunc-rEF (EF ≤ 40%); N = 377, 23.0%], worsened EF (HFworEF; N = 83, 5.1%), and improved EF (HFimpEF; N = 563, 34.4%). We then evaluated the subsequent composite outcome of cardiovascular death and HF readmission. During 1 year after discharge, 53% of patients with HF with reduced EF and 67% of those with HF with mildly reduced EF (HFmrEF) transitioned to other categories, whereas 92% of those with HF with preserved EF (HFpEF) remained within the same category. Patients with HFimpEF were more likely to be younger and had relatively preserved renal function, whereas those with HFworEF were the oldest and had more comorbidities among the five groups. After multivariable adjustment, patients with HFimpEF and HFunc-pEF had a lower risk for composite outcomes when referenced to patients with HFunc-rEF [hazard ratio (95% confidence interval), P-value: 0.28 (0.16-0.49), P < 0.001, and 0.40 (0.25-0.63), P < 0.001, respectively]. Conversely, patients with HFunc-mrEF and HFworEF had a comparable risk [0.44 (0.18-1.07), P = 0.07, and 0.63 (0.29-1.39), P = 0.26, respectively]. CONCLUSIONS: A substantial number of patients with HF experienced transitions to other categories after discharge. Notably, patients with decreased EF experienced a worse prognosis, even with slight decreases (e.g. HFpEF transitioning to HFmrEF). These findings emphasize the significance of longitudinal assessments of systolic function to better manage patients following acute decompensation.

Age-specific induction of mutant p53 drives clonal hematopoiesis and acute myeloid leukemia in adult mice.

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem cells (HSCs) collaborate with mutant p53 to predispose toward myeloid transformation rather than lymphoma development. Our study unveils new insights into the cooperative impact of HSC age, Trp53 mutations, and Mdm2 haploinsufficiency on clonal hematopoiesis and the development of myeloid malignancies.

Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.

Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti-lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition-mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition-mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.

[False positive (18)F-FDG PET/CT uptake by fat necrosis during chemotherapy for malignant lymphoma].

A 44-year-old man with advanced follicular lymphoma received 8 cycles of chemotherapy, which resulted in the complete disappearance of the original disease. However, a new abdominal mass with positive (18)F-FDG PET/CT uptake appeared after 5 cycles and this was maintained until 3 weeks after the completion of 8 cycles. Open biopsy showed a benign mass with fat necrosis. Although PET/CT is useful in evaluating residual lymphoma after chemotherapy, various benign conditions such as a result of post-chemotherapy inflammation, even in new locations without prior disease, should be noted as causes of false positive uptake.

Evolution of sodium-glucose co-transporter 2 inhibitors from a glucose-lowering drug to a pivotal therapeutic agent for cardio-renal-metabolic syndrome.

Cardio-renal-metabolic (CRM) syndrome, which involves type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and heart failure (HF), is a serious healthcare issue globally, with high morbidity and mortality. The disorders that comprise CRM syndrome are independent can mutually affect and accelerate the exacerbation of each other, thereby substantially increasing the risk of mortality and impairing quality of life. To manage CRM syndrome by preventing vicious interactions among individual disorders, a holistic treatment approach that can simultaneously address multiple disorders underpinning CRM syndrome is of great importance. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose levels by inhibiting glucose reabsorption in the renal proximal tubule and were first indicated for the treatment of T2DM. Several cardiovascular outcome trials have demonstrated that SGLT2i not only lower blood glucose but also reduce the risk of hospitalization for HF and worsening renal function in patients with T2DM. Results have also suggested that the observed cardiorenal benefits of SGLT2i may be independent of their blood glucose-lowering effects. Several randomized controlled trials subsequently assessed the efficacy and safety of SGLT2i in patients without T2DM, and revealed considerable benefits of SGLT2i treatment against HF and CKD, regardless of the presence of T2DM. Thus, SGLT2i have become an essential therapeutic option to prevent the onset, slow the progression, and improve the prognosis of CRM syndrome. This review assesses the evolution of SGLT2i from a glucose-lowering drug to a therapeutic agent for CRM syndrome by evaluating epoch-making clinical studies, including randomized control trials and real-world studies.

Molecular Mechanisms of Ferroptosis and Updates of Ferroptosis Studies in Cancers and Leukemia.

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Growing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is largely lacking. In this review, we summarize the current understanding of ferroptosis-regulating mechanisms with respect to the metabolism of phospholipids and iron as well as major anti-oxidative pathways that protect cells from ferroptosis. We also highlight the diverse impact of p53, a master regulator of cell death and cellular metabolic processes, on the regulation of ferroptosis. Lastly, we discuss recent ferroptosis studies in leukemia and provide a future perspective for the development of promising anti-leukemia therapies implementing ferroptosis induction.

Association between salivary proteases and protease inhibitors linked with viral infections and oral inflammatory diseases.

INTRODUCTION: Despite the role of transmembrane protease, serine 2 (TMPRSS2) in facilitating the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the primary cause of the global COVID-19 pandemic, the interaction of extracellular and intracellular proteases in this process remains poorly elucidated. Thus, we monitored the salivary expression concentration (SEC) of TMPRSS2 and its inhibitor, alpha-1 antitrypsin (A1AT), and investigated whether oral inflammatory diseases affected the SEC of both proteins. MATERIALS AND METHODS: We collected saliva samples before and after surgical treatment of inflammatory cystic diseases (radicular and inflammatory dentigerous cysts) in 25 patients. The SEC of TMPRSS2 and A1AT was measured using enzyme-linked immunosorbent assay. SEC in multiple patient status groups and subgroups of each status were investigated. Finally, the correlation between TMPRSS2 and A1AT SEC was analyzed. RESULTS: The TMPRSS2 and A1AT SEC did not significantly change pre- or post-treatment. The TMPRSS2 SEC was significantly higher before and after treatment in patients aged >50 years, patients with radicular cysts, and patients with the basic disease. A1AT SEC was significantly decreased after treatment in the acute inflammation, large-sized, and patients without basic disease groups. No significant correlation was observed between the SEC of either protein before and after treatment. DISCUSSION: Individual-specific SEC for TMPRSS2 may be influenced by age, lesion type, and basic disease; however, oral inflammatory diseases may not have a direct effect. Moreover, the extent of oral inflammatory diseases and the presence of basic diseases may be associated with A1AT SEC. Furthermore, the SEC between the two proteins may be independent.

Cost-Effectiveness Analysis of Initiating Type 2 Diabetes Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor Versus Conventional Therapy in Japan.

INTRODUCTION: Many patients with type 2 diabetes mellitus (T2DM) suffer from complications that impose substantial burdens on prognosis and medical costs. Accumulating evidence has demonstrated the clinical benefit of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular and renal complications. However, the health economic impact of SGLT2i remains unclear. The aim of this study was to evaluate the cost-effectiveness of initiating antidiabetic therapy with an SGLT2i using Japanese real-world data. METHODS: We constructed a natural history model incorporating heart failure (HF), myocardial infarction, stroke, chronic kidney disease, and end-stage renal disease (ESRD) as complications. The target population comprised patients with T2DM who newly initiated their first oral glucose-lowering drugs. By using a population-based microsimulation, we estimated the 10-year medical costs in Japanese yen (JPY) and outcomes (hospitalization for/development of complications and quality-adjusted life years [QALY]) for patients who initiated antidiabetic therapy with an SGLT2i or conventional therapy. Sensitivity analyses included a probabilistic sensitivity analysis (PSA) with 1,000,000 iterations. RESULTS: In the base-case analysis, the total medical cost per person was JPY 1,638,806 versus JPY 1,825,033 and the QALYs were 8.732 versus 8.513 for the SGLT2i strategy versus the conventional strategy, respectively. Thus, initiating treatment with an SGLT2i was dominant, more effective (QALY gain), and lower cost. When treating 10,000 patients, the SGLT2i strategy would reduce all-cause deaths by 410 (552 vs 962), HF events by 201 (897 vs 1098), and ESRD events by 16 (16 vs 32) versus the conventional strategy. The PSA revealed that the probability of dominance for initiating SGLT2i therapy was 90.5%, demonstrating the robustness of the results. CONCLUSION: Our results suggest that initiating T2DM treatment with SGLT2i, aimed at managing cardiovascular and renal complications from the early stages of diabetes, can improve the clinical outcome and reduce cost burden of T2DM.

Manifestation of Heart Failure and Chronic Kidney Disease are Associated with Increased Mortality Risk in Early Stages of Type 2 Diabetes Mellitus: Analysis of a Japanese Real-World Hospital Claims Database.

INTRODUCTION: To assess the initial manifestation of comorbidities and their impact on mortality risk in patients with type 2 diabetes mellitus (T2DM) without a history of cardiovascular or renal complications (i.e., in the early stages of T2DM) compared with patients without T2DM. METHODS: We performed a retrospective cohort study using a Japanese hospital claims database. The incidence rates of comorbidities (chronic kidney disease [CKD], heart failure [HF], myocardial infarction [MI], peripheral arterial disease [PAD], and stroke) and mortality risk were compared between patients with T2DM and age-/sex-matched patients without T2DM (matched 1:2). RESULTS: Among the comorbidities assessed in this study, CKD and/or HF was the most frequent initial manifestation in the patients with T2DM (n = 426,186) with an incidence rate 2.02 times greater than that in matched patients without T2DM (n = 1,018,609). The mortality risk was also greater in patients with T2DM than in patients without T2DM with a hazard ratio of 1.73. In both patients with and without T2DM, the presence of CKD or HF was associated with greater mortality risks compared with the presence of MI, PAD, or stroke. CONCLUSIONS: The high incidence of CKD or HF manifestation can contribute to the augmented mortality risk in patients in the early stages of T2DM compared with patients without T2DM. These findings highlight the importance of early interventions for preventing/treating CKD and HF to improve the prognosis of patients with T2DM.

Changes in Treatment Satisfaction Over 3 Years in Patients With Type 2 Diabetes After Initiating Second-line Treatment.

CONTEXT: J-DISCOVER is a prospective observational cohort study aiming to understand the current management of patients with early-stage type 2 diabetes mellitus (T2DM) in Japan, enrolling patients initiating second-line treatment. OBJECTIVE: The current analysis examined the change in treatment satisfaction during the study period and factors affecting this change among patients in J-DISCOVER. METHODS: We used data from the J-DISCOVER study, in which 1798 patients with T2DM aged ≥ 20 years were enrolled from 142 sites across Japan. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). RESULTS: The mean DTSQ treatment satisfaction score increased from 25.9 points at baseline to 27.3 points at 6 months, which was maintained through 36 months. Among the baseline characteristics examined, higher baseline DTSQ treatment satisfaction scores (P < 0.0001), older age (≥ 75 vs < 65 years, P = 0.0096), living alone (P = 0.0356), and type of facility (clinics vs hospitals, P = 0.0044) had a significantly negative impact on the changes in DTSQ treatment satisfaction scores. Improvement in mean glycated hemoglobin (HbA1c) from baseline (7.7%) to 36 months (7.1%) was associated with positive changes in the DTSQ treatment satisfaction score (P = 0.0003). CONCLUSION: Changes in DTSQ treatment satisfaction scores were related to HbA1c improvement, suggesting that the management strategy was appropriately planned for each patient. The results also suggest that the availability of social support for patients with T2DM who are elderly or living alone may be an important factor affecting treatment satisfaction, adherence, and clinical outcomes.