Reduction of Cardiovascular Events and Related Healthcare Expenditures through Achieving Population-Level Targets of Dietary Salt Intake in Japan: A Simulation Model Based on the National Health and Nutrition Survey

Reducing population dietary salt intake is expected to help prevent cardiovascular disease and thus constrain increasing national healthcare expenditures in Japan’s super-aged society. We aimed to estimate the impact of achieving global and national salt-reduction targets (8, <6, and <5 grams/day) on cardiovascular events and national healthcare spending in Japan. Using published data including mean salt intake and systolic blood pressure from the 2019 National Health and Nutrition Survey, we developed a Markov model of a closed cohort of adults aged 40–79 years in 2019 (n = 66,955,000) transitioning among six health states based on the disease course of ischemic heart disease (IHD) and stroke. If mean salt intake were to remain at 2019 levels over 10 years, cumulative incident cases in the cohort would be approximately 2.0 million for IHD and 2.6 million for stroke, costing USD 61.6 billion for IHD and USD 104.6 billion for stroke. Compared with the status quo, reducing mean salt intake towards the targets over 10 years would avert 1–3% of IHD and stroke events and save up to 2% of related national healthcare costs. Attaining dietary salt-reduction goals among adults would yield moderate health economic benefits in Japan.     

A case of primary small cell neuroendocrine carcinoma of the uterus

Neuroendocrine carcinoma of the uterine endometrium is extremely rare and found in <1% of all primary endometrial carcinomas. We report a case of neuroendocrine carcinoma of the endometrium detected in a 65-year-old woman and focus our attention on the main imaging features. The low apparent diffusion coefficient value and high maximum standardized uptake value for neuroendocrine cancer serve to distinguish this cancer from endometrial cancer.     

Single Nucleotide Variants of the Human TIM-1 IgV Domain with Reduced Ability to Promote Viral Entry into Cells

Human T-cell immunoglobulin mucin 1 (hTIM-1) is known to promote cellular entry of enveloped viruses. Previous studies suggested that the polymorphisms of hTIM-1 affected its function. Here, we analyzed single nucleotide variants (SNVs) of hTIM-1 to determine their ability to promote cellular entry of viruses using pseudotyped vesicular stomatitis Indiana virus (VSIV). We obtained hTIM-1 sequences from a public database (Ensembl genome browser) and identified 35 missense SNVs in 3 loops of the hTIM-1 immunoglobulin variable (IgV) domain, which had been reported to interact with the Ebola virus glycoprotein (GP) and phosphatidylserine (PS) in the viral envelope. HEK293T cells transiently expressing wildtype hTIM-1 or its SNV mutants were infected with VSIVs pseudotyped with filovirus or arenavirus GPs, and their infectivities were compared. Eleven of the thirty-five SNV substitutions reduced the efficiency of hTIM-1-mediated entry of pseudotyped VSIVs. These SNV substitutions were found not only around the PS-binding pocket but also in other regions of the molecule. Taken together, our findings suggest that some SNVs of the hTIM-1 IgV domain have impaired ability to interact with PS and/or viral GPs in the viral envelope, which may affect the hTIM-1 function to promote viral entry into cells.     

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE‐1 (phase 2) Japanese cohort

Chimeric antigen receptor (CAR) T cells targeting B‐cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE‐1 study of ciltacabtagene autoleucel (cilta‐cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), patients received a single cilta‐cel infusion at a target dose of 0.75 × 10⁶ (range, 0.5–1.0 × 10⁶CAR‐positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta‐cel. Thirteen patients underwent apheresis, nine of whom received cilta‐cel infusion. Eight patients who received cilta‐cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below‐target dose of cilta‐cel also achieved a best response of VGPR. MRD negativity (10⁻⁵ threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta‐cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR‐T cell neurotoxicity was reported. A positive benefit/risk profile for cilta‐cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.     

Mirizzi Syndrome Type IV Successfully Treated with Peroral Single-operator Cholangioscopy-guided Electrohydraulic Lithotripsy: A Case Report with Literature Review

A 76-year-old man presented with liver dysfunction and intrahepatic bile duct dilatation. Imaging studies showed two large stones that had become impacted in the common hepatic duct, which was fused with the gallbladder. The patient was diagnosed with Mirizzi syndrome type IV. Hepaticojejunostomy and stone removal failed due to dense gallbladder adhesions involving the right hepatic artery. The bile flow was temporarily restored; however, the patient experienced cholangitis 16 months later. The stones were extracted via peroral single-operator cholangioscopy (SOC)-guided electrohydraulic lithotripsy. This is the first case in which stones were completely removed by SOC-guided treatment in a patient with Mirizzi syndrome type IV.     

Incidence of thromboembolic complications in hospitalized COVID-19 patients in a medical ward in Japan: A single-center retrospective and prospective observational study

Background:A high incidence of thromboembolic complications is one of the hallmarks of COVID-19. However, there may be a difference in the incidence of thromboembolic complications between Asian and Western people. In addition, few prospective studies have been conducted to determine the incidence of thromboembolic complications in hospitalized COVID-19 patients in medical wards in Japan.Methods:A single-center retrospective and prospective cohort study was conducted to determine the incidence of thromboembolic complications in symptomatic COVID-19 patients in a medical ward in a Japanese hospital. All 1116 consecutive COVID-19 patients who were admitted to our hospital from November 1, 2020, to October 26, 2021, were included. The primary outcome was any thromboembolic complications, which included venous thromboembolism, myocardial infarction, ischemic stroke, and other arterial embolisms.Results:The median patient age was 50 (IQR, 37–61), 402 (36.0%) were women, 1005 (90.1%) were Japanese, the median body mass index was 24.1 (IQR, 21.6–27.2), and 43 (3.9%) had Padua scores of at least 4 points at admission. Regarding the severity of COVID-19, 543 (48.7%), 315 (28.2%), 204 (18.3%), and 54 (4.8%) patients had mild, moderate, severe, and critical COVID-19, respectively. Nine patients (0.8%) died, and 47 patients (4.2%) were transferred to other hospitals for intensive care. The primary outcome occurred in only 5 patients (0.5%; 95% CI, 0.1–0.8) and consisted of 3 ischemic strokes, 2 limb ischemia events, and one asymptomatic pulmonary embolism. Even in the 204 patients with severe COVID-19, the prevalence of thromboembolic complications was only 2.5% (95% CI, 0.3–4.6).Conclusion:Thromboembolic complications of COVID-19 are rare even in severe cases in a medical ward in a Japanese hospital. Further studies are needed to identify severe COVID-19 patients with a higher risk for thromboembolic complications in Japan.     

Aberrant B1 cell migration into the thymus results in activation of CD4 T cells through its potent antigen-presenting activity in the development of murine lupus

B1 cells have different origin and function from conventional B (B2) cells and are considered to be involved in autoantibody production in the development of autoimmune disease. We found that B1 cells preferentially accumulated in the target organs including thymus in aged BWF1 mice, a murine model for systemic lupus erythematosus, and that B lymphocyte chemoattractant (BLC/CXCL13) expression was increased in the thymus before the onset of lupus nephritis, while stromal cell-derived factor-1 (SDF-1/CXCL12) and secondary lymphoid tissue chemokine (SLC/CCL21) expression remained unchanged. Adhesion molecules such as peripheral node addressin (PNAd), ICAM-1, and VCAM-1 were also expressed on endothelial cells in the enlarged thymic perivascular space (PVS) in aged BWF1 mice. BLC protein and PNAd were co-localized on these high-endothelial-venules-like vessels in enlarged PVS. B1 cells expressed higher level of costimulatory molecules and showed a potent antigen-presenting activity in allogeneic mixed lymphocyte reaction comparable to splenic dendritic cells. Interestingly, B1 cells stimulated proliferation of autologous thymic CD4 T cells in the presence of IL-2. These results indicate that aberrant B1 cell trafficking into the thymus due to ectopic high expression of BLC may result in an activation of self-reactive T cells in the development of murine lupus.