Feasibility of contrast-free left atrial appendage closure with WATCHMAN FLX device for patients with chronic kidney disease.

Contrast media are generally necessary for transcatheter left atrial appendage closure (LAAC), however, it should be avoided in patients with chronic kidney disease (CKD). The objective of this study was to evaluate the safety and feasibility of contrast-free LAAC with WATCHMAN FLX device for patients with CKD. Among 141 patients undergoing LAAC using the WATCHMAN FLX between May 2021 and March 2023, we performed LAAC without contrast media in 10 patients. Procedural and follow-up results were evaluated. The device size was selected based on the transesophageal echocardiographic (TEE) measurements. The device shape was assessed by fluoroscopy, and the device position was adjusted by TEE images. The mean age was 78 ± 4.9 years, CHADS2 score was 3.2 ± 1.1, and the estimated glomerular filtration rate (eGFR) was 28 ± 12 mL/min/1.73m2. The procedure was completed without contrast media in ten patients. Partial recapture of the device was required in four patients, but the initially selected device was finally implanted in all patients. Mean procedure time was significantly shorter in the contrast-free LAAC than in the contrast-use LAAC (41.6 ± 14.1 min vs 30.3 ± 7.6 min, p = 0.01). Postprocedural eGFR did not change from baseline, and there were no adverse events during the hospital stay. Follow-up TEE or cardiac computed tomography performed within 3 months after the procedure revealed no device-related thrombus or peri-device leak > 3 mm, and oral antithrombotic therapy was discontinued in all patients. Our experience shows that contrast-free LAAC using the WATCHMAN FLX device was safe and feasible. Non-contrast LAAC is one of the therapeutic options for patients with severe CKD.

Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets.

The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.

A review of food poisoning caused by local food in Japan.

Increasingly popular worldwide, Japanese cuisine includes several raw preparations such as sashimi and sushi; however, limited information on food poisoning from Japanese local food is available in English literature. Without appropriate knowledge, physicians may underdiagnose traveler's diarrhea among people returning from Japan. To provide accurate information to primary care physicians worldwide, we conducted a narrative review on food poisoning research published in Japanese and English over the past four years, considering the frequency and clinical importance of various presentations.

Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease.

The prognosis of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142 HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p = .008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p = .011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p = .035, p = .002 and p = .030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD.

Modification of single-nucleotide polymorphism in a fully humanized CYP3A mouse by genome editing technology.

Cytochrome P450, family 3, subfamily A (CYP3A) enzymes metabolize approximately 50% of commercially available drugs. Recently, we developed fully humanized transchromosomic (Tc) CYP3A mice with the CYP3A cluster including CYP3A4, CYP3A5, CYP3A7, and CYP3A43. Our humanized CYP3A mice have the CYP3A5*3 (g.6986G) allele, resulting in the almost absence of CYP3A5 protein expression in the liver and intestine. To produce model mice for predicting CYP3A5's contribution to pharmacokinetics, we performed a single-nucleotide polymorphism (SNP) modification of CYP3A5 (g.6986G to A, *3 to *1) on the CYP3A cluster using genome editing in  both mouse ES cells and fertilized eggs, and produced humanized CYP3A5*1 mice recapitulating the CYP3A5*1 carrier phenotype in humans. The humanized CYP3A mouse with CYP3A5*1 is the first Tc mouse for predicting the SNP effect on pharmacokinetics in humans. The combination of Tc technology and genome editing enables the production of useful humanized models that reflect humans with different SNPs.