Heating-free, room-temperature operation of a radiofrequency-to-light signal transducer with a membrane oscillator and a built-in metasurface mirror

We present an electro-mechano-optical radiofrequency (rf)-to-light signal transducer robust against laser heating and thus operational at room temperature. A metal-free, low-loss metasurface mirror and an aluminum electrode made separately on a Si₃N₄ membrane oscillator comprise a chain of electro-mechanical and opto-mechanical systems, mediating electrical and optical signals through the (2, 2)-mode characteristic oscillation. We demonstrate up-conversion of rf signals at 175.2 MHz by 6 orders of magnitude in frequency to an optical regime with the transfer efficiency of 2.3 × 10⁻⁹, also showing stable operation due to reduced laser heating of the mirror

A Diagnostic Algorithm for Eosinophilic Granulomatosis with Polyangiitis Initially Diagnosed as Lumbar Disc Hernia or Lumbar Spinal Stenosis: Personal Experience and Review of the Literature

Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome) is a rare systemic vasculitis and is difficult to diagnose. EGPA has a number of symptoms including peripheral dysesthesia caused by mononeuropathy multiplex, which is similar to radiculopathy due to lumbar disc hernia or lumbar spinal stenosis. Therefore, EGPA patients with mononeuropathy multiplex often visit orthopedic clinics, but orthopedic doctors and spine neurosurgeons have limited experience in diagnosing EGPA because of its rarity. We report a consecutive series of patients who were initially diagnosed as having lumbar disc hernia or lumbar spinal stenosis by at least 2 medical institutions from March 2006 to April 2013 but whose final diagnosis was EGPA. All patients had past histories of asthma or eosinophilic pneumonia, and four out of five had peripheral edema. Laboratory data showed abnormally increased eosinophil counts, and nerve conduction studies of all patients revealed axonal damage patterns. All patients recovered from paralysis to a functional level after high-dose steroid treatment. We shortened the duration of diagnosis from 49 days to one day by adopting a diagnostic algorithm after experiencing the first case

Safety confirmation of induced pluripotent stem cell-derived cardiomyocyte patch transplantation for ischemic cardiomyopathy: first three case reports

IntroductionWith the expected increase in patients with heart failure and ischemic 15 cardiomyopathy, the development of myocardial regenerative medicine using cell transplantation as a novel treatment method is progressing. This first-in-human clinical trial aimed to confirm the safety of cardiomyocyte patch transplantation derived from allogeneic induced pluripotent stem (iPS) cells based on the results of several preclinical studies.Study designThe inclusion criteria were left ventricular ejection fraction of 35% or less; heart failure symptoms of New York Heart Association class III or higher despite existing therapies such as revascularization; and a 1-year observation period that included a 3-month immunosuppressive drug administration period after transplantation of iPS cell-derived cardiomyocyte patches to evaluate adverse events, cardiac function, myocardial blood flow, heart failure symptoms, and immune response.ResultsIn the first three cases of this trial, no transplanted cell-related adverse events were observed during the 1-year observation period, and improvement in heart failure symptoms was observed. In addition, improvements in left ventricular contractility and myocardial blood flow were observed in two of the three patients. Regarding immune response, an increase in transplant cell-specific antibody titer was observed in all three patients after immunosuppressive drug administration. In one patient with poor improvement in cardiac function and myocardial blood flow, an increase in antibody titer against HLA-DQ was observed even before cell transplantation.ConclusionsOur case findings demonstrate that the transplantation of iPS cell-derived cardiomyocyte patches for ischemic cardiomyopathy can be safely performed; however, further investigation of the therapeutic effect and its relationship with an immune response is needed by accumulating the number of patients through continued clinical trials

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients

Objectives Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years. Methods Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. Results In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. Conclusions Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia

センチネルリンパ節生検を施行した腋窩リンパ節微小転移乳癌症例の検討

N0乳癌において症例を選べば，センチネルリンパ節転移陽性例であっても，腋窩リンパ節郭清（ALND）の省略が可能であると報告されている．微小転移（pN1mi）乳癌においても，同様の結果が得られている．当科でセンチネルリンパ節生検（SLNB）を施行し，pN1mi であった66例を研究対象とした．SLNB の方法は，99mTc-フチン酸を用いたRI 法とインドシアニングリーンを用いた色素法の併用法で行った．SLNB 群52例とSLNB → ALND 群14例に分け，予後を中心に検討し，ALND 省略の可能性について検討した．結果は，１）SLNB 群とSLNB → ALND 群で無病生存率および全生存率に有意差を認めなかった．２）乳房切除症例でも同様の結果であった．３）スキップ症例や術後にpN1mi と判明する症例が存在する．pN1mi 症例では乳房の術式にかかわらずALND の省略が可能である．It has been reported that axillary lymph node dissection (ALND) can be safely omitted if we carefully select breast cancer patients with sentinel lymph node metastases, including breast cancer patients with micrometastases (pN1mi). The subjects were 66 breast cancer patients with pN1mi who underwent sentinel lymph node biopsy (SLNB) in our department. SLNB was performed by the dual method using 99mTc-phytate and indocyanine green. We divided the subjects into the SLNB group (n=52) and SLNB → ALND group (n=14). Clinico-pathological factors, in particular prognosis of the patients were retrospectively studied. 1) No significant difference in disease-free survival and overall survival between the SLNB → ALND group and the SLNB group. 2) The similar findings were observed in patients who underwent mastectomy. 3) The pN1mi patients consisted of patients with so-called skip metastases and patients whose micrometastases were found in permanent sections after surgery. The omission of ALND is possible regardless of surgical methods, i.e., mastectomy or breast-conserving surgery, in pN1mi patients

Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD‐J (Flow‐Mediated Dilation Japan) Study A

BackgroundThe usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known.Methods and ResultsWe measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed.ConclusionsIn patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

FMD, PWV, and Cardiovascular Events

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target