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Pasteurellosis is a common zoonotic infection that occurs after an animal bite or scratch (B/S). We compared the clinical features of six patients with non-B/S pasteurellosis with those of 14 patients with B/S infections. Pasteurella multocida was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all six non-B/S infections, whereas 13 of the 14 B/S infections were identified with diagnostic kits. The non-B/S infections were pneumonia (n = 3), skin and soft tissue infections (n = 2), and bacteremia (n = 1). Pneumonia occurred in two patients with underlying pulmonary disease, whereas ventilator-associated pneumonia developed in one patient with cerebral infarction. Pasteurella multocida was isolated from a blood specimen and nasal swab from a patient with liver cirrhosis (Child-Pugh class C) and diabetes. Cellulitis developed in one patient with diabetes and normal-pressure hydrocephalus, who had an open wound following a fall, and in one patient with diabetes and a foot ulcer. Three patients with non-B/S infections had no pet and no episode of recent animal contact. The rate of moderate-to-severe comorbidities was significantly higher in patients with non-B/S infections than in those with B/S infections (100% and 14.3%, respectively, p < 0.001). In conclusion, non-B/S infections can develop in patients with chronic pulmonary disease, invasive mechanical ventilation, or open wounds, or who are immunocompromised, irrespective of obvious animal exposure. In contrast to B/S infections, non-B/S pasteurellosis should be considered opportunistic., Competing Interests: Declaration of competing interest All the authors declare that they have no conflicts of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency., Methods: This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023., Results: We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM&#95;138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency., Conclusion: GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K + channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated., Objective: We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants., Methods: The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated., Results: We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect., Conclusion: The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Wild birds could be a reservoir of medically relevant microorganisms, particularly multidrug-resistant Enterococcus spp. Resistant bacteria's epidemiology and transmission between animals and humans has grown, and their zoonotic potential cannot be ignored. This is the first study to evaluate the status of vancomycin resistant enterococci (VRE) in various wild bird species using meta-analysis and a systematic review. In this study, the pooled prevalence was obtained by analyzing data from published articles on the occurrence of VRE in wild bird species. It's unclear how the antibiotic resistance gene transfer cycle affects wild birds. Google Scholar and PubMed were used to conduct the research. The data and study methodology was assessed and extracted by two reviewers independently, with a third reviewing the results. Heterogeneity between study and publication bias were analyzed using the random effect model. Thirty-eight studies were included in the meta-analysis. 382 out of the 4144 isolates tested, were VRE. The pooled prevalence of VRE among wild birds was estimated at 11.0% (95% CI; 6.9 -17.2%; I 2 = 93.204%; P < 0.001). There was high variability between study (t 2 = 2.156; heterogeneity I 2 = 93.204% with chi-square (Q) = 544.413, degrees of freedom (df) = 37, and P < 0.001). Egger's test verified the funnel plot's bias, while result from the leave-one-out forest plot had no effect on the pooled prevalence., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: NGLY1-associated congenital disorder of deglycosylation (CDDG1: OMIM #615273) is a rare autosomal recessive disorder caused by a functional impairment of endoplasmic reticulum in degradation of glycoproteins. Neurocognitive dysfunctions have been documented in patients with CDDG1; however, deteriorating phenotypes of affected individuals remain elusive., Case Presentation: A Japanese boy with delayed psychomotor development showed ataxic movements from age 5 years and myoclonic seizures from age 12 years. Appetite loss, motor and cognitive decline became evident at age 12 years. Electrophysiological studies identified paroxysmal discharges on myoclonic seizure and a giant somatosensory evoked potential. Perampanel was effective for controlling myoclonic seizures. Exome sequencing revealed that the patient carried compound heterozygous variants in NGLY1, NM&#95;018297.4: c.857G > A and c.-17&#95;12del, which were inherited from mother and father, respectively. A literature review confirmed that myoclonic seizures were observed in 28.5% of patients with epilepsy. No other patients had progressive myoclonic epilepsy or cognitive decline in association with loss-of-function variations in NGLY1., Conclusion: Our data provides evidence that a group of patients with CDDG1 manifest slowly progressive myoclonic epilepsy and cognitive decline during the long-term clinical course., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest concerning the present study., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Frontalis suspension surgery is commonly used for the repair of congenital ptosis and involutional blepharoptosis with poor levator function. Grafts for this procedure have been developed using a variety of different materials, each with advantages and disadvantages. The retroauricular fascia graft might be beneficial in this surgery. This article reports the surgical results of blepharoptosis, who were treated with the retroauricular fascia, which is a new autologous graft for the frontalis suspension technique. This case series study targeted patients with ptosis who underwent frontalis suspension surgery with the retroauricular fascia graft at Wakayama Medical University in Japan between May 2016 and May 2023. Patients with insufficient follow-up (<6 months) were excluded from the study. Eligible patients were categorized into one of the following three assessment groups: "good" (improvement of palpebral fissure height without laterality, Margin reflex distance-1 gap between right and left side <0.5 mm), "fair" (improvement of palpebral fissure height with laterality), or "poor" (poor improvement of palpebral fissure height). Thirty-five eyes in 25 patients were treated with the retroauricular fascia graft. The mean postoperative follow-up was 27 months. Eight patients were classified as good (32%), 15 as fair (60%), and two as poor (8%). Two patients (8%) had postoperative lagophthalmos. No patients had eyelash inversion, tarsal deformity, or recurrence of ptosis. Scars along the edge of the hairline were inconspicuous and there were no hypertrophic scars. Functional reconstruction of the eyelids using the retroauricular fascia graft technique is described here for the first time. This grafting technique may be a useful alternative for frontalis suspension surgery because it can be harvested with easy access and without leaving conspicuous scars., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Introduction: The efficacy of radiotherapy for symptomatic relief of malignant psoas syndrome (MPS) remains unknown because there are limited publications with high level evidence, including analyses with sufficient number of cases, clinical trials, and systematic reviews about radiotherapy for MPS. We aimed to investigate the characteristics of and symptom relief rates in patients treated with radiotherapy for MPS in palliative intent., Methods: In this single-center retrospective study, we analyzed data of 22 consecutive patients treated with radiotherapy for MPS at our institution in Japan between 2012 and 2022. We recorded patient characteristics, including primary site, invasion pattern, recognition of MPS by the attending physician, radiation regimen, biological effective dose with α/β = 10 Gy (BED 10 ), and adverse events. Since no objective evaluation index for palliative radiotherapy for non-bone metastases has been established, we modified and used an International Consensus on Palliative Radiotherapy Endpoint, which was originally used for bone metastases, to evaluate symptom relief in the present retrospective study. "Response" was defined as symptom relief described in medical records or the use of analgesic medications reduced by ≥25% within 3 months post-initiation of radiotherapy., Results: Genitourinary organs (41%) were the most common primary-tumor sites. MPS was caused by metastasis in the iliopsoas muscle in 14 patients (64%) and by direct invasion of the primary tumor in eight patients (36%). Since the optimal radiation dose for MPS has not been established, the radiation dose varied from low dose, which are used in palliative radiotherapy for painful bone metastases, to high dose with conventional fraction using 1.8 to 2 Gy per fraction, with a median BED 10 of 48 Gy (range, 10.6-79.2 Gy). Fifteen patients (68%) achieved a response. No acute nor late adverse events of grade 2 or higher, according to Common Terminology Criteria for Adverse Events version 5.0, were reported during the observation period., Conclusion: Radiotherapy for symptomatic MPS might be an effective treatment option with a high response rate (68%) and minimal adverse events. Since the present study is a retrospective study with small number of cases, a prospective study with a larger sample size is required., (Copyright © 2023. Published by Elsevier Inc.)

Background: This study aimed to establish reference equations for single-breath lung carbon monoxide diffusing capacity (D LCO ), alveolar volume (V A ), and transfer coefficient of the lungs for carbon monoxide (K CO , sometimes written as D LCO /V A ) in the Japanese population. A generalised additive model for location size and shape (GAMLSS) was used to build each equation., Methods: To collect pulmonary function data throughout a broad age range, we prospectively obtained pulmonary function data from healthy volunteers and retrospectively obtained data from patients with normal diffusing capacity aged 16-85 years., Results: In total, 702 tests were conducted. The validation group z-scores, except for D LCO in males, showed substantial discrepancies between the Global Lung Initiative (GLI) baseline prediction equations and the present study's prediction equations, indicating the need for a new reference value prediction approach. The root mean square errors of the D LCO , V A , and K CO reference values obtained from the present study's prediction equations were lower than those derived from the GLI and previous linear regression equations., Conclusions: Reference values obtained in this study were more appropriate for our sample than those derived from the existing baseline prediction equations. This research's contribution is the development of a more precise prediction equation that can be used to establish a reference value range for pulmonary diffusing capacity., Ethics and Dissemination: This research does not include any dissemination plan (publications, data deposition and curation)., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Despite optimal treatment, a residual inflammatory risk often remains in patients with atherosclerotic cardiovascular disease. In a US-based phase 2 trial, ziltivekimab, a fully human monoclonal antibody targeting the interleukin-6 ligand, significantly reduced biomarkers of inflammation compared with placebo in patients at high atherosclerotic risk. Here, we report the efficacy and safety of ziltivekimab in Japanese patients., Methods: RESCUE-2 was a randomized, double-blind, 12-week, phase 2 trial. Participants aged ≥20 years with stage 3-5 non-dialysis-dependent chronic kidney disease and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to receive placebo (n = 13) or subcutaneous ziltivekimab 15 mg (n = 11) or 30 mg (n = 12) at Weeks 0, 4, and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT; mean of Week 10 and Week 12 values)., Results: At EOT, median hsCRP levels were reduced by 96.2 % in the 15 mg group (p < 0.0001 versus placebo), by 93.4 % in the 30 mg group (p = 0.002 versus placebo), and by 27.0 % in the placebo group. Serum amyloid A and fibrinogen levels were also reduced significantly. Ziltivekimab was well tolerated and did not affect total cholesterol to high-density lipoprotein cholesterol ratios. There was a small, but statistically significant increase in triglyceride levels with ziltivekimab 15 mg and 30 mg compared with placebo., Conclusions: The efficacy and safety results support the development of ziltivekimab for secondary prevention and the treatment of patients at high atherosclerotic risk., Clinicaltrials: gov identifier, NCT04626505., Competing Interests: Declaration of competing interest Yukihiro Wada has no conflict of interest. Camilla Jensen, Sina Meyer, and Amir Mohseni Zonoozi, are employees of Novo Nordisk A/S. Hirokazu Honda is a scientific advisor for Astellas Pharma, Bayer Yakuhin, Kyowa Kirin, Mitsubishi Tanabe Pharma, and Torii Pharmaceutical. He has received research funds from Chugai Pharmaceutical, Kyowa Kirin, Otsuka Pharmaceutical, and Torii Pharmaceutical, as well as lecture fees from Astellas Pharma, Bayer Yakuhin, Chugai Pharmaceutical, Kissei Pharmaceutical, Kyowa Kirin, Mitsubishi Tanabe Pharma, and Torii Pharmaceutical., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon., Methods: We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure., Results: Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain., Conclusions: Bayesian penetrance estimates provide a continuous framework for variant interpretation., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Many drugs have been marketed for treating coronavirus disease 2019 (COVID-19) infection, the disease that has caused a worldwide pandemic. However, in reported clinical trials, almost 30% of patients with COVID-19 did not show any health improvement. The 28-day survival rate was 69.5% when patients who required highflow oxygen therapy (HFNC), ventilation, and extracorporeal membrane oxygenation (ECMO) management were treated with remdesivir. The mortality rate of patients receiving 6 mg dexamethasone was 27%, and that of patients treated with tocilizumab and steroids was 31%. These results are unsatisfactory, and treatment for patients with severe respiratory failure has not yet been established. In our institution, we used remdesivir, methylprednisolone (mPSL) pulse therapy, and tocilizumab in 20 patients with COVID-19 whose PaO2/FIO2 (P/F) ratio was <200, and obtained good results for this combination therapy without any adverse events. In this study, we report the possible efficacy and safety of this treatment., Competing Interests: Conflict of Interest The authors state that they have no conflicts of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Production of 99 Mo/ 99m Tc using an electron linear accelerator (linac) and activated carbon (AC)-based 99m Tc generator (linac-AC) is an alternative approach to the conventional fission production of 99 Mo/ 99m Tc. As a preliminary investigation of the clinical applicability of a linac-AC-derived 99m Tc radiopharmaceutical, the biodistribution of linac-AC-derived [ 99m Tc]sodium pertechnetate ([ 99m Tc]NaTcO 4 ) was measured and compared against fission-derived [ 99m Tc]NaTcO 4 at one time point., Methods: 99 Mo was produced by irradiating nonenriched MoO 3 targets with bremsstrahlung photons generated from 55.5-MeV linac electron beams. 99m Tc was then separated and purified from the 99 Mo using an AC-based 99m Tc generator. Subsequently, biodistribution of the linac-AC-derived [ 99m Tc]NaTcO 4 in healthy female Slc:ICR mice (n = 6) was measured by dissection and compared with that of fission-derived [ 99m Tc]NaTcO 4 (n = 4) at 30 min after injection., Results: The two types of [ 99m Tc]NaTcO 4 exhibited similar biodistribution in all the organs and tissues examined: the uptakes of [ 99m Tc]NaTcO 4 prepared from the linac-AC method and those prepared from the fission method were 138.9 ± 69.9%ID/g and 160.6 ± 49.2%ID/g in the thyroids, respectively, 33.4 ± 5.5%ID/g and 29.4 ± 9.1%ID/g in the salivary glands, respectively, and less than 10%ID/g in blood and all the other organs. No adverse effects were observed in the mice administered with either [ 99m Tc]NaTcO 4 ., Conclusion: The clinical applicability of linac-AC-derived [ 99m Tc]NaTcO 4 was suggested by its similar biodistribution with fission-derived [ 99m Tc]NaTcO 4 at one time point. Further biodistribution studies at multiple time points are encouraged to demonstrate the bioequivalence between linac-AC- and fission-derived [ 99m Tc]NaTcO 4 ., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes., Methods: Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations., Results: Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required., Conclusions: Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future., Competing Interests: Conflict of Interest None of the authors have any conflicts of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Epstein-Barr virus (EBV) is a member of the herpesvirus family that is known to ubiquitously infect people worldwide. However, the actual prevalence of EBV infection in diseased patients in Nigeria, remains unknown. This study was thus conducted to ascertain the true prevalence., Methods: A systematic review and meta-analysis of published data was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Electronic databases including PubMed, Scopus, ScienceDirect, and Google Scholar were searched for studies reporting the occurrence of EBV infection among patients with established diseases. Studies were included if they assessed EBV infection in diseased patients in Nigeria. Data were extracted and subsequently analysed using R software. Funnel plot and Egger's regression test was used to assess publication bias, while JBI prevalence tool was used to assess study quality., Results: A total of 13 studies covering 228 cases of EBV infection among 1157 diseased patients were included. Summary estimates were computed using random-effects model. The pooled prevalence of EBV infection was 20.3% (95% CI: 10.8-34.9, I 2  ​= ​92.26, p ​< ​0.001). When stratified according to the type of disease, higher estimates were obtained for patients suffering from Kaposi's sarcoma (98.7%, 95% CI: 82.2-99.9) and Nasopharyngeal malignancy (85.7%, 95% CI: 70.0-93.9). A prevalence of 13.4% (95% CI: 6.0-27.4) and 12.2% (95% CI: 4.8-27.8) was derived for the most reported patient populations, lymphoma and HIV, respectively., Conclusion: This first meta-analysis on the prevalence of EBV among Nigerian patients suffering from various diseases reveals a prevalence that emphasises the need to routinely monitor EBV infection in all EBV-associated diseases in Nigeria., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Indian Association of Medical Microbiologists. Published by Elsevier B.V. All rights reserved.)

It is widely accepted that uptake and efflux transporters on clearance organs play crucial roles in drug disposition. Although in vitro transporter assay system can identify the intrinsic properties of the target transporters, it is not so easy to precisely predict in vivo pharmacokinetic parameters from in vitro data. Positron emission tomography (PET) imaging is a useful tool to directly assess the activity of drug transporters in humans. We recently developed a practical synthetic method for fluorine-18-labeled pitavastatin ([ 18 F]PTV) as a PET probe for quantitative evaluation of hepatobiliary transport. In the present study, we conducted clinical PET imaging with [ 18 F]PTV and compared the pharmacokinetic properties of the probe for healthy subjects with or without rifampicin pretreatment. Rifampicin pretreatment significantly suppressed the hepatic maximum concentration and biliary excretion of the probe to 52% and 34% of the control values, respectively. Rifampicin treatment markedly decreased hepatic uptake clearance (21% of the control), and moderately canalicular efflux clearance with regard to hepatic concentration (52% of the control). These results demonstrate that [ 18 F]PTV is a useful probe for clinical investigation of the activities of hepatobiliary uptake/efflux transporters in humans., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Purpose: Up to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein Na V 1.5. Recent studies suggested that Na V 1.5 can dimerize, and some variants exert dominant negative effects. In this study, we sought to explore the generality of missense variant Na V 1.5 dominant negative effects and their clinical severity., Methods: We identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database., Results: In heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019)., Conclusion: Most SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS., Competing Interests: Conflict of Interest The authors, M.J.O., A.M., B.L., Y.W., L.H., J.F.S., L.S., D.M.R., and A.M.G., have all read the paper and reviewed potential conflicts of interest. The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Vascular endothelial growth factor (VEGF) signaling plays a central role in vascular development and maintenance of vascular homeostasis. In endothelial cells (ECs), VEGF activates the gene expression of angiogenic transcription factors (TFs), followed by induction of downstream angiogenic responsive genes. Recent findings support that histone modification dynamics contribute to the transcriptional control of genes that are important for EC functions. Lysine demethylase 2B (KDM2B) demethylates histone H3K4me3 and H3K36me2/3 and mediates the monoubiquitination of histone H2AK119. KDM2B functions as a transcriptional repressor in somatic cell reprogramming and tumor development. However, the role of KDM2B in VEGF signaling remains to be elucidated. Here, we show that KDM2B knockdown enhances VEGF-induced angiogenesis in cultured human ECs via increased migration and proliferation. In contrast, ectopic expression of KDM2B inhibits angiogenesis. The function of KDM2B may depend on its catalytic Jumonji C domain. Genome-wide analysis further reveals that KDM2B selectively controls the transcription of VEGF-induced angiogenic TFs that are associated with increased H3K4me3/H3K36me3 and decreased H2AK119ub. These findings suggest an essential role of KDM2B in VEGF signaling in ECs. As dysregulation of VEGF signaling in ECs is involved in various diseases, including cancer, KDM2B may be a potential therapeutic target in VEGF-mediated vasculopathic diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Sarcopenia is defined as a combination of low skeletal muscle mass index (SMI), weak muscle strength, and reduced physical function. Recently, many studies have reported that the creatinine/cystatin C ratio (Cr/CysC) is useful for evaluating muscle mass. We designed a cross-sectional study with separate model development and validation groups to develop a prediction equation to estimate bioimpedance analysis (BIA)-measured SMI with Cr/CysC., Design: The current study was a retrospective cross-sectional study., Setting and Participants: The model development group included 908 subjects (288 men and 620 women) from the Frail Elderly in the Sasayama-Tamba Area (FESTA) study, and the validation group included 263 subjects (112 men and 151 women) from participants in the medical checkup program at the Anti-Aging Center in Ehime Prefecture., Measures: Multivariate regression analysis indicated that age, hemoglobin (Hb), body weight (BW), and Cr/CysC were independently associated with SMI in both men and women. The SMI prediction equation was developed as follows: Men:4.17-0.012×Age+1.24×(Cr/CysC)-0.0513×Hb+0.0598×BW Women:3.55-0.00765×Age+0.852×(Cr/CysC)-0.0627×Hb+0.0614×BW RESULTS: The SMI prediction equation was applied to the validation group and strong correlations were observed between the BIA-measured and predicted SMI (pSMI) in men and women. According to the receiver operator characteristic (ROC) analysis, the areas under the curve were 0.93 (specificity 89.0%, sensitivity 87.2%) among men and 0.88 (specificity 83.6%, sensitivity 79.6%) among women for using pSMI to identify low SMI in the model development group. The pSMI also indicated high accuracy in ROC analysis for low SMI in the validation group. The Bland-Altman plot regression showed good agreement between BIA-measured and pSMI., Conclusions and Implications: Our new prediction equation to estimate SMI is easy to calculate in daily clinical practice and would be useful for diagnosing sarcopenia., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2- 18 F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid ( 18 F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl- 11 C]methionine ( 11 C-MET) and 2-Deoxy-2- 18 F-fluoro-D-glucose ( 18 F-FDG). 18 F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18 F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11 C-MET and 18 F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18 F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18 F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11 C-MET and 18 F-FDG. 18 F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Transesophageal echocardiography (TEE) is the gold standard for detecting thrombi in the left atrium (LA) and left atrial appendage (LAA) prior to pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF). Although TEE has a good safety profile, it was recently reported that TEE preceding PVI can cause esophageal mucosal injuries (EMIs). The exact mechanism remains to be elucidated. In the present study, we investigated the incidence and risk factors of TEE-related EMI (TEE-EMI) among patients who underwent PVI for AF., Methods and Results: This study included 262 consecutive patients who underwent PVI with preoperative TEE using a 3D TEE probe and postoperative esophagogastroduodenoscopy. TEE-EMIs were observed in 16 (6.1%) patients (18 lesions), whereas PVI-related EMIs were found in 5 (1.9%) patients (8 lesions). All TEE-EMIs were observed in the upper or middle esophagus and occurred more frequently in the right region of the upper esophagus and the left anterior region of the middle esophagus; only one patient experienced mild chest discomfort. In the multivariate analysis, advanced age was an independent risk factor for TEE-EMIs (odds ratio 1.08, 95% confidence interval 1.01-1.16; P = 0.0274)., Conclusions: The incidence of TEE-EMIs with 3D TEE probes was relatively high in the upper or middle esophagus, anatomically close to the LA, among patients who underwent PVI. Advanced age could pose a significant risk. These findings may warrant consideration of other methods to rule out LA/LAA thrombi, especially in elderly patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Novel diagnostic and therapeutic options are urgently needed for patients with metastatic castration-resistant prostate cancer (CRPC). PSMA-617 is one of the most promising ligands that bind to prostate specific membrane antigen (PSMA), the cell surface biomarker of CRPC. Of the radiolabeled PSMA ligands developed to date, [ 68 Ga]Ga-PSMA-617 is most commonly used for PSMA positron emission tomography (PET) prior to radioligand therapy (RLT) with [ 177 Lu]Lu-PSMA-617. However, the presence of 68 Ga radioactivity (half-life 68 m) in urine at the early PET imaging time point complicates optimization of the therapeutic dose of PSMA-617 labeled with 177 Lu (half-life 6.7 d). Thus, PET imaging with the long-lived positron emitter 89 Zr (half-life 3.3 d) would be better suited in order to optimize the dose of [ 177 Lu]Lu-PSMA-617 as 89 Zr PET allows scans after excretion of the radioactive urine. Until now, PSMA-617 could not be radiolabeled with 89 Zr with high radiochemical yield due to poor incorporation of 89 Zr into 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Here we report a novel method for radiolabeling PSMA-617 with 89 Zr and the preliminary results of small-animal PET with [ 89 Zr]Zr-PSMA-617., Methods: We labeled PSMA-617 with 89 Zr in a 1:1 mixture of DMSO and HEPES buffer at 90 °C for 30 min, followed by quality control analysis by HPLC. We then determined the dissociation constant (K d ) and logD values of [ 89 Zr]Zr-PSMA-617. We obtained PET images of [ 89 Zr]Zr-PSMA-617 at 24 h in mice bearing both LNCaP (PSMA-positive) and PC-3 (PSMA-negative) tumors (N = 5). The ex vivo [ 89 Zr]Zr-PSMA-617 biodistribution was then examined separately using tissue samples of LNCaP-bearing mice at 2 h (N = 4) and 24 h (N = 4)., Results: [ 89 Zr]Zr-PSMA-617 was prepared with a radiochemical yield of 70 ± 9%. The K d value was 6.8 ± 3.5 nM. The logD value was -4.05 ± 0.20. PET images showed the highest uptake in LNCaP tumors (maximum standardized uptake value, SUV max  = 0.98 ± 0.32) and low uptake in kidneys (SUV max  = 0.18 ± 0.7) due to the absence of urine radioactivity., Conclusion: [ 89 Zr]Zr-PSMA-617 was successfully prepared using DMSO and HEPES buffer. [ 89 Zr]Zr-PSMA-617 visualized PSMA-positive LNCaP tumors in the absence of radioactive urine 24 h p.i., Advances in Knowledge and Implications for Patient Care: This method of radiolabeling PSMA-617 with 89 Zr using DMSO would be suitable for future clinical trials. Prediction of radiation dose by using [ 89 Zr]Zr-PSMA-617 leads to the safe and effective RLT with [ 177 Lu]Lu-PSMA-617., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ryota Imura and Hiroyuki Ida are employees of JFE Engineering Corporation. This research was partially conducted with research funds of the JFE Engineering Corporation. No other potential conflicts of interest relevant to this article exist., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cholinergic anti-inflammatory pathway (CAP) describes a neuronal-inflammatory reflex centered on systemic cytokine regulation by α7 nicotinic acetylcholine receptor (α7nAChR) activation of spleen-residue macrophage. However, the CAP mechanism attenuating distal tissue inflammation, inducing a low level of systemic inflammation, is lesser known. In this study, we hypothesized that CAP regulates monocyte accessibility by influencing their adhesion to endothelial cells. Using RNA-seq analysis, we identified that α1,3-Fucosyltransferase 7 (FucT-VII), the enzyme required for processing selectin ligands, was significantly downregulated by α7nAChR agonist among other cell-cell adhesion genes. The α7nAChR agonist inhibited monocytic cell line U-937 binding to P-selectin and adhesion to endothelial cells. Furthermore, α7nAChR agonist selectivity was confirmed by α7nAChR knockdown assays, showing that FUT7 inhibition and adhesion attenuation by the agonist was abolished by siRNA targeting α7nAChR encoding gene. Consistently, FUT7 knockdown inhibited the adhesive properties of U-937 and prevented them to adhere to endothelial cells. Overexpression of FUT7 also abrogated the adhesion attenuation induced by GTS-21 indicating that FUT7 inhibition was sufficient for inhibiting adhesion by α7nAChR activation. Our work demonstrated that α7nAChR activation regulates monocyte adhesion to endothelial cells through FUT7 inhibition, providing a novel insight into the CAP mechanism., Competing Interests: Declaration of competing interest Tsuyoshi Inoue reports financial support was provided by Kyowa Kirin Co Ltd., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The prognostic nutritional index (PNI) is used to assess immune and nutritional status, and is a prognostic factor for several malignant tumors. However, little evidence exists regarding the predictive impact of prognostic nutritional index (PNI) after local ablation therapy for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the value of PNI to predict recurrence and survival after operative microwave ablation in patients with early-stage HCC., Methods: This retrospective study included 341 patients who underwent operative microwave ablation for HCC in Barcelona Clinic Liver Cancer (BCLC) stage 0-A at our institute between 2007 and 2015. We analyzed overall survival (OS) and recurrence-free survival (RFS), and evaluated factors related to prognosis in multivariate Cox regression analyses., Results: The OS rates at 1, 3, 5, and 10 years after microwave ablation were 100%, 92.7%, 85.1%, and 57.5% in patients with high-PNI levels, and 96.5%, 78.2%, 59.7%, and 20.7% in patients with low-PNI levels, respectively (P < 0.001). The RFS rates at 1, 3, 5, and 10 years after microwave ablation were 96.3%, 75.2%, 55.4%, and 30.4% in patients with high-PNI levels, and 94.4%, 48.8%, 36.4%, and 13.1% in patients with low-PNI levels, respectively (P < 0.001). In multivariate analyses, preoperative PNI level was an independent prognostic factor for both OS and RFS., Conclusion: Our results revealed the preoperative PNI level was a simple and novel predictive marker of survival and recurrence after microwave ablation in patients with early-stage HCC., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021. Published by Elsevier Taiwan LLC.)

Introduction: Risk factors for seriously ill coronavirus disease 19 (COVID-19) patients have been reported in several studies. However, to date, few studies have reported simple risk assessment tools for distinguishing patients becoming severely ill after initial diagnosis. Hence, this study aimed to develop a simple clinical risk nomogram predicting oxygenation risk in patients with COVID-19 at the first triage., Methods: This retrospective study involved a chart review of the medical records of 84 patients diagnosed with COVID-19 between February 2020 and March 2021 at ten medical facilities. The patients were divided into requiring no oxygen therapy (non-severe group) and requiring oxygen therapy (severe group). Patient characteristics were compared between the two groups. We utilized univariate logistic regression analysis to confirm determinants of high risks of requiring oxygen therapy in patients with moderate COVID-19., Results: Thirty-five patients ware in severe group and forty-nine patients were in non-severe group. In comparison with patients in the non-severe group, patients in the severe group were significantly older with higher body mass index (BMI), and had a history of hypertension and diabetes. Serum blood urea nitrogen (BUN), lactic acid dehydrogenase (LDH), and C-reactive protein (CRP) levels were significantly higher in the severe group. Multivariate analysis showed that older age, higher BMI, and higher BUN levels were significantly associated with oxygen requirements., Conclusions: This study demonstrated that age, BMI, and BUN were independent risk factors in the moderate-to-severe COVID-19 group. Elderly patients with higher BMI and BUN require close monitoring and early treatment initiation., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: We repaired aortic coarctation and interrupted aortic arch with extended end-to-end anastomosis (EAA) through median sternotomy and performed lesser curvature augmentation with a pulmonary autograft patch (PAP) in selected patients with a long gap between anastomotic sites. We reviewed these outcomes and geometric implications., Methods: All neonates and infants with biventricular morphology who underwent aortic arch reconstruction through median sternotomy between 2005 and 2019 were evaluated. Aortic arch geometry was analyzed with computed tomography routinely performed before and after surgery from 2009 on., Results: There were 91 consecutive patients (median age, 1.2 months). Ten patients received PAP. One early death and no late deaths were noted. Overall survival was 98.9% at 10 years. Two left bronchomalacia and 1 recoarctation occurred in patients with EAA. Freedom from recoarctation was 97.4% at 10 years. We examined 68 patients with computed tomography. We used PAP in patients with a significantly longer gap between anastomotic sites indexed by the square root of the body surface area; its cutoff value was 29.0 mm/m (area under the curve, 0.86 mm/m). The PAP created a significantly greater arch angle (median, 91° versus 83°) and arch/descending diameter ratio (median, 1.2 versus 1.0) and preserved the arch width indexed by the square root of the body surface area (median, before surgery: 35.7 versus 34.4 mm/m; after surgery: 36.5 versus 29.9mm/m), compared with EAA., Conclusions: Aortic arch reconstruction with the current combined strategy provides satisfactory outcomes. Guided by geometric analysis, lesser curvature augmentation can be applied to patients who might experience recoarctation or airway compression with a directly anastomosed aortic arch., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to evaluate the characteristics, quality, and related factors of the Japanese Clinical Practice Guidelines (CPGs) published in recent years., Study Design and Setting: In this cross-sectional, meta-epidemiological study, we conducted a Google search for CPGs published by 30 Japanese medical societies that are the basis for training specialties between 2018 and 2019. We used the Appraisal of Guidelines for Research & Evaluation II (AGREE II) tool and the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement to evaluate the quality., Results: We included 53 systematic review-based CPGs. The median score was 0.54 (IQR, 0.38-0.62) for Stakeholder involvement, 0.57 (IQR, 0.51-0.66) in Rigor of development, 0.33 (IQR 0.21-0.46) in Applicability, and 0.63 (IQR 0.46-0.73) in Editorial independence. The number of guideline developers/clinical question ratio (odds ratio [OR]: 4.14, 95% confidence interval [CI]: 1.97, 8.70) and the adopted guideline development methods (OR: 3.69, 95% CI: 1.14, 12.0) were significantly related to the Rigor of development., Conclusion: The quality of Japanese CPGs published in recent years remains low. Our study suggests that increasing contributors and adopting the latest guideline development methods at the beginning of the project may improve the quality of the Japanese CPGs., (Copyright © 2021 Elsevier Inc. All rights reserved.)