Intratracheal trimerized nanobody cocktail administration suppresses weight loss and prolongs survival of SARS-CoV-2 infected mice

新型コロナウイルスを中和するアルパカ抗体 --マウス実験で有効性を確認--. 京都大学プレスリリース. 2023-02-17.BACKGROUND: SARS-CoV-2 Omicron variants are highly resistant to vaccine-induced immunity and human monoclonal antibodies. METHODS: We previously reported that two nanobodies, P17 and P86, potently neutralize SARS-CoV-2 VOCs. In this study, we modified these nanobodies into trimers, called TP17 and TP86 and tested their neutralization activities against Omicron BA.1 and subvariant BA.2 using pseudovirus assays. Next, we used TP17 and TP86 nanobody cocktail to treat ACE2 transgenic mice infected with lethal dose of SARS-CoV-2 strains, original, Delta and Omicron BA.1. RESULTS: Here, we demonstrate that a novel nanobody TP86 potently neutralizes both BA.1 and BA.2 Omicron variants, and that the TP17 and TP86 nanobody cocktail broadly neutralizes in vitro all VOCs as well as original strain. Furthermore, intratracheal administration of this nanobody cocktail suppresses weight loss and prolongs survival of human ACE2 transgenic mice infected with SARS-CoV-2 strains, original, Delta and Omicron BA.1. CONCLUSIONS: Intratracheal trimerized nanobody cocktail administration suppresses weight loss and prolongs survival of SARS-CoV-2 infected mice

Association between Body Mass Index and Prognosis of Patients Hospitalized With Heart Failure

The prognostic implications of very low body mass index (BMI) values remain unclear in patients with acute decompensated heart failure (ADHF). This study aimed to investigate the prognostic impact of BMI classification based on the World Health Organization criteria in patients with ADHF. Among 3509 patients with ADHF and available BMI data at discharge in 19 participating hospitals in Japan between October 2014 and March 2016, the study population was divided into five groups; (1) Severely underweight: BMI < 16 kg/m², (2) Underweight: BMI ≥ 16 kg/m² and < 18.5 kg/m², (3) Normal weight: BMI ≥ 18.5 kg/m² and < 25 kg/m², (4) Overweight: BMI ≥ 25 kg/m² and < 30 kg/m² (5) Obese: BMI ≥ 30 kg/m². The primary outcome measure was all-cause death. The median follow-up duration was 471 days, with 96.4% follow up at 1-year. The cumulative 1-year incidence of all-cause death was higher in underweight groups, and lower in overweight groups (Severely underweight: 36.3%, Underweight: 23.9%, Normal weight: 14.4%, Overweight: 7.9%, and Obese: 9.0%, P < 0.001). After adjusting confounders, the excess mortality risk remained significant in the severely underweight group (HR, 2.32; 95%CI, 1.83–2.94; P < 0.001), and in the underweight group (HR, 1.31; 95%CI, 1.08–1.59; P = 0.005) relative to the normal weight group, while the lower mortality risk was no longer significant in the overweight group (HR, 0.82; 95%CI, 0.62–1.10; P = 0.18) and in the obese group (HR, 1.09; 95%CI, 0.65–1.85; P = 0.74). Very low BMI was associated with a higher risk for one-year mortality after discharge in patients with ADHF

Association between changes in loop diuretic dose and outcomes in acute heart failure

AIMS: Little is known about the association between the starting of or dose changes in loop diuretics during acute heart failure (AHF) hospitalization and post-discharge outcomes. We investigated the clinical impact of starting loop diuretics and changing the loop diuretics dose during hospitalization on post-discharge outcomes. METHODS AND RESULTS: From the Kyoto Congestive Heart Failure registry, 3665 consecutive patients hospitalized for HF and discharged alive were included in this study. We analysed 1906 patients without loop diuretics on admission and were discharged alive and 1759 patients who received loop diuretics on admission and were discharged alive. The primary outcome measure was all-cause death. Of the 1906 patients without loop diuretics on admission, 1366 (71.7%) patients started loop diuretics during the index AHF hospitalization. Starting loop diuretics was not associated with lower post-discharge mortality [adjusted hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.68-1.25]. Of the 1759 patients who received loop diuretics on admission, loop diuretic dose was decreased in 23.8%, unchanged in 44.6%, and increased in 31.6% of the patients. Changes in the dose at discharge compared with no change in dose were not associated with lower risk of post-discharge mortality (decrease relative to no change: adjusted HR 0.98, 95% CI 0.76-1.28; increase relative to no change: adjusted HR 1.00, 95% CI 0.78-1.27). Compared with no loop diuretics at discharge, a loop diuretics dose of ≥80 mg at discharge was associated with higher post-discharge mortality risk. CONCLUSIONS: In patients with AHF, we found no association between the starting of loop diuretics and post-discharge outcomes and between dose changes and post-discharge outcomes

Coronary angiography in patients with acute heart failure: from the KCHF registry

[Aims] Little is known about the characteristics and outcomes of patients who undergo coronary angiography during heart failure (HF) hospitalization, as well as those with coronary stenosis, and those who underwent coronary revascularization. [Methods and results] We analysed 2163 patients who were hospitalized for HF without acute coronary syndrome or prior HF hospitalization. We compared patient characteristics and 1 year clinical outcomes according to (i) patients with versus without coronary angiography, (ii) patients with versus without coronary stenosis, and (iii) patients with versus without coronary revascularization. The primary outcome measure was the composite of all-cause death or HF hospitalization. Coronary angiography was performed in 37.0% of patients. In the multivariable logistic regression analysis, factors independently associated with coronary angiography were age < 80 years [adjusted odds ratio (OR) = 1.76, 95% confidence interval (CI) = 1.41–2.20, P < 0.001], men (adjusted OR = 1.28, 95% CI = 1.03–1.59, P = 0.02), diabetes (adjusted OR = 1.27, 95% CI = 1.02–1.60, P = 0.04), no atrial fibrillation or flutter (adjusted OR = 1.45, 95% CI = 1.17–1.82, P < 0.001), no prior device implantation (adjusted OR = 1.81, 95% CI = 1.13–2.91, P = 0.01), current smoking (adjusted OR = 1.40, 95% CI = 1.05–1.87, P = 0.02), no cognitive dysfunction (adjusted OR = 1.90, 95% CI = 1.34–2.69, P < 0.001), ambulatory status (adjusted OR = 2.89, 95% CI = 2.03–4.10, P < 0.001), HF with reduced ejection fraction (adjusted OR = 1.55, 95% CI = 1.24–1.93, P < 0.001), estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 (adjusted OR = 1.93, 95% CI = 1.45–2.58, P < 0.001), no anaemia (adjusted OR = 1.27, 95% CI = 1.02–1.59, P = 0.04), and no prescription of β-blockers prior to admission (adjusted OR = 1.32, 95% CI = 1.03–1.68, P = 0.03). Patients who underwent coronary angiography had a lower risk of the primary outcome [adjusted hazard ratio (HR) = 0.70, 95% CI = 0.58–0.85, P < 0.001]. Among the patients who underwent coronary angiography, those with coronary stenosis (38.9%) did not have lower risk of the primary outcome measure than those without coronary stenosis (adjusted HR = 0.93, 95% CI = 0.65–1.32, P = 0.68). Among the patients with coronary stenosis, those with coronary revascularization (54.3%) did not have higher risk of the primary outcome measure than those without coronary revascularization (adjusted HR = 1.36, 95% CI = 0.84–2.21, P = 0.22). [Conclusions] In patients with acute HF, patients who underwent coronary angiography had a lower risk of clinical outcomes and were significantly different from those who did not undergo coronary angiography

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

臓器チップ技術を用いて新型コロナウイルスが血管へ侵入するメカニズムを解明 --Claudin-5発現抑制による呼吸器の血管内皮バリア破壊--. 京都大学プレスリリース. 2022-09-22.A study using an organ-on-a-chip reveals a mechanism of SARS-CoV-2 invasion into blood vessels --Disruption of vascular endothelial barrier in respiratory organs by decreasing Claudin-5 expression--. 京都大学プレスリリース. 2022-09-27.In the initial process of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects respiratory epithelial cells and then transfers to other organs the blood vessels. It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism. In this study, we investigated the effect of SARS-CoV-2 on the endothelial barrier using an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin–mediated adherens junctions. Consistently, the gene and protein expression levels of CLDN5 in the lungs of a patient with COVID-19 were decreased. CLDN5 overexpression or Fluvastatin treatment rescued the SARS-CoV-2–induced respiratory endothelial barrier disruption. We concluded that the down-regulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2–induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a therapeutic strategy against COVID-19

Ischemic Stroke in Acute Decompensated Heart Failure: From the KCHF Registry

[Background] Heart failure (HF) is a known risk factor for ischemic stroke, but data regarding ischemic stroke during hospitalization for acute decompensated HF (ADHF) are limited. [Methods and Results] We analyzed the data from a multicenter registry (Kyoto Congestive Heart Failure [KCHF] Registry) that enrolled 4056 consecutive patients with ADHF in Japan (mean age, 78 years; men, 2238 patients [55%]; acute coronary syndrome [ACS], 239 patients [5.9%]). We investigated the incidence and predictors of ischemic stroke during hospitalization for ADHF. During the hospitalization, 63 patients (1.6%) developed ischemic stroke. The median interval from admission to the onset of ischemic stroke was 7 [interquartile range: 2–14] days, and the most common underlying cause was cardioembolism (64%). Men (OR, 1.87; 95%CI, 1.11–3.24), ACS (OR, 2.31; 95%CI, 1.01–4.93), absence of prior HF hospitalization (OR, 2.21; 95%CI, 1.24–4.21), and high B‐type natriuretic peptide (BNP)/N‐terminal proBNP (NT‐proBNP) levels (above the median) at admission (OR, 3.15; 95%CI, 1.84–5.60) were independently associated with ischemic stroke. In patients without ACS, the independent risk factors for ischemic stroke were fully consistent with those in the main analysis. Higher quartiles of BNP/NT‐proBNP levels were significantly associated with higher incidence of ischemic stroke (P for trend, <0.001). Patients with ischemic stroke showed higher in‐hospital mortality, longer length of hospital stay, and poorer functional status at discharge. [Conclusions] During hospitalization for ADHF, 1.6% of the patients developed ischemic stroke. Men, ACS, absence of prior HF hospitalization, and high BNP/NT‐proBNP levels at admission were independently associated with ischemic stroke

VaTEST III : validation of 8 potential super-earths from TESS data

Funding: The ULiege’s contribution to SPECULOOS has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) (grant Agreement n◦ 336480/SPECULOOS). This research is in part funded by the European Union’s Horizon 2020 research and innovation programme (grants agreements n◦ 803193/BEBOP), and from the Science and Technology Facilities Council (STFC; grant n◦ ST/S00193X/1, and ST/W000385/1).NASA’s all-sky survey mission, the Transiting Exoplanet Survey Satellite (TESS), is specifically engineered to detect exoplanets that transit bright stars. Thus far, TESS has successfully identified approximately 400 transiting exoplanets, in addition to roughly 6 000 candidate exoplanets pending confirmation. In this study, we present the results of our ongoing project, the Validation of Transiting Exoplanets using Statistical Tools (VaTEST). Our dedicated effort is focused on the confirmation and characterisation of new exoplanets through the application of statistical validation tools. Through a combination of ground-based telescope data, high-resolution imaging, and the utilisation of the statistical validation tool known as TRICERATOPS, we have successfully discovered eight potential super-Earths. These planets bear the designations: TOI-238b (1.61 +0.09−0.10 R ⊕ ), TOI-771b (1.42 +0.11−0.09 R ⊕ ), TOI-871b (1.66 +0.11−0.11 R ⊕ ), TOI-1467b (1.83 +0.16−0.15 R ⊕ ), TOI-1739b (1.69 +0.10−0.08 R ⊕ ), TOI-2068b (1.82 +0.16−0.15 R ⊕ ), TOI-4559b (1.42 +0.13−0.11 R ⊕ ), and TOI-5799b (1.62 +0.19−0.13 R ⊕ ). Among all these planets, six of them fall within the region known as ‘keystone planets’, which makes them particularly interesting for study. Based on the location of TOI-771b and TOI-4559b below the radius valley we characterised them as likely super-Earths, though radial velocity mass measurements for these planets will provide more details about their characterisation. It is noteworthy that planets within the size range investigated herein are absent from our own solar system, making their study crucial for gaining insights into the evolutionary stages between Earth and Neptune.Peer reviewe

Geodemographics profiling of influenza A and B virus infections in community neighborhoods in Japan

<p>Abstract</p> <p>Background</p> <p>The spread of influenza viruses in a community are influenced by several factors, but no reports have focused on the relationship between the incidence of influenza and characteristics of small neighborhoods in a community. We aimed to clarify the relationship between the incidence of influenza and neighborhood characteristics using GIS and identified the type of small areas where influenza occurs frequently or infrequently.</p> <p>Methods</p> <p>Of the 19,077 registered influenza cases, we analyzed 11,437 influenza A and 5,193 influenza B cases that were diagnosed by the rapid antigen test in 66-86 medical facilities in Isahaya City, Japan, from 2004 to 2008. We used the commercial geodemographics dataset, Mosaic Japan to categorize and classify each neighborhood. Furthermore, we calculated the index value of influenza in crude and age adjusted rates to evaluate the incidence of influenza by Mosaic segmentation. Additional age structure analysis was performed to geodemographics segmentation to explore the relationship between influenza and family structure.</p> <p>Results</p> <p>The observed number of influenza A and B patients in the neighborhoods where young couples with small children lived was approximately 10-40% higher than the expected number (p < 0.01) during all seasons. On the contrary, the number of patients in the neighborhoods of the aging society in a rural area was 20-50% lower than the expected number (p < 0.01) during all seasons. This tendency was consistent after age adjustment except in the case of influenza B, which lost significance in higher incidence areas, but the overall results indicated high transmission of influenza in areas where young families with children lived.</p> <p>Conclusions</p> <p>Our analysis indicated that the incidence of influenza A and B in neighborhood groups is related to the family structure, especially the presence of children in households. Simple statistical analysis of geodemographics data is an effective method to understand the differences in the incidence of influenza among neighborhood groups, and it provides a valuable basis for community strategies to control influenza.</p

ナマ シラス ノ セイ ショク ニヨル カンセン ガ ウタガワレタ クジラ フクショクモンジョウチュウ ショウ ノ 1レイ

埼玉県在住の男性・64 歳.2012 年11 月初旬,近医で日本海裂頭条虫症の診断を受け,駆虫目的で本院消化器内科を紹介受診.外来で駆虫治療したところ,全長約250 cm の白色紐状で,全体的に肉厚感のある虫体を排出した.虫体は形態学的特徴より日本海裂頭条虫ではなく,クジラ複殖門条虫が強く疑われたため,遺伝子解析を行った.PCR によって増幅されたcytochrome c oxidase subunit 1 遺伝子(cox1)の全長塩基配列を解析したところ,既知のクジラ複殖門条虫の塩基配列と99%の相同性を示したことから,本症例はクジラ複殖門条虫症と確定した.該当患者は,便に白色紐状物が混入する2&#12316;3 か月前に,生シラスを生食しており,これが感染源となった可能性が高いと考えられた.We have reported a case of infection with whale tapeworm,Diplogonoporus balaenopterae, in Dokkyo MedicalUniversity Hospital. The patient, a 64-year-old Japanesemale, living in Saitama Prefecture was admitted to our hospitalon Nov. 1st 2012, owing to pieces of tapeworm beingdischarged. He was treated with Biltricide&reg; (20 mg/kg)and Magcorol P&reg;( 100 g) in the hospital and he expelled atapeworm about 250 cm, in length along with the scolex afterabout 2 hours of treatment. Based on the morphologicalfeatures of the strobila and the scolex we strongly suspectedthat the tapeworm belongs to the genus Diplogonoporus.To identify the species of the discharged tapeworm, thecomplete cox1 gene was amplified by PCR and the nucleotidesequence was analyzed. The sequence showed 99 %homology against those from D. balaenopterae. From theseresults the patient was diagnosed as a diplogonoporiasiscaused by D. balaenopterae, whale tapeworm. We could notfind any proglottides of tapeworm nor eggs in stools whenwe performed follow up medical examinations three monthsafter treatment. Therefore it can be concluded that the patientwas cured of this disease. In most cases the infectionsource of the whale tapeworm to humans is reported ascoming from marine fish such as sardines and bonitos. Thepatient had frequently consumed various kinds of raw marinefish, and we suspect that the infection source can beattributed to eating raw whitebait