Relationship Between Cryoprotectant Potential and Protein Hydration in Aqueous Zwitterionic Solutions.

The cryoprotectant potential of 3-(1-(2-(2-methoxyethoxy)ethyl)imidazol-3-io)butane-1-carboxylate (OE2imC3C) for proteins necessitates assessment to elucidate its relationship with protein hydration. To reveal this relationship, we assessed the protein stability (pre-freezing and post-thawing) and melting behavior in dilute aqueous protein-OE2imC3C solutions containing varying mole fractions (x) of OE2imC3C (x = 0, 7.7 × 10-3, and 1.7 × 10-2) using Fourier-transform infrared (FTIR) and near-UV circular dichroism (near-UV CD) spectroscopy and differential scanning calorimetry (DSC) techniques. Following freezing/thawing using a deep freezer, protein stability in aqueous OE2imC3C solutions (x = 1.7 × 10-2) preserved the folded state owing to the protein-OE2imC3C interaction, whereas stability at x = 7.7 × 10-3 was reduced. These results indicate that the protein cryoprotectant potential in aqueous OE2imC3C solutions at x = 1.7 × 10-2 is higher than that at x = 7.7 × 10-3, owing to the preferential binding of OE2imC3C with proteins.

Relationship Between Quantitative Tracheal Geometry and Clinical Course in Various Types of Vascular Ring.

To investigate the relationship between quantitative tracheal geometry and clinical course among various types of vascular ring and to identify factors correlating with symptom presentation. Patients with vascular ring diagnosed between April 2010 and December 2022 were included. All the patients were classified as type 1 (complete double aortic arch); type 2 (incomplete double aortic arch); type 3 (circumflex aorta); type 4 (right aortic arch and aberrant left subclavian artery with a left retroesophageal diverticulum of Kommerell); or type 5 (mirror-imaged right aortic arch with retroesophageal aortic diverticulum). Their clinical characteristics and quantitative variables on computed tomography (CT) were compared. Of the 50 patients enrolled, those with type 1 tended to have a smaller luminal tracheal diameter at the level of the ring. The median symptom-free survival time was shortest in this group (16.0 days [95% confidence interval (CI): 9.4-51.0]), followed by type 3 (138.0 days [95% CI: 0.0-851.4]). Type 1 (hazard ratio [HR]: 9.0; 95% CI: 2.3-35.0; P = 0.001), type 3 (HR: 4.2; 95% CI: 1.4-13.2; P = 0.013), and the percentage of tracheal narrowing in the anteroposterior projection (HR: 0.87; 95% CI: 0.78-0.96; P = 0.008) were significantly associated with symptom presentation in the time-dependent course. The aortic arch encircling the entire circumference in type 1 and high-pressure vasculature in front of the vertebral body in types 1 and 3 may contribute to raising the risk of symptom presentation.

Characterization of proinflammatory cytokines profile during acute SARS-CoV-2 infection in people with human immunodeficiency virus.

Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were assessed in people with HIV (PWH) with effective cART. There were no significant differences in any of the tested cytokines between COVID-19 severity in PWH, while most of them were significantly higher in individuals with severe disease in HIV-uninfected individuals, suggesting that excess cytokines release by hyper-inflammatory responses does not occur in severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, especially between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that PWH are in an enhanced inflammatory state. Loss of the several inter-cytokine correlations were observed in in vitro LPS stimuli-driven cytokines production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially due to the underlying inflammatory state and/or impairment of innate immune cells.

A predictive model for HIV-related lymphoma.

OBJECTIVES: To address the paucity of HIV-related lymphoma (HRL)-specific prognostic scores for the Japanese population by analyzing domestic cases of HRL and constructing a predictive model. DESIGN: A single-center retrospective study coupled with a review of case reports of HRL. METHODS: We reviewed all patients with HRL treated at our hospital between 2007 and 2023 and conducted a comprehensive search for case reports of HRL from Japan using public databases. A multivariate analysis for overall survival (OS) was performed using clinical parameters, leading to the formulation of the HIV-Japanese Prognostic Index (HIV-JPI). RESULTS: A total of 19 patients with HRL were identified in our institution, whereas the literature review yielded 44 cases. In the HIV-JPI, a weighted score of 1 was assigned to the following factors: age at least 45 years, HIV-RNA at least 8.0×10 4  copies/ml, Epstein-Barr virus-encoded small RNA positivity, and Ann Arbor classification stage IV. The overall score ranged from 0 to 4. We defined the low-risk group as scores ranging from 0 to 2 and the high-risk group as scores ranging from 3 to 4. The 3-year OS probability of the high-risk group [30.8%; 95% confidence interval (CI): 9.5-55.4%) was significantly poorer than that of the low-risk group (76.8%; 95% CI: 52.8-89.7%; P  < 0.01). CONCLUSION: This retrospective analysis established pivotal prognostic factors for HRL in Japanese patients. The HIV-JPI, derived exclusively from Japanese patients, highlights the potential for stratified treatments and emphasizes the need for broader studies to further refine this clinical prediction model.

Sucrose Solution Ingestion Exacerbates Dinitrofluorobenzene-Induced Allergic Contact Dermatitis in Rats.

Allergic dermatitis is a skin disease with growing prevalence worldwide that has been associated with diets high in fats and sugars. Regular consumption of sucrose-containing beverages may increase the risk for several health problems, including allergic diseases and particularly asthma, but the association between sucrose consumption and allergic dermatitis is understudied. We investigated the effects of sucrose solution intake on allergic contact dermatitis in rats and found early exacerbation of 2,4-dinitrofluorobenzene (DNFB)-induced disease symptoms and altered composition of the gut microbiota after 14 d of intake. The levels of short-chain fatty acids-produced by fermentation by the intestinal microbiota-were not affected in the cecal contents and feces but decreased in the blood; this effect was especially notable for acetate. To restore blood acetate concentrations, triacetin was mixed with a 10% sucrose solution and fed to the rat model. This strategy prevented the early exacerbation of DNFB-induced symptoms. The decreased absorption of short-chain fatty acids from the intestinal lumen was not linked to the decreased expression of short-chain fatty acid transporters in the small intestine; instead, the mechanism involves a reduction in the sodium concentration in the intestinal lumen due to increased expression of sodium-glucose transporter 1 (SGLT1).

Disseminated Mycobacterium kansasii infection due to surgical site infection following allogeneic hematopoietic stem cell transplantation: A case report and literature review.

This report details a rare case of surgical site infection (SSI) caused by Mycobacterium kansasii following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a 53-year-old patient with IgA-κ type multiple myeloma. After undergoing multiple chemotherapy regimens and two stem cell transplants, the patient developed an SSI 31-month post-transplantation, manifesting as an intracranial abscess at the site of a previous craniotomy. M. kansasii was isolated from the drainage fluid, marking this instance as a unique case in the literature of nontuberculous mycobacteria (NTM) infection post-allo-HSCT with such a delayed onset. The patient's treatment included targeted antimicrobial therapy based on susceptibility testing, resulting in eventual resolution of the infection, although the patient later succumbed to multiple myeloma relapse. This case underscores the critical need to consider NTM infections in the differential diagnosis of persistent fevers and SSIs in immunocompromised patients, particularly those with chronic graft-versus-host disease. It highlights the importance of early diagnostic and therapeutic interventions to manage these infections effectively. This report contributes to the limited but growing body of literature on NTM infections post-allo-HSCT and emphasizes the need for vigilance in monitoring postoperative patients, especially those with prolonged immunosuppression.

Pioneering cord blood transplantation in relapsed/refractory HIV-related lymphoma: a case study with concurrent intramuscular antiretroviral therapy.

A 44-year-old HIV-positive man diagnosed with diffuse large B-cell lymphoma in 2021 achieved complete remission with six cycles of R-CHOP therapy but had a relapse in November 2022. ESHAP therapy failed to induce remission, leading to complete remission with four cycles of Pola-BR therapy. Post-failure of autologous stem cell harvest, cord blood transplantation (CBT) was performed in June 2023. Notably, this case used recently approved intramuscular antiretroviral therapy (ART) with cabotegravir and rilpivirine, addressing gastrointestinal complications during CBT. This innovative use of intramuscular ART in the treatment of malignancy represents a first in the field, offering a pioneering approach to HIV-related lymphoma.

Protein Cryoprotectant Ability of the Aqueous Zwitterionic Solution.

Protein cryopreservation is important for the long-term storage of unstable proteins. Recently, we found that N-acetylglucosaminyltransferase-V (GnT-V) can be cryopreserved in a deep freezer without temperature control using a dilute binary aqueous solution of 3-(1-(2-(2-methoxyethoxy)ethyl)imidazol-3-io)butane-1-carboxylate (OE2imC3C) [10 wt %, mole fraction of solute (x) = 7.75 × 10-3], an artificial zwitterion. However, it is unclear which solvent properties are required in these media to preserve unstable proteins, such as GnT-V. In this study, we investigated the melting phenomena and solution structure of dilute binary aqueous OE2imC3C solutions [x = 0-2.96 × 10-2 (0-30 wt %)] using differential scanning calorimetry (DSC) and Raman and Fourier transform infrared (FTIR) spectroscopies combined with molecular dynamics (MD) simulation to compare the cryoprotectant ability of OE2imC3C with two general cryoprotectants (CPAs), glycerol and dimethyl sulfoxide. DSC results indicated that aqueous OE2imC3C solutions can be melted at lower temperatures with less energy than the control CPA solution, with increasing x, primarily due to OE2imC3C having a higher content of unfrozen water molecules. Moreover, Raman and FTIR results showed that the high content of unfrozen water molecules in aqueous OE2imC3C solutions was due to the hydration around the ionic parts (the COO- group and imidazolium ring) and the OCH2CH2O segment. In addition, the MD simulation results showed that there were fewer structured water molecules around the OCH2CH2O segment than the hydration water molecules around the ionic parts. These solvent properties suggest that dilute aqueous OE2imC3C solutions are effective in preventing freezing, even in a deep freezer. Therefore, this medium has the potential to act as a novel cryoprotectant for proteins in biotechnology and biomedical fields.

Infectious virus shedding duration reflects secretory IgA antibody response latency after SARS-CoV-2 infection.

Infectious virus shedding from individuals infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is used to estimate human-to-human transmission risk. Control of SARS-CoV-2 transmission requires identifying the immune correlates that protect infectious virus shedding. Mucosal immunity prevents infection by SARS-CoV-2, which replicates in the respiratory epithelium and spreads rapidly to other hosts. However, whether mucosal immunity prevents the shedding of the infectious virus in SARS-CoV-2-infected individuals is unknown. We examined the relationship between viral RNA shedding dynamics, duration of infectious virus shedding, and mucosal antibody responses during SARS-CoV-2 infection. Anti-spike secretory IgA antibodies (S-IgA) reduced viral RNA load and infectivity more than anti-spike IgG/IgA antibodies in infected nasopharyngeal samples. Compared with the IgG/IgA response, the anti-spike S-IgA post-infection responses affected the viral RNA shedding dynamics and predicted the duration of infectious virus shedding regardless of the immune history. These findings highlight the importance of anti-spike S-IgA responses in individuals infected with SARS-CoV-2 for preventing infectious virus shedding and SARS-CoV-2 transmission. Developing medical countermeasures to shorten S-IgA response time may help control human-to-human transmission of SARS-CoV-2 infection and prevent future respiratory virus pandemics.

Frequency of subclinical interstitial lung disease in COVID-19 autopsy cases: potential risk factors of severe pneumonia.

Risk factors of severe coronavirus disease 2019 (COVID-19) have been previously reported; however, histological risk factors have not been defined thus far. The aim of this study was to clarify subclinical hidden interstitial lung disease (ILD) as a risk factor of severe pneumonia associated with COVID-19. We carefully examined autopsied lungs and chest computed tomography scanning (CT) images from patients with COVID-19 for interstitial lesions and then analyzed their relationship with disease severity. Among the autopsy series, subclinical ILD was found in 13/27 cases (48%) in the COVID-19 group, and in contrast, 8/65 (12%) in the control autopsy group (p = 0.0006; Fisher's exact test). We reviewed CT images from the COVID-19 autopsy cases and verified that subclinical ILD was histologically detectable in the CT images. Then, we retrospectively examined CT images from another series of COVID-19 cases in the Yokohama, Japan area between February-August 2020 for interstitial lesions and analyzed the relationship to the severity of COVID-19 pneumonia. Interstitial lesion was more frequently found in the group with the moderate II/severe disease than in the moderate I/mild disease (severity was evaluated according to the COVID-19 severity classification system of the Ministry of Health, Labor, and Welfare [Japan]) (moderate II/severe, 11/15, 73.3% versus moderate I/mild, 108/245, 44.1%; Fisher exact test, p = 0.0333). In conclusion, it was suggested that subclinical ILD could be an important risk factor for severe COVID-19 pneumonia. A benefit of these findings could be the development of a risk assessment system using high resolution CT images for fatal COVID-19 pneumonia.

Clinical Characteristics of Corynebacterium ulcerans Infection, Japan.

Corynebacterium ulcerans is a closely related bacterium to the diphtheria bacterium C. diphtheriae, and some C. ulcerans strains produce toxins that are similar to diphtheria toxin. C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. Infection with C. ulcerans can cause respiratory or nonrespiratory symptoms in patients. Recently, the microorganism has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in Japan. To clarify the overall clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection, we analyzed 34 cases of C. ulcerans that occurred in Japan during 2001-2020. During 2010-2020, the incidence rate of C. ulcerans infection increased markedly, and the overall mortality rate was 5.9%. It is recommended that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection.

Clinical Characteristics and Outcomes Among Travelers With Severe Dengue : A GeoSentinel Analysis.

BACKGROUND: Dengue virus is a flavivirus transmitted by Aedes mosquitoes and is an important cause of illness worldwide. Data on the severity of travel-associated dengue illness are limited. OBJECTIVE: To describe the epidemiology, clinical characteristics, and outcomes among international travelers with severe dengue or dengue with warning signs as defined by the 2009 World Health Organization classification (that is, complicated dengue). DESIGN: Retrospective chart review and analysis of travelers with complicated dengue reported to GeoSentinel from January 2007 through July 2022. SETTING: 20 of 71 international GeoSentinel sites. PATIENTS: Returning travelers with complicated dengue. MEASUREMENTS: Routinely collected surveillance data plus chart review with abstraction of clinical information using predefined grading criteria to characterize the manifestations of complicated dengue. RESULTS: Of 5958 patients with dengue, 95 (2%) had complicated dengue. Eighty-six (91%) patients had a supplemental questionnaire completed. Eighty-five of 86 (99%) patients had warning signs, and 27 (31%) were classified as severe. Median age was 34 years (range, 8 to 91 years); 48 (56%) were female. Patients acquired dengue most frequently in the Caribbean (n = 27 [31%]) and Southeast Asia (n = 21 [24%]). Frequent reasons for travel were tourism (46%) and visiting friends and relatives (32%). Twenty-one of 84 (25%) patients had comorbidities. Seventy-eight (91%) patients were hospitalized. One patient died of nondengue-related illnesses. Common laboratory findings and signs were thrombocytopenia (78%), elevated aminotransferase (62%), bleeding (52%), and plasma leakage (20%). Among severe cases, ophthalmologic pathology (n = 3), severe liver disease (n = 3), myocarditis (n = 2), and neurologic symptoms (n = 2) were reported. Of 44 patients with serologic data, 32 confirmed cases were classified as primary dengue (IgM+/IgG-) and 12 as secondary (IgM-/IgG+) dengue. LIMITATIONS: Data for some variables could not be retrieved by chart review for some patients. The generalizability of our observations may be limited. CONCLUSION: Complicated dengue is relatively rare in travelers. Clinicians should monitor patients with dengue closely for warning signs that may indicate progression to severe disease. Risk factors for developing complications of dengue in travelers need further prospective study. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention, International Society of Travel Medicine, Public Health Agency of Canada, and GeoSentinel Foundation.

Left bronchial compression after an arterial switch operation with the LeCompte maneuver for transposition of the great arteries: A case report and literature review.

Left bronchial compression is a rarely reported, postoperative complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries. Postoperative neopulmonary root dilatation and the anterior-posterior, anatomical relationship of the great vessels may cause this condition. Hypoxic pulmonary vasoconstriction may mask the condition even if the left bronchus has been severely obstructed. The apparent inconsistency between the abnormally decreased pulmonary blood flow and the absence of any irregularities in the vascular structure that might account for it suggested hypoxic pulmonary vasoconstriction to be the cause. We present herein a case of left bronchial compression presenting malacia after an arterial switch operation with the LeCompte maneuver and also present a review of seven, other, reported cases. Learning objectives: Left bronchial compression is a rare complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries and is possibly caused by root dilatation and the anatomical relationship of the great vessels. Hypoxic pulmonary vasoconstriction may mask the condition.

Earliest histopathological changes in COVID-19 pneumonia with comprehensive gene expression analyses: A case series study.

AIMS: In COVID-19 pneumonia, early detection and appropriate treatment are essential to prevent severe exacerbation. Therefore, it is important to understand the initiating events of COVID-19 pneumonia. However, at present, the literature about early stage disease has been very limited. Here, we investigated the earliest histopathological changes and gene expression profiles associated with COVID-19 pneumonia. METHODS AND RESULTS: We carefully examined 25 autopsied cases with different clinical courses. Dilation of capillaries and edematous thickening of the alveolar septa were found even in areas that macroscopically looked almost normal. Pneumocytes, histocytes/macrophages, and vascular endothelial cells were immunohistochemically positive for tissue factor, which is an important early responder to tissue injuries. Comprehensive gene expression analyses revealed that those lesions presented differential profiles compared to those of control lungs and were associated with a significant upregulation of the lysosomal pathway. CONCLUSIONS: Alveolar capillary dilation and edematous thickening may be the earliest histopathological change detected in COVID-19 pneumonia. Intensive investigations of such lesions may lead to an understanding of the initiating event of not only COVID-19 pneumonia but also of general diffuse alveolar damage.

Epidemiological trends of traveler's diarrhea in Japan: An analysis of imported infectious disease registry data from 2017-2022.

Traveler's diarrhea (TD) is a global problem, and identifying the causative organisms of TD is important for adequate treatment. Therefore, this study retrospectively analyzed TD cases in patients who returned to Japan after traveling abroad to determine the causative organisms by travel region. We included patients with a final diagnosis of TD registered in the Japan Registry for Infectious Diseases from Abroad database from September 25, 2017, to September 1, 2022, from 14 medical institutions. A total of 919 patients were analyzed; the causative TD pathogen was identified in 188 cases (20%), of which 154 were caused by diarrheagenic bacteria, the most common being Campylobacter spp. (64%). A 2.2 mg/dL C-reactive protein concentration cutoff value had some predictive ability for bacterial TD (negative predictive value, 89%). Therefore, the C-reactive protein level may help rule out bacterial diarrhea and prevent unnecessary antimicrobial administration when patients cannot provide a stool specimen.

Pericardial effusion after congenital heart surgery.

Objective: Pericardial effusion after cardiac surgery remains an important cause of morbidity and mortality. We describe the risk factors of pericardial effusion after congenital heart surgery through analyzing data from a nationwide, multi-institutional registry. Methods: The Japan Congenital Cardiovascular Surgery Database, which reflects routine clinical care in Japan, was used for this retrospective cohort study. Multivariable regression analysis was done after univariable comparison of patients with pericardial effusion and no pericardial effusion. Results: The study enrolled 64,777 patients registered with the Japan Congenital Cardiovascular Surgery Database between 2008 and 2016; 909 of these had postoperative pericardial effusion (1.4%) and were analyzed along with 63,868 patients without pericardial effusion. Univariable analysis found no difference between the groups in terms of gender, early delivery, or preoperative mechanical ventilatory support. In the pericardial effusion group, cardiopulmonary bypass use was lower (58.4% vs 62.1%), whereas the cardiopulmonary bypass time (176.9 vs 139.9 minutes) and aortic crossclamp time (75.1 vs 62.2 minutes) were longer, and 30-day mortality was higher (4.1% vs 2.2%). Multivariable analysis identified trisomy 21 (odds ratio, 1.54), 22q.11 deletion (odds ratio, 2.17), first-time cardiac surgery (odds ratio, 2.01), and blood transfusion (odds ratio, 1.43) as independent risk factors of postoperative pericardial effusion. In contrast, neonates, infants, ventricular septal defect, atrial septal defect, tetralogy of Fallot repair, and arterial switch operation were correlated with a low risk of pericardial effusion development. Conclusions: The incidence of postoperative pericardial effusion in congenital cardiac surgery was 1.4%. Trisomy 21, 22q.11 deletion, first-time cardiac surgery, and blood transfusion were identified as the principal factors predicting the need for pericardial effusion drainage.

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

Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1-5. 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.

Intramural aortic course in anomalous origin of single coronary artery from the right pulmonary artery: A case report and review of the literature.

Preoperatively determining the intramural aortic course in a case of anomalous origin of single coronary artery from the right pulmonary artery is important for planning surgery, such as the unroofing technique. A thin wall separating the ascending aorta from the common coronary artery on transthoracic echocardiography and a crescent-shaped cross-section of the common coronary artery on computed tomography demonstrate an intramural aortic course of the common coronary artery. We present herein a case of anomalous origin of single coronary artery from the right pulmonary artery with an intramural aortic course and review eight other reported cases. .