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Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

BackgroundThe coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known.ObjectivesThis study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia.MethodsThe International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison.ResultsProcedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020.ConclusionsThe COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

ObjectivesThis study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic.BackgroundThe COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality.MethodsData were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States.ResultsReductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p

BACKGROUND: Total cavopulmonary connection (TCPC) is associated with a lower risk of incident atrial arrhythmias as compared to atriopulmonary Fontan, but the risk of recurrent atrial arrhythmias is unknown in this population. The purpose of this study was to determine the incidence and risk factors for recurrent atrial arrhythmias and thromboembolic complications in patients with TCPC. METHODS: This is a retrospective multicenter study conducted by the Alliance for Adult Research in Congenital Cardiology (AARCC), 2000-2018. The inclusion criteria were TCPC patients (age > 15 years) with prior history of atrial arrhythmia. RESULTS: A total of 103 patients (age 26 ± 7 years; male 58 [56%]) met inclusion criteria. The mean age at initial arrhythmia diagnosis was 13 ± 5 years, and atrial arrhythmias were classified as atrial flutter/tachycardia in 85 (83%) and atrial fibrillation in 18 (17%). The median duration of follow-up from the first episode of atrial arrhythmia was 14.9 (12.1-17.3) years, and during this period 64 (62%) patients had recurrent atrial arrhythmias (atrial flutter/tachycardia 51 [80%] and atrial fibrillation 13 [20%]) with annual incidence of 4.4%. Older age was a risk factor for arrhythmia recurrence while the use of a class III anti-arrhythmic drug was associated with a lower risk of recurrent arrhythmias. The incidence of thromboembolic complication was 0.6% per year, and the cumulative incidence was 4% and 7% at 5 and 10 years respectively from the time of first atrial arrhythmia diagnosis. There were no identifiable risk factors for thromboembolic complications in this cohort. CONCLUSIONS: Although TCPC provides superior flow dynamics and lower risk of incident atrial arrhythmias, there is a significant risk of recurrent arrhythmias among TCPC patients with a prior history of atrial arrhythmias. These patients may require more intensive arrhythmia surveillance as compared to other TCPC patients.

Tsunami hazard analysis is an essential step for designing buildings and infrastructure and for safeguarding people and assets in coastal areas. Coastal communities on Vancouver Island are under threat from the Cascadia megathrust earthquakes and tsunamis. Due to the deterministic nature of current megathrust earthquake scenarios, probabilistic tsunami hazard analysis has not been conducted for the coast of Vancouver Island. To address this research gap, this study presents a new probabilistic tsunami hazard model for Vancouver Island from the Cascadia megathrust subduction events. To account for uncertainties of the possible rupture scenarios more comprehensively, time-dependent earthquake occurrence modeling and stochastic rupture modeling are integrated. The time-dependent earthquake model can capture a multi-modal distribution of inter-arrival time data on the Cascadia megathrust events. On the other hand, the stochastic rupture model can consider variable fault geometry, position, and earthquake slip distribution within the subduction zone. The results indicate that the consideration of different inter-arrival time distributions can result in noticeable differences in terms of site-specific tsunami hazard curves and uniform tsunami hazard curves at different return period levels. At present, the use of the one-component renewal model tends to overestimate the tsunami hazard values compared to the three-component Gaussian mixture model. With the increase in the elapsed time since the last event and the duration of tsunami hazard assessment, the differences tend to be smaller. Inspecting the regional variability of the tsunami hazards, specific segments of the Vancouver Island coast are likely to experience higher tsunami hazards due to the directed tsunami waves from the main subduction zone and due to the local underwater topography.

Objective(s): Advanced Hodgkin Lymphoma has a higher probability of relapse and recurrence. Classical clinicopathological parameters including the International Prognostic Score (IPS) have not been reliable in predicting prognosis or tailoring treatment. Since FDG PET/CT is the standard of care in staging Hodgkin Lymphoma, this study attempted to evaluate the clinical utility of baseline metabolic tumor parameters in a cohort of advanced Hodgkin lymphoma (stage III and IV).Methods: Histology-proven advanced Hodgkin Patients presenting to our institute between 2012-2016 and treated with chemo-radiotherapy (ABVD / AEVD) were followed up till 2019. Quantitative PET/CT and clinicopathological parameters were used to estimate the Event Free Survival (EFS) in 100 patients. Kaplan-Meier method with log-rank test was used to compare the survival times of prognostic factors.Results: At a median follow-up of 48.83 months (IQR:33.31-63.05 months), the five-year-EFS was 81%. Of the 100 patients, 16 had relapsed (16%) and none died at the last follow-up. On Univariate analysis, among non-PET parameters bulky disease (P=0.03) and B-symptoms (P=0.04) were significant while among PET/CT parameters SUVmax (p=0.001), SUVmean (P=0.002), WBMTV2.5 (P

Abstract Purpose Immune‐checkpoint inhibitors (ICIs) are effective against advanced non‐small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. Methods We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those ≥75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. Results We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75–85) and 66 (range, 34–74) years. The median progression‐free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first‐ or second‐line ICI treatment (p = 0.011) and more immune‐related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. Conclusion ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker.

Abstract The primary somatosensory cortex (S1) is a hub for body sensation of both innocuous and noxious signals, yet its role in somatosensation versus pain is debated. Despite known contributions of S1 to sensory gain modulation, its causal involvement in subjective sensory experiences remains elusive. Here, in mouse S1, we reveal the involvement of cortical output neurons in layers 5 (L5) and 6 (L6) in the perception of innocuous and noxious somatosensory signals. We find that L6 activation can drive aversive hypersensitivity and spontaneous nocifensive behavior. Linking behavior to neuronal mechanisms, we find that L6 enhances thalamic somatosensory responses, and in parallel, strongly suppresses L5 neurons. Directly suppressing L5 reproduced the pronociceptive phenotype induced by L6 activation, suggesting an anti-nociceptive function for L5 output. Indeed, L5 activation reduced sensory sensitivity and reversed inflammatory allodynia. Together, these findings reveal a layer-specific and bidirectional role for S1 in modulating subjective sensory experiences.

Abstract Background Syphilis is a chronic disease that progresses in the primary, secondary, latent, and tertiary stages. Pulmonary manifestations of syphilis are rare, and their histological features have not been well-described. Case presentation A 78-year-old man was referred to our hospital because of a solitary nodular shadow in the right middle lung field on a chest radiograph. Five years prior, a rash appeared on both legs. He was tested for syphilis at a public health center, and the non-treponemal test result was negative. When he was approximately 35 years old, he had unspecified sexual intercourse. Chest computed tomography showed a 13-mm nodule with a cavity in S6 of the right lower lobe of the lung. Robot-assisted resection of the right lower lobe was performed because of suspected localized right lower lobe lung cancer. A cicatricial variant of organizing pneumonia (CiOP) was observed, and immunohistochemistry identified Treponema pallidum inside the macrophages in the nodule cavity. The rapid plasma regain (RPR) value was negative, and the Treponema pallidum hemagglutination assay was positive. The patient was diagnosed as having secondary syphilis with pulmonary involvement. Insidious progression of secondary syphilis may result in CiOP and a negative RPR test result. Conclusions We report the first case of pulmonary syphilis with a histological pattern of CiOP. It may be asymptomatic and difficult to diagnose because the RPR test may be negative for a long period of time. When either non-treponemal or treponemal test results are positive, the possibility of pulmonary syphilis should be considered along with appropriate medical treatment.

Abstract Background Tinnitus affects around 15% of the population and can be a debilitating condition for a sizeable part of them. However, effective evidence-based treatments are scarce. One recommended treatment for tinnitus is cognitive behavioral therapy which has been found to be effective when delivered online. However, more treatments including mindfulness-based interventions have been studied recently in an attempt to facilitate the availability of effective treatments. There are promising findings showing great effects in reducing tinnitus-induced distress and some evidence about the efficacy of such intervention delivered online. However, there is a lack of evidence on how these two treatments compare against one another. Therefore, the aim of this study will be to compare Internet-delivered cognitive behavioral therapy for tinnitus against an Internet-delivered mindfulness-based tinnitus stress reduction intervention in a three-armed randomized controlled trial with a waiting list control condition. Methods This study will be a randomized controlled trial seeking to recruit Lithuanian-speaking individuals suffering from chronic tinnitus. The self-report measure Tinnitus Handicap Inventory will be used. Self-referred participants will be randomized into one of three study arms: Internet-delivered cognitive behavioral therapy, Internet-delivered mindfulness-based tinnitus stress reduction intervention, or a waiting-list control group. Post-treatment measures will be taken at the end of the 8-week-long intervention (or waiting). Long-term efficacy will be measured 3 and 12 months post-treatment. Discussion Internet-delivered interventions offer a range of benefits for delivering evidence-based treatments. This is the first randomized controlled trial to directly compare Internet-delivered CBT and MBTSR for tinnitus in a non-inferiority trial. Trial registration ClinicalTrials.gov NCT05705323. Registered on January 30, 2023.

Human norovirus is the leading cause of acute nonbacterial gastroenteritis in people of all ages worldwide. Currently, no licensed norovirus vaccine, pharmaceutical drug, or therapy is available for the control of norovirus infection. Here, we used a rice transgenic system, MucoRice, to produce a variable domain of a llama heavy-chain antibody fragment (VHH) specific for human norovirus (MucoRice-VHH). VHH is a small heat- and acid-stable protein that resembles a monoclonal antibody. Consequently, VHHs have become attractive and useful antibodies (Abs) for oral immunotherapy against intestinal infectious diseases. MucoRice-VHH constructs were generated at high yields in rice seeds by using an overexpression system with RNA interference to suppress the production of the major rice endogenous storage proteins. The average production levels of monomeric VHH (7C6) to GII.4 norovirus and heterodimeric VHH (7C6-1E4) to GII.4 and GII.17 noroviruses in rice seed were 0.54 and 0.28% (w/w), respectively, as phosphate buffered saline (PBS)-soluble VHHs. By using a human norovirus propagation system in human induced pluripotent stem-cell-derived intestinal epithelial cells (IECs), we demonstrated the high neutralizing activity of MucoRice expressing monomeric VHH (7C6) against GII.4 norovirus and of heterodimeric VHH (7C6-1E4) against both GII.4 and GII.17 noroviruses. In addition, MucoRice-VHH (7C6-1E4) retained neutralizing activity even after heat treatment at 90°C for 20 min. These results build a fundamental platform for the continued development of MucoRice-VHH heterodimer as a candidate for oral immunotherapy and for prophylaxis against GII.4 and GII.17 noroviruses in not only healthy adults and children but also immunocompromised patients and the elderly.

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has adversely affected diagnosis and treatment of noncommunicable diseases. Its effects on delivery of diagnostic care for cardiovascular disease, which remains the leading cause of death worldwide, have not been quantified.ObjectivesThe study sought to assess COVID-19's impact on global cardiovascular diagnostic procedural volumes and safety practices.MethodsThe International Atomic Energy Agency conducted a worldwide survey assessing alterations in cardiovascular procedure volumes and safety practices resulting from COVID-19. Noninvasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019. Availability of personal protective equipment and pandemic-related testing practice changes were ascertained.ResultsSurveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures, in 108 countries. Procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Transthoracic echocardiography decreased by 59%, transesophageal echocardiography 76%, and stress tests 78%, which varied between stress modalities. Coronary angiography (invasive or computed tomography) decreased 55% (p

In this study, yeasts from the gut of O. barnabita larvae were isolated and molecularly identified. It is worth noting that this research provides the first analysis of the gut yeast community in O. barnabita larvae in Lithuania, which is a significant contribution to the field. Two hermit-like L3-praepupa instars were collected from a decaying oak log in Lithuania. The isolation, morphology, biochemistry, and physiology of the yeast isolates were characterized using standards commonly employed in yeast taxonomy studies. The isolates were identified by sequencing the large subunit (26S) rDNA (D1/D2 domain of the LSU). All gut compartments were colonized by the yeast. A total of 45 yeast strains were obtained from the gut of both O. barnabita larvae, with 23 strains originating from Larva 1, 16 strains from Larva 2, and 6 strains from the galleries. According to our identification results of the 45 yeast strains, most of the species were related to Ascomycota, with most of them belonging to the Saccharomycetales order. Yeasts of the genera Candida, Debaryomyces, Meyerozyma, Priceomyces, Schwanniomyces, Spencermartinsiella, Trichomonascus, and Blastobotrys were present in gut of O. barnabita larvae. Species of the Trichosporonales order represented the Basidiomycota phylum.

The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects.

Injuries represent a serious concern for football players, with a significant loss in terms of sport participation and long periods of rehabilitation. According to the 2019/20 UEFA Élite Club Injury Report, the average incidence of injuries during training is 2.8 per 1000 h of training, with an average absence from training of 20 days. In addition, injured athletes are 4 to 7 times more likely to relapse than uninjured athletes. High workloads and reduced recovery periods represent two of the most important modifiable risk factors. In this context, prevention and an adequate rehabilitation protocol are vital in managing injuries, reducing their incidence, and improving the return to competition. In recent years, technological development has provided new tools in rehabilitation, and Virtual reality (VR) has shown interesting results in treating neurologic and orthopedic pathologies. Virtual Reality (VR) technology finds application in the sports industry as a tool to examine athletes’ technical movements. The primary objective is to detect the biomechanical risk factors associated with anterior cruciate ligament injury. Additionally, VR can be used to train athletes in field-specific techniques and create safe and controlled therapeutic environments for post-injury recovery. Moreover, VR offers a customizable approach to treatment based on individual player data. It can be employed for both prevention and rehabilitation, tailoring the rehabilitation and training protocols according to the athletes’ specific needs.

The concept of an optical profiler based on optical resonance was proposed, highlighting the initial requirements for mode number estimation. We proposed a method for estimating the longitudinal mode number of a laser propagating in an external cavity diode laser with high accuracy, utilizing dual-periodic diffraction gratings. These gratings were fabricated using interference lithography. To estimate the mode number, the wavelengths of two different modes are compared. Therefore, the greater the difference between the wavelengths, the higher the accuracy of the mode number determination. While the mode number difference was approximately 35 when using a conventional diffraction grating, this could be increased by a factor of 20 to around 700 using the dual-periodic grating. The relative accuracy achieved was 1.4 × 10−5.