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The membrane-embedded γ-secretase complex processively cleaves within the transmembrane domain of amyloid precursor protein (APP) to produce 37-to-43-residue amyloid β-peptides (Aβ) of Alzheimer’s disease (AD). Despite its importance in pathogenesis, the mechanism of processive proteolysis by γ-secretase remains poorly understood. Here, mass spectrometry and Western blotting were used to quantify the efficiency of tripeptide trimming of wild-type (WT) and familial AD (FAD) mutant Aβ49. In comparison to WT Aβ49, the efficiency of tripeptide trimming was similar for the I45F, A42T, and V46F Aβ49 FAD mutants but substantially diminished for the I45T and T48P mutants. In parallel with biochemical experiments, all-atom simulations using a novel peptide Gaussian accelerated molecular dynamics (Pep-GaMD) method were applied to investigate the tripeptide trimming of Aβ49 by γ-secretase. The starting structure was the active γ-secretase bound to Aβ49 and APP intracellular domain (AICD), as generated from our previous study that captured the activation of γ-secretase for the initial endoproteolytic cleavage of APP (Bhattarai, A, et al. ACS Cent. Sci. 2020, 6, 969–983). Pep-GaMD simulations captured remarkable structural rearrangements of both the enzyme and substrate, in which hydrogen-bonded catalytic aspartates and water became poised for tripeptide trimming of Aβ49 to Aβ46. These structural changes required a positively charged N-terminus of endoproteolytic coproduct AICD, which could dissociate during conformational rearrangements of the protease and Aβ49. The simulation findings were highly consistent with biochemical experimental data. Taken together, our complementary biochemical experiments and Pep-GaMD simulations have enabled elucidation of the mechanism of tripeptide trimming of Aβ49 by γ-secretase.

Introduction. Direct-acting antivirals (DAAs) have significantly improved the efficacy and tolerability of the treatment of hepatitis C virus (HCV). However, studies conducted on actual patients with the aim of predicting the risk associated with treatment failure are lacking. Methods. Our study enrolled 334 new HCV patients and assessed the effectiveness of treatment and predicted the risk of failure to achieve sustained virological response (SVR) by developing a multiple logistic model. Our study compared the variables between the two groups, those who did (group 0, n = 239 ) and did not achieve SVR (group 1, n = 95 ). Results. The cure rate of HCV at 12th week in our study was 71.56%. We found that advanced cirrhosis, HCV genotype, HBV coinfection, rapid virological response (RVR), fibrosis index (FIB-4) score, serum levels of AST, ALP, hemoglobin, and viral load before treatment were prognostic factors associated with rate of failure to achieve SVR at week 12 of DAA therapy. In the multiple logistic model, eight significant predictors including advanced cirrhosis status, HCV genotype, RVR, AST/ALP levels, FIB-4 score, and viral load before treatment predicted the risk of failure with excellent model performance (area under the receiver operating characteristic curve (AUCROC) [95% CI] =0.986 (0.971-0.999)). RVR and advanced cirrhosis were the two strongest predictors with odd ratios (95% CI) =9.72 (2.8, 39.28) and 51.54 (6.39, 139.82), respectively. Conclusion. The multiple logistic regression model included significant factors to estimate the probability of failure to achieve SVR, which could improve HCV treatment strategy.

Background Circular RNA (circRNA), a class of RNA molecule with a loop structure, has recently attracted researchers due to its diverse biological functions and potential biomarkers of human diseases. Most of the current circRNA detection methods from RNA-sequencing (RNA-Seq) data utilize the mapping information of paired-end (PE) reads to eliminate false positives. However, much of the practical RNA-Seq data such as cross-linking immunoprecipitation sequencing (CLIP-Seq) data usually contain single-end (SE) reads. It is not clear how well these tools perform on SE RNA-Seq data. Results In this study, we present a systematic evaluation of six advanced RNA-based methods and two CLIP-Seq based methods for detecting circRNAs from SE RNA-Seq data. The performances of the methods are rigorously assessed based on precision, sensitivity, F1 score, and true discovery rate. We investigate the impacts of read length, false positive ratio, sequencing depth and PE mapping information on the performances of the methods using simulated SE RNA-Seq simulated datasets. The real datasets used in this study consist of four experimental RNA-Seq datasets with ≥100bp read length and 124 CLIP-Seq samples from 45 studies that contain mostly short-read (≤50bp) RNA-Seq data. The simulation study shows that the sensitivities of most of the methods can be improved by increasing either read length or sequencing depth, and that the levels of false positive rates significantly affect the precision of all methods. Furthermore, the PE mapping information can improve the method’s precision but can not always guarantee the increase of F1 score. Overall, no method is dominant for all SE RNA-Seq data. The RNA-based methods perform better for the long-read datasets but are worse for the short-read datasets. In contrast, the CLIP-Seq based methods outperform the RNA-Seq based methods for all the short-read samples. Combining the results of these methods can significantly improve precision in the CLIP-Seq data. Conclusions The results provide a systematic evaluation of circRNA detection methods on SE RNA-Seq data that would facilitate researchers’ strategies in circRNA analysis.

BackgroundStreet food plays a valuable role in several Asian countries including Vietnam. Improving the safety of street food is an important responsibility for many local food authorities. This study aims to characterize the business profile of fixed and mobile street food vendors, and to compare their compliance with the food safety criteria.MethodsA cross-sectional study was conducted using a questionnaire and observational checklist to assess the ten Vietnamese food safety criteria prescribed under Decision No. 3199/2000/QD-BYT for street food vendors in Can Tho city. A total of 400 street food vendors, composed of fixed and mobile vendors, in urban areas of the city were randomly selected for the survey.ResultsThe study showed significant differences between the two types of street food vendors in educational level (p= 0.017); business profile, including types of foods vended, area in use, number of employees, training in food safety, and business registration paperwork; and the status of compliance with the ten-food hygiene and safety criteria (p< 0.01). Poisson regression analysis found that education attainment (IRR = 1.228,p= 0.015), food safety training (IRR = 4.855,p< 0.01), total business capital (IRR = 1.004, p = 0.031) and total area in use (IRR = 1.007,p= 0.001) appeared to be significantly positively associated with food safety and hygiene compliance. In contrast, mobile vending type was negatively associated with the likelihood of adhering to the ten criteria (IRR = 0.547,p= 0.005).ConclusionsThese findings emphasize the need for training and education programs to improve food safety knowledge and practice among street food vendors. Basic infrastructure and services, especially clean water, proper sanitation, and waste disposal facilities, should be provided to help street food vendors better practice food safety and hygiene regulations.

Introduction: An early detection of impaired functional performance is critical to enhance symptom management for patients with chronic obstructive pulmonary disease (COPD). However, conventional functional measures based on walking assessments are often impractical for small clinics where the available space to administrate gait-based test is limited. This study examined the feasibility and effectiveness of an upper-extremity frailty meter (FM) in identifying digital measures of functional performance and assessing frailty in COPD patients. Methods: Forty-eight patients with COPD (age = 68.8 ± 8.5 years, body mass index [BMI] = 28.7 ± 5.8 kg/m2) and 49 controls (age = 70.0 ± 3.0 years, BMI = 28.7 ± 6.1 kg/m2) were recruited. All participants performed a 20-s repetitive elbow flexion-extension test using a wrist-worn FM sensor. Functional performance was quantified by FM metrics, including speed (slowness), range of motion (rigidity), power (weakness), flexion and extension time (slowness), as well as speed and power reduction (exhaustion). Conventional functional measures, including timed-up-and-go test, gait and balance tests, and 5 repetition sit-to-stand test, were also performed. Results: Compared to controls, COPD patients exhibited deteriorated performances in all conventional functional assessments (d = 0.64–1.26, p < 0.010) and all FM metrics (d = 0.45–1.54, p < 0.050). FM metrics had significant agreements with conventional assessment tools (|r| = 0.35–0.55, p ≤ 0.001). FM metrics efficiently identified COPD patients with pre-frailty and frailty (d = 0.82–2.12, p < 0.050). Conclusion: This study proposes the feasibility of using a 20-s repetitive elbow flexion-extension test and wrist-worn sensor-derived frailty metrics as an alternative and practical solution to evaluate functional performance in COPD patients. Its simplicity and low risk for test administration may also facilitate its application for remote patient monitoring. Furthermore, in settings where the administration of walking test is impractical, for example, when ventilator support is needed or space is limited, FM may be used as an alternative solution. Future studies are encouraged to use the FM to quantitatively monitor the progressive decline in functional performance and quantify outcomes of rehabilitation interventions.

Historically, the ulnar artery has rarely been considered for arterial cannulation as it is less easily palpated than the radial artery. With the current routine use of ultrasound in pediatric patients, the ulnar is as accessible as the radial and could be viewed as an equivalent site for cannulation.The purpose of this study was to compare ulnar and radial artery suitability for arterial cannulation in pediatric patients using 2-dimensional ultrasound.We examined the ulnar and radial arteries of pediatric patients aged birth to 6 years who were scheduled to undergo general anesthesia. Following anesthesia induction, the investigators positioned the patient's wrist to 30-45 degrees of extension and obtained images of the ulnar and radial arteries in the transverse and longitudinal planes. Assessments of the arteries' anterior-posterior diameter, cross-sectional area and depth were made by visual inspection at the time of image acquisition and by electronic caliper measurement of recorded images.In 108 patients, mean anterior-posterior diameter of the ulnar artery was larger than the radial artery in the transverse view, longitudinal view, and cross-sectional area in 63.6%, 59.4%, and 60.4% of patients (p = .002, .004, and .006, respectively). Mean ulnar artery size was, on average, larger than the radial artery by 7.7%, 8.1%, and 12.9% in the transverse AP diameter, longitudinal AP diameter, and cross-sectional area (95% CI 3.1-12.4%; 3.2-13.0%; 4.4-21.5%). The investigator's visual evaluation of vessel size at the bedside showed substantial agreement with the measured cross-sectional area (linear-weighted kappa of 0.73). In a subset of 13 patients age24 months, the mean depth of the ulnar artery was 2.13 mm compared to 1.65 mm for the radial artery (difference -0.48 mm 95% CI 1.08-0.12).The ulnar artery was larger than the radial artery in 60% of pediatric patients thus may offer an arterial cannulation site advantage due to its larger size. The use of 2-dimensional ultrasound examination allows accurate assessment of upper extremity distal arteries in order to optimize site selection for arterial cannulation in pediatric patients.

To explore the use of wearable sensors for objective measurement of motor impairment in spinocerebellar ataxia (SCA) patients during clinical assessments of gait and balance. In total, 14 patients with genetically confirmed SCA (mean age 61.6 ± 8.6 years) and 4 healthy controls (mean age 49.0 ± 16.4 years) were recruited through the Massachusetts General Hospital (MGH) Ataxia Center. Participants donned seven inertial sensors while performing two independent trials of gait and balance assessments from the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS2). Univariate analysis was used to identify sensor-derived metrics from wearable sensors that discriminate motor function between the SCA and control groups. Multivariate linear regression models were used to estimate the subjective in-person SARA/BARS2 ratings. Spearman correlation coefficients were used to evaluate the performance of the model. Stride length variability, stride duration, cadence, stance phase, pelvis sway, and turn duration were different between SCA and controls (p

Objective: To describe the burden of severe acute respiratory infection (SARI) and the infrastructure and current practices of SARI management in hospitals in Viet Nam. Methods: We conducted a short observational study at critical care units (CCUs) in 32 district hospitals and 16 provincial hospitals in five provinces in Viet Nam from March to July 2019. We collected data on hospital equipment and medicines used in SARI management. At the patient level, data were collected for 14 consecutive days on all patients presenting to CCUs, including information on demographics, intervention and treatment within 24 hours of CCU admission and 7-day outcome. Results: There were significant differences between district and provincial hospitals in the availability of microbial culture, rapid influenza diagnostic tests, inflammatory markers and mechanical ventilation. Among 1722 eligible patients admitted to CCUs, there were 395 (22.9%) patients with SARI. The median age of SARI patients was 74 (interquartile range: 58–84) years; 49.1% were male. Although systemic antibiotics were available in all hospitals and were empirically given to 93.4% of patients, oseltamivir was available in 25% of hospitals, and only 0.5% of patients received empiric oseltamivir within 24 hours of admission. The 7-day mortality was 6.6% (26/395). Independent factors associated with 7-day mortality were septic shock and requiring respiratory support within 24 hours of admission. Discussion: SARI is a major burden on CCUs in Viet Nam. Barriers to delivering quality care include the limited availability of diagnostics and medication and non-protocolized management of SARI in CCUs.

Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.

The study presents a novel approach to objectively assessing the upper-extremity motor symptoms in spinocerebellar ataxia (SCA) using data collected via a wearable sensor worn on the patient’s wrist during upper-extremity tasks associated with the Assessment and Rating of Ataxia (SARA). First, we developed an algorithm for detecting/extracting the cycles of the finger-to-nose test (FNT). We extracted multiple features from the detected cycles and identified features and parameters correlated with the SARA scores. Additionally, we developed models to predict the severity of symptoms based on the FNT. The proposed technique was validated on a dataset comprising the seventeen (n = 17) participants’ assessments. The cycle detection technique showed an accuracy of 97.6% in a Bland–Altman analysis and a 94% accuracy (F1-score of 0.93) in predicting the severity of the FNT. Furthermore, the dependency of the upper-extremity tests was investigated through statistical analysis, and the results confirm dependency and potential redundancies in the upper-extremity SARA assessments. Our findings pave the way to enhance the utility of objective measures of SCA assessments. The proposed wearable-based platform has the potential to eliminate subjectivity and inter-rater variabilities in assessing ataxia.

Leaves of Combretum quadrangulare Kurz showed potent α-glucosidase inhibition. Two new cycloartane-type triterpenes, combretic acids D and E were isolated from the bioactive fraction. The chemical structures were determined using NMR and MS methods. Combretic acid D represents for the first cycloartane having a dihydrofuran ring in the side chain. Combretic acids D and E showed significant α-glucosidase inhibition, with IC

In recent years, extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) have emerged as a potential cell-free therapy against osteoarthritis (OA). Thus, we investigated the therapeutic effects of EVs released by cytokine-primed umbilical cord-derived MSCs (UCMSCs) on osteoarthritic chondrocyte physiology. Priming UCMSCs individually with transforming growth factor beta (TGFβ), interferon alpha (IFNα), or tumor necrosis factor alpha (TNFα) significantly reduced the sorting of miR-181b-3p but not miR-320a-3p; two negative regulators of chondrocyte regeneration, into EVs. However, the EV treatment did not show any significant effect on chondrocyte proliferation. Meanwhile, EVs from both non-priming and cytokine-primed UCMSCs induced migration at later time points of measurement. Moreover, TGFβ-primed UCMSCs secreted EVs that could upregulate the expression of chondrogenesis markers (COL2 and ACAN) and downregulate fibrotic markers (COL1 and RUNX2) in chondrocytes. Hence, priming UCMSCs with cytokines can deliver selective therapeutic effects of EV treatment in OA and chondrocyte-related disorders.

A structural understanding of the mechanism by which antibodies bind SARS-CoV-2 at the atomic level is highly desirable as it can tell the development of more effective antibodies to treat Covid-19. Here, we use steered molecular dynamics (SMD) and coarse-grained simulations to estimate the binding affinity of the monoclonal antibodies CR3022 and 4A8 to the SARS-CoV-2 receptor-binding domain (RBD) and SARS-CoV-2 N-terminal domain (NTD). Consistent with experiments, our SMD and coarse-grained simulations both indicate that CR3022 has a higher affinity for SARS-CoV-2 RBD than 4A8 for the NTD, and the coarse-grained simulations indicate the former binds three times stronger to its respective epitope. This finding shows that CR3022 is a candidate for Covid-19 therapy and is likely a better choice than 4A8. Energetic decomposition of the interaction energies between these two complexes reveals that electrostatic interactions explain the difference in the observed binding affinity between the two complexes. This result could lead to a new approach for developing anti-Covid-19 antibodies in which good candidates must contain charged amino acids in the area of contact with the virus.

Emerging zoonotic diseases exert a significant burden on human health and have considerable socioeconomic impact worldwide. In Asia, live animals as well as animal products are commonly sold in informal markets. The interaction of humans, live domestic animals for sale, food products, and wild and scavenging animals, creates a risk for emerging infectious diseases. Such markets have been in the spotlight as sources of zoonotic viruses, for example, avian influenza viruses and coronaviruses, Here, we bring data together on the global impact of live and wet markets on the emergence of zoonotic diseases. We discuss how benefits can be maximized and risks minimized and conclude that current regulations should be implemented or revised, to mitigate the risk of new diseases emerging in the future.

The COVID-19 pandemic affected the food supply chain, retailers, and consumers owing to infection awareness. This study evaluated the impacts COVID-19 on ASF retailers’ businesses and consumers’ livelihoods, as well as their knowledge toward the disease, attitudes, and food safety practices to prevent infections. The study includes a cross-sectional component that was conducted in urban/peri-urban (U/PU) and rural areas in Chiang Mai province. In another part of the study, a structured questionnaire was developed for animal source food (ASF) retailers and consumers, with three primary parts for data analysis: general information, COVID-19 impacts, and knowledge, attitudes, and practices (KAP) assessment. Data corresponding to three periods of interest (before the COVID-19 outbreak, during partial lockdown, and present) were gathered and analyzed. In this study, 155 retailers and 150 consumers participated, of which the majority of the respondents were female (70.3% and 82.7%, respectively) with average ages of 47.4 and 44.9 years, respectively. The most noticeable effect of COVID-19 was a decline in income for retailers and consumers. The KAP scores of consumers in both areas were not significantly different, whereas the retailer attitudes toward COVID-19 prevention and food safety practices scored more highly in rural areas than in U/PU. During the partial lockdown, food safety practices significantly improved relative to the time preceding the outbreak, and these practices have remained constant to the present day. The results revealed that gender, age group, business type, and type of ASF retailers were associated with the KAP of the retailers, whereas gender, age group, education, number of family members, and occupation were associated with the KAP of the consumers. Our findings provide in-depth information about the effects of COVID-19 on ASF retailers and consumers, as well as their KAP regarding the outbreak and food safety, which may serve as support in developing policies for improved health and food safety.

This paper discusses a novel approach to an EEG (electroencephalogram)-based driver distraction classification by using brain connectivity estimators as features. Ten healthy volunteers with more than one year of driving experience and an average age of 24.3 participated in a virtual reality environment with two conditions, a simple math problem-solving task and a lane-keeping task to mimic the distracted driving task and a non-distracted driving task, respectively. Independent component analysis (ICA) was conducted on the selected epochs of six selected components relevant to the frontal, central, parietal, occipital, left motor, and right motor areas. Granger–Geweke causality (GGC), directed transfer function (DTF), partial directed coherence (PDC), and generalized partial directed coherence (GPDC) brain connectivity estimators were used to calculate the connectivity matrixes. These connectivity matrixes were used as features to train the support vector machine (SVM) with the radial basis function (RBF) and classify the distracted and non-distracted driving tasks. GGC, DTF, PDC, and GPDC connectivity estimators yielded the classification accuracies of 82.27%, 70.02%, 86.19%, and 80.95%, respectively. Further analysis of the PDC connectivity estimator was conducted to determine the best window to differentiate between the distracted and non-distracted driving tasks. This study suggests that the PDC connectivity estimator can yield better classification accuracy for driver distractions.

Long-term oxygen therapy in COPD is usually supervised through home-care respiratory programs. Such programs often involve an intensive education intervention at the initiation of long-term oxygen therapy, followed by an extended follow-up period that aims toward home oxygen adherence. The objective of this study was to estimate the cost-effectiveness ratio of such a maintenance program.A simulation model was developed that compared 2 strategies after the intensive education intervention: (1) enrollment and (2) no enrollment in a maintenance program. The study population consisted of a hypothetical cohort of 200 patients (100 patients per group; mean age, 74 years; 45% men; mean FEVOver a 5-year period, an extended home-visit program may prevent 9 deaths and provide an additional 39 years of life and 24 quality-adjusted life-years. Compared with usual care (ie, no enrollment in the maintenance program), the incremental cost-effectiveness ratio was Can $17,197 per quality-adjusted life-years gained. Sensitivity analyses demonstrated the robustness of the model. Only a reduction in adherence of 25% per year would increase the incremental cost-effectiveness ratio per quality-adjusted life-years beyond the threshold of Can $50,000 that is usually considered as acceptable from a health-care system perspective.An extended home-visit program to maintain or improve adherence to long-term oxygen therapy in patients with COPD would most likely be cost-effective.

Targeted monotherapies usually fail due to development of resistance by a subgroup of cells that evolve into recurrent tumors. Alveolar rhabdomyosarcoma is an aggressive myogenic soft-tissue cancer that is associated with a characteristic PAX3-FOXO1 gene fusion encoding a novel fusion transcription factor. In our myoblast model of PAX3-FOXO1–induced rhabdomyosarcoma, deinduction of PAX3-FOXO1 simulates a targeted therapy that antagonizes the fusion oncoprotein. This simulated therapy results initially in regression of the primary tumors, but PAX3-FOXO1–independent recurrent tumors eventually form after a delay. We report here that upregulation of FGF8, a direct transcriptional target of PAX3-FOXO1, is a mechanism responsible for PAX3-FOXO1–independent tumor recurrence. As a transcriptional target of PAX3-FOXO1, FGF8 promoted oncogenic activity in PAX3-FOXO1–expressing primary tumors that developed in the myoblast system. In the recurrent tumors forming after PAX3-FOXO1 deinduction, FGF8 expression was necessary and sufficient to induce PAX3-FOXO1–independent tumor growth through an autocrine mechanism. FGF8 was also expressed in human PAX3-FOXO1–expressing rhabdomyosarcoma cell lines and contributed to proliferation and transformation. In a human rhabdomyosarcoma cell line with reduced PAX3-FOXO1 expression, FGF8 upregulation rescued oncogenicity and simulated recurrence after PAX3-FOXO1–targeted therapy. We propose that deregulated expression of a PAX3-FOXO1 transcriptional target can generate resistance to therapy directed against this oncogenic transcription factor and postulate that this resistance mechanism may ultimately be countered by therapeutic approaches that antagonize the corresponding downstream pathways. Significance: In a model of cancer initiated by a fusion transcription factor, constitutive activation of a downstream transcriptional target leads to fusion oncoprotein-independent recurrences, thereby highlighting a novel progression mechanism and therapeutic target.

Central nervous system (CNS) infection is a serious neurologic condition, although the etiology remains unknown in >50% of patients. We used metagenomic next-generation sequencing to detect viruses in 204 cerebrospinal fluid (CSF) samples from patients with acute CNS infection who were enrolled from Vietnam hospitals during 2012-2016. We detected 8 viral species in 107/204 (52.4%) of CSF samples. After virus-specific PCR confirmation, the detection rate was lowered to 30/204 (14.7%). Enteroviruses were the most common viruses detected (n = 23), followed by hepatitis B virus (3), HIV (2), molluscum contagiosum virus (1), and gemycircularvirus (1). Analysis of enterovirus sequences revealed the predominance of echovirus 30 (9). Phylogenetically, the echovirus 30 strains belonged to genogroup V and VIIb. Our results expanded knowledge about the clinical burden of enterovirus in Vietnam and underscore the challenges of identifying a plausible viral pathogen in CSF of patients with CNS infections.

The bacterial domain produces numerous types of sphingolipids with various physiological functions. In the human microbiome, commensal and pathogenic bacteria use these lipids to modulate the host inflammatory system. Despite their growing importance, their biosynthetic pathway remains undefined since several key eukaryotic ceramide synthesis enzymes have no bacterial homolog. Here we used genomic and biochemical approaches to identify six proteins comprising the complete pathway for bacterial ceramide synthesis. Bioinformatic analyses revealed the widespread potential for bacterial ceramide synthesis leading to our discovery of a Gram-positive species that produces ceramides. Biochemical evidence demonstrated that the bacterial pathway operates in a different order from that in eukaryotes. Furthermore, phylogenetic analyses support the hypothesis that the bacterial and eukaryotic ceramide pathways evolved independently.

A promising approach to combat Covid-19 infections is the development of effective antiviral antibodies that target the SARS-CoV-2 spike protein. Understanding the structures and molecular mechanisms underlying the binding of antibodies to SARS-CoV-2 can contribute to quickly achieving this goal. Recently, a cocktail of REGN10987 and REGN10933 antibodies was shown to be an excellent candidate for the treatment of Covid-19. Here, using all-atom steered molecular dynamics and coarse-grained umbrella sampling, we examine the interactions of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein with REGN10987 and REGN10933 separately as well as together. Both computational methods show that REGN10933 binds to RBD more strongly than REGN10987. Importantly, the cocktail binds to RBD (simultaneous binding) more strongly than its components. The dissociation constants of REGN10987-RBD and REGN10933-RBD complexes calculated from the coarse-grained simulations are in good agreement with the experimental data. Thus, REGN10933 is probably a better candidate for treating Covid-19 than REGN10987, although the cocktail appears to neutralize the virus more efficiently than REGN10933 or REGN10987 alone. The association of REGN10987 with RBD is driven by van der Waals interactions, while electrostatic interactions dominate in the case of REGN10933 and the cocktail. We also studied the effectiveness of these antibodies on the two most dangerous variants Delta and Omicron. Consistent with recent experimental reports, our results confirmed that the Omicron variant reduces the neutralizing activity of REGN10933, REGN10987, and REGN10933+REGN10987 with the K417N, N440K, L484A, and Q498R mutations playing a decisive role, while the Delta variant slightly changes their activity.

This study aimed to describe the cardiovascular injury and clinical features of multisystem inflammatory syndrome in children (MIS-C) related to coronavirus disease 2019 (COVID-19) in Ho Chi Minh City, Vietnam.This was a retrospective cohort study of children with MIS-C (from September 1, 2021 to February 28, 2022) in Children's Hospital 1, Ho Chi Minh City. Demographics, clinical history, significant underlying conditions, clinical manifestations, laboratory investigations, and medical management were analyzed.A total of 76 patients were included (median age, 5.9 years old, 2 months-16 years). The male/female ratio was 1.6/1. Most patients (75/76) had no previous medical conditions. The mean time from acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to symptom onset was 39 days. During an acute SARS-CoV-2 infection, these patients are either asymptomatic or mildly symptomatic. In addition to fever, gastrointestinal symptoms were also prominent, as observed in our study, with 75%, 73.7%, and 72.3% of patients presenting with abdominal pain, vomiting, and loose stools, respectively. The levels of inflammatory markers increased upon admission and returned to normal levels after treatment. Echocardiography revealed decreased myocardial contractility and coronary injury in 16 (21.1%) and 32 (42.1%) patients, respectively. Most cases (72/76) had no fever within 3 days of intravenous immunoglobulin (IVIG) and methylprednisolone treatment. No deaths occurred in this study. The mean duration of hospitalization was 7.2 days.Cardiovascular involvement was observed in approximately 53.9% of the patients. Anti-inflammatory treatment with IVIG and methylprednisolone had a favorable short-term outcome. However, long-term follow-up studies on post-discharge MIS-C cases are needed to make appropriate treatment recommendations in the acute phase.

ObjectivesTo determine women’s perception of the risk of food safety and how it relates to diet, health and decision making as part of formative research for a market-based intervention that aims to improve the safety of animal-source foods sold in informal markets.DesignQualitative study including in-depth personal interviews with 24 caregivers were conducted and complemented with a second follow-up PhotoVoice interview, which allowed the women to photograph their meals and perceptions of food safety and nutrition. Interview data were analysed using thematic analysis in MAXQDA. Participants were purposively sampled from a larger Safe Food, Fair Food for Cambodia study, conducted from May to August 2018.SettingUrban and periurban neighborhoods of Phnom Penh, Cambodia.Participants24 female caregivers (mothers and grandmothers) of children under age 5, each interviewed twice.FindingsA primary food safety concern expressed was that chemicals (pesticides and other agricultural additives) in animal-source foods, fruits and vegetables may impact the health of their families by causing diarrhoea and problems during pregnancy. This fear created a lack of trust in markets, which influenced their food purchasing behaviours and strategies for making the food safer for their families. These mitigation strategies, including food selection and cleaning, vary among the women but are perceived as important to be able to provide their families with what they define as safe meals.ConclusionsInterventions that wish to decrease rates of foodborne illness and increase animal source food consumption should also address the belief that the food system has been compromised by the addition of pesticides and agricultural additives.

The global spread of COVID-19 is devastating health systems and economies worldwide. While the use of vaccines has yielded encouraging results, the emergence of new variants of SARS-CoV-2 shows that combating COVID-19 remains a big challenge. One of the most promising treatments is the use of not only antibodies, but also nanobodies. Recent experimental studies revealed that the combination of antibody and nanobody can significantly improve their neutralizing ability through binding to the SARS-CoV-2 spike protein, but the molecular mechanisms underlying this observation remain largely unknown. In this work, we investigated the binding affinity of the CR3022 antibody and H11-H4 nanobody to the SARS-CoV-2 receptor binding domain (RBD) using molecular modeling. Both all-atom steered molecular dynamics simulations and coarse-grained umbrella sampling showed that, consistent with the experiment, CR3022 associates with RBD more strongly than H11-H4. We predict that the combination of CR3022 and H11-H4 considerably increases their binding affinity to the spike protein. The electrostatic interaction was found to control the association strength of CR3022, but the van der Waals interaction dominates in the case of H11-H4. However, our study for a larger set of nanobodies and antibodies showed that the relative role of these interactions depends on the specific complex. Importantly, we showed Beta, Gamma, Lambda, and Mu variants reduce the H11-H4 activity while Alpha, Kappa and Delta variants increase its neutralizing ability, which is in line with experiment reporting that the nanobody elicited from the llama is very promising for fighting against the Delta variant.

As part of an ongoing search for new protein tyrosine phosphatase 1B inhibitors and glucose uptake stimulators from nature, a new coumarin, selaginolide A (1) and four known isoflavones (2‒5) were isolated from the ethanol extract of a Vietnamese medicinal plant Selaginella rolandi-principis. The chemical structures of the isolates were elucidated by extensive analysis of spectroscopic and physicochemical data. Compounds 3‒5 have been identified from Selaginella genus for the first time. The antidiabetic properties of the isolates (1‒5) were investigated using in vitro assay on 2-NBDG uptake in 3T3-L1 adipocytes and against PTP1B and α-glucosidase enzyme activities as well. Compounds 1 exhibited the most potency with inhibitory IC50 values of 7.40 ± 0.28 and 7.52 ± 0.37 µM against PTP1B and α-glucosidase, respectively. Compounds 3 and 5 possessed potential inhibitions on PTP1B enzyme with IC50 values of 23.02 ± 1.29 and 11.08 ± 0.92 µM and moderate inhibitions on α-glucosidase with IC50 values of 36.47 ± 1.87 and 55.73 ± 2.58 µM, respectively. Compounds 2 and 4 showed weak PTP1B inhibitory activity (IC50 > 30 µM) but displayed remarkable α-glucosidase inhibition with IC50 values of 3.39 ± 0.87 and 9.72 ± 0.62 µM, respectively. Furthermore, ursolic acid as a positive control (IC50 3.42 ± 0.26 µM) and compounds 1 and 5 acted as mixed-competitive inhibitors against PTP1B enzyme with Ki values of 6.46, 10.28, and 15.01 µM, respectively. In addition, compounds 1 and 5 also showed potent stimulatory effects on 2-NBDG uptake at a concentration of 10 µM. The obtained result might suggest the potential of new coumarin (1) as a new type of natural PTP1B and α-glucosidase inhibitor for further research and development of antidiabetic and obese agents. Graphic abstract

Purpose: Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. Experimental Design: We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. Results: Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. Conclusions: This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.

Introduction Influenza surveillance in Argentina reported influenza-like illness at a rate of 3500/100,000, a hospitalization rate of 15.5/100,000, and a death rate of 0.32/100,000 annually in adults aged over 65 years. The high burden of disease may be due to a combination of immunosenescence and the suboptimal clinical effectiveness of conventional, non-adjuvanted influenza vaccines in this age group. There is a clinical need for more effective influenza vaccines in this population. This study evaluated the cost-effectiveness of an MF59®-adjuvanted trivalent influenza vaccine (aTIV) in adults aged over 65 years in Argentina compared with the non-adjuvanted trivalent influenza vaccine (TIV) used under the current national vaccination policy. Methods A decision tree cost-effectiveness model was developed to estimate the cost-effectiveness of switching from TIV to aTIV in Argentinian older adults. The model compared cost and health benefits of vaccination in one influenza season from the payer perspective. The main predictions included survival, quality-adjusted survival, and costs. Model inputs were sourced from Argentina or internationally where local data was considered inaccurate. Vaccine efficacy assumptions were extracted from recently published, peer-reviewed scientific literature. Results Switching from TIV to aTIV would result in 170 deaths averted and 1310 incremental quality-adjusted life years (QALYs) gained. The incremental cost-effectiveness ratio per QALY was US $2660.59 from the payer perspective. In all sensitivity analyses, aTIV remained highly cost-effective. The probabilistic sensitivity analyses showed a 95% CI per QALY of US $113.74–7721.67. Conclusion Introducing an adjuvanted influenza vaccine in Argentina is potentially beneficial and cost-effective relative to the currently-used TIV through the reduction of disease burden and utilization of healthcare resources.

Background The One Health concept promotes the enhancement of human, animal and ecosystem health through multi-sectorial governance support and policies to combat health security threats. In Vietnam, antimicrobial resistance (AMR) in animal and human health settings poses a significant threat, but one that could be minimised by adopting a One Health approach to AMR surveillance. To advance understanding of the willingness and abilities of the human and animal health sectors to undertake investigations of AMR with a One Health approach, we explored the perceptions and experiences of those tasked with investigating AMR in Vietnam, and the benefits a multi-sectorial approach offers. Methods This study used qualitative methodology to provide key informants’ perspectives from the animal and human health sectors. Two scenarios of food-borne AMR bacteria found within the pork value chain were used as case studies to investigate challenges and opportunities for improving collaboration across different stakeholders and to understand benefits offered by a One Health approach surveillance system. Fifteen semi-structured interviews with 11 participants from the animal and six from the human health sectors at the central level in Hanoi and the provincial level in Thai Nguyen were conducted. Results Eight themes emerged from the transcripts of the interviews. From the participants perspectives on the benefits of a One Health approach: (1) Communication and multi-sectorial collaboration; (2) Building comprehensive knowledge; (3) Improving likelihood of success. Five themes emerged from participants views of the challenges to investigate AMR: (4) Diagnostic capacity; (5) Availability and access to antibiotics (6) Tracing ability within the Vietnamese food chain; (7) Personal benefits and (8) Managing the system. Conclusion The findings of this study suggest that there is potential to strengthen multi-sectorial collaboration between the animal and human health sectors by building upon existing informal networks. Based on these results, we recommend an inclusive approach to multi-sectorial communication supported by government network activities to facilitate partnerships and create cross-disciplinary awareness and participation. The themes relating to diagnostic capacity show that both sectors are facing challenges to undertake investigations in AMR. Our results indicate that the need to strengthen the animal health sector is more pronounced.

BACKGROUND Esophageal invasion in hypopharyngeal cancer is an uncommon lesion and has a poor prognosis. Total pharyngo-laryngo-esophagectomy is the most effective treatment option. Reconstruction of the gastrointestinal tract in the same period of surgery is required. There are many different options, such as pedicle flap, gastric pull-up, pedicled transverse colon flaps, and free flap. In cases where only cervical esophagectomy is required, with benefits for patients, jejunal free flap is the first choice to reconstruct the esophagus. However, the extensive surgical resection requires interdisciplinary collaboration among surgical specialities, which is not always available. CASE REPORT A 52-year-old male patient came to us with a chief concern of dysphagia, which first appeared 3 months ago. Rigid fiberoptic and direct laryngoscopes indirectly observed the tumor at the posterior wall; it had passed the esophagus opening and infiltrated to the cervical esophagus, with the rightmost part spread into the right pyriform sinus. Histopathology studies of the tumor showed a squamous cell carcinoma. The patient underwent total pharyngo-laryngo-cervico-esophagectomy, reconstructed with a jejunal free flap, and adjuvant radiation therapy after surgery. At follow-up 1 year after surgery, the patient was significantly recovery with no signs of tumor recurrence, no difficulties of oral intake, and his speech was restored by electrolarynx. CONCLUSIONS We reported the case of a patient with hypopharyngeal cancer who underwent total pharyngo-laryngo-cervico-esophagectomy and esophagus reconstruction using a jejunal free flap, performed for the first time in Vietnam. As expected, with good oncological and functional results, the degree of invasiveness and sequelae of the surgery can be well tolerated.

Crosstalk between metabolic and signaling events that induce tumor metastasis remains elusive. Here, we determine how oncogenic sphingosine 1-phosphate (S1P) metabolism induces intracellular C3 complement activation to enhance migration/metastasis. We demonstrate that increased S1P metabolism activates C3 complement processing through S1P receptor 1 (S1PR1). S1P/S1PR1-activated intracellular C3b-α'

Thioesterases are enzymes that hydrolyze thioester bonds in numerous biochemical pathways, for example in fatty acid synthesis. This work reports known functions, structures, and mechanisms of updated thioesterase enzyme families, which are classified into 35 families based on sequence similarity. Each thioesterase family is based on at least one experimentally characterized enzyme, and most families have enzymes that have been crystallized and their tertiary structure resolved. Classifying thioesterases into families allows to predict tertiary structures and infer catalytic residues and mechanisms of all sequences in a family, which is particularly useful because the majority of known protein sequence have no experimental characterization. Phylogenetic analysis of experimentally characterized thioesterases that have structures with the two main structural folds reveal convergent and divergent evolution. Based on tertiary structure superimposition, catalytic residues are predicted.

Interstitial, e.g. subcutaneous (SC) or intradermal (ID), administration of monoclonal antibodies (mAb) is less invasive than intravenous administration and leads to mAb uptake into both lymphatic and blood capillaries draining the injection site. Interstitial administration, however, is hindered by the presence of hyaluronan (HA), a glycosaminoglycan that is a major fluid barrier in the interstitial space. The transient removal of HA with recombinant human hyaluronidase (rHuPH20) helps facilitate the interstitial administration of often high therapeutic doses of mAb in the clinic. rHuPH20's impact on the systemic pharmacokinetics of several mAbs has been previously described, however effects on route of absorption (lymph vs blood) are unknown. The current study has therefore explored the lymphatic transport and bioavailability of cetuximab and trastuzumab after SC and ID coadministration in the presence and absence of rHuPH20 in rats. After SC administration cetuximab absolute bioavailability increased from 67 % to 80 % in the presence of rHuPH20. Cetuximab recovery in the lymphatics also increased after SC (35.8 % to 49.4 %) and ID (26.7 % to 58.8 %) administration in the presence of rHuPH20. When the injection volume (and therefore dose) was increased 10-fold in the presence of rHuPH20 cetuximab plasma exposure increased approximately linearly (12- and 8.9-fold respectively after SC and ID administration), although the proportional contribution of cetuximab lymphatic transport reduced slightly (6.2-fold increase for both administration routes). In contrast, co-administration with rHuPH20 did not lead to increases in plasma exposure for trastuzumab after SC or ID administration, most likely reflecting the fact that the reported absolute bioavailability of trastuzumab (in the absence of rHuPH20) is high (∼77-99 %). However, lymphatic transport of trastuzumab did increase when coadministered ID with rHuPH20 in spite of the lack of change to overall bioavailability. The data suggest that co-administration with rHuPH20 is able to increase the volume of mAb that can be administered interstitially, and in some instances can increase the amount absorbed into both the blood and the lymph. In the current studies the ability of rHuPH20 to enhance interstitial bioavailability was higher for cetuximab where intrinsic interstitial bioavailability was low, when compared to trastuzumab where interstitial bioavailability was high.

Objective:To examine whether mothers’ perceived neighbourhood food access is associated with their own and their young children’s consumption of animal-flesh food, fruits and vegetables in peri-urban areas of Cambodia.Design:A cross-sectional survey measured food consumption frequency and perceived neighbourhood food access, the latter including six dimensions of food availability, affordability, convenience, quality, safety and desirability. Multivariate logistic regression was used to assess the association between perceived food access and food consumption.Setting:Peri-urban districts of Phnom Penh and Siem Reap, CambodiaParticipants:198 mothers of children between 6 and 24 months old.Results:Over 25 % of the mothers and 40 % of the children had low consumption (< once a day) of either animal-flesh food or fruits and vegetables. Compared with perceived high food access, perceived low food access was associated with an adjusted 5·6-fold and 4·3-fold greater odds of low animal-flesh food consumption among mothers (95 % CI 2·54, 12·46) and children (95 % CI 2·20, 8·60), respectively. Similarly, relative to perceived high food access, perceived low food access was associated with 7·6-times and 5·1-times higher adjusted odds of low fruits and vegetables consumption among mothers (95 % CI 3·22, 18·02) and children (95 % CI 2·69, 9·83), respectively.Conclusions:Mothers’ perceived neighbourhood food access was an important predictor of their own and their young children’s nutrient-rich food consumption in peri-urban Cambodia. Future work is needed to confirm our findings in other urban settings and examine the role of neighbourhood food environment in the consumption of both nutrient-rich and nutrient-poor food.

Background We have observed an increased expression of negative markers in some clinical-grade, xeno- and serum-free cultured adipose-derived mesenchymal stem/stromal cell (ADMSC) samples. It gave rise to concern that xeno- and serum-free conditions might have unexpected effects on human ADMSCs. This study aims to test this hypothesis for two xeno- and serum-free media, PowerStem MSC1 media (PS) and StemMACS MSC Expansion Media (SM), that support the in vitro expansion of ADMSCs. Methods We investigated the expression of negative markers in 42 clinical-grade ADMSC samples expanded in PS. Next, we cultured ADMSCs from seven donors in PS and SM and examined their growth and colony-forming ability, surface marker expression, differentiation, cell cycle and senescence, as well as genetic stability of two passages representing an early and late passage for therapeutic MSCs. Results 15 of 42 clinical-grade PS-expanded ADMSC samples showed an increased expression of negative markers ranging from 2.73% to 34.24%, which positively correlated with the age of donors. This rise of negative markers was related to an upregulation of Human Leukocyte Antigen – DR (HLA-DR). In addition, the PS-cultured cells presented decreased growth ability, lower frequencies of cells in S/G2/M phases, and increased ß-galactosidase activity in passage 7 suggesting their senescent feature compared to those grown in SM. Although MSCs of both PS and SM cultures were capable of multilineage differentiation, the PS-cultured cells demonstrated chromosomal abnormalities in passage 7 compared to the normal karyotype of their SM counterparts. Conclusions These findings suggest that the SM media is more suitable for the expansion of therapeutic ADMSCs than PS. The study also hints a change of ADMSC features at more advanced passages and with increased donor’s age. Thus, it emphasizes the necessity to cover these aspects in the quality control of therapeutic MSC products. Graphical abstract

The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and 6 other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes 4 genes that are overexpressed in amplicon-positive RMS. Among these genes, only serine hydroxymethyltransferase 2 (SHMT2) was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in amplicon-positive RMS cells suppressed growth, transformation, and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrates that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

An increasing number of disease-modifying therapies (DMTs) are being approved for treatment of multiple sclerosis …

Background Primary ciliary dyskinesia (PCD) is a mostly autosomal recessive, genetic disease of abnormal motile cilia function, resulting in bronchiectasis, infertility, organ laterality defects, and chronic otolaryngology disease. Though motile, ependymal cilia influencing cerebrospinal fluid flow in the central nervous system share many aspects of structure and function with motile cilia in the respiratory tract, hydrocephalus is rarely associated with PCD. Recently, pathogenic variants in FOXJ1 (Chr 17q25.1) were identified causing PCD associated with hydrocephalus, reduced respiratory cilia number, axonemal microtubule disorganization, and occurring in a de novo, autosomal dominant inheritance pattern. Method Two patients with chronic oto‐sino‐pulmonary disease and hydrocephalus underwent candidate testing of FOXJ1. Coding region and splice junctions were sequenced and analyzed under the auspices of Genetic Disorders of Mucociliary Clearance Consortium. Results Upon sequencing of the entire coding region and splice‐junctions, heterozygous, pathogenic variants in FOXJ1 were discovered in exon 3 of two patients: an 11‐month‐old female with situs inversus totalis (NM_001454.4: c.945delC (p.Phe315Leufs*18)) and a 51 year‐old male, post‐double lung transplantation (NM_001454.4: c.929_932delACTG (p.Asp310Glyfs*22)). FOXJ1 variants were not detected in the available parents and the siblings of these probands. Conclusion FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus. Physicians treating patients with hydrocephalus and chronic oto‐sino‐pulmonary disease should be aware of this PCD association and test for FOXJ1 variants., Variants in FOXJ1 are a rare cause of respiratory ciliary dysfunction and hydrocephalus, but few cases have been previously illustrated. We report 2 cases of primary ciliary dyskinesia (PCD) with hydrocephalus, both caused by de novo, autosomal dominant, variants in FOXJ1. FOXJ1 should be examined in patients with hydrocephalus and classic PCD symptoms of chronic oto‐sino‐pulmonary disease, neonatal respiratory distress, and organ laterality defects.

Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. Whereas many studies have investigated the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. In this study, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries, hypothesizing that the high prevalence of infection in patients with PTL may result in specific changes in the T cell and B cell repertoires. We analyzed TCR β-chain (TCR-β) and IgH diversity, CDR3 lengths, clonal sharing, and preferential usage of variable and joining gene segments. Both TCR-β and IgH repertoires had shorter CDR3s compared with those in maternal blood. In cord blood samples, we found that CDR3 lengths correlated with gestational age, with shorter CDR3s in preterm neonates suggesting a less developed repertoire. Preterm cord blood displayed preferential usage of a number of genes. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features and convergence with maternal TCR-β clones compared with that of term infants. The higher clonal convergence in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal–fetal immune repertoire in term and preterm patients and contribute to a better understanding of neonate immune repertoire development and potential changes associated with PTL.

Japanese encephalitis (JE) is the major cause of viral encephalitis (VE) in most Asian-Pacific countries. In Vietnam, there is no nationwide surveillance system for JE due to lack of medical facilities and diagnoses. Culex tritaeniorhynchus, Culex vishnui, and Culex quinquefasciatus have been identified as the major JE vectors in Vietnam. The main objective of this study was to forecast a risk map of Culex mosquitoes in Hanoi, which is one of the most densely populated cities in Vietnam. A total of 10,775 female adult Culex mosquitoes were collected from 513 trapping locations. We collected temperature and precipitation information during the study period and its preceding month. In addition, the other predictor variables (e.g., normalized difference vegetation index [NDVI], land use/land cover and human population density), were collected for our analysis. The final model selected for estimating the Culex mosquito abundance included centered rainfall, quadratic term rainfall, rice cover ratio, forest cover ratio, and human population density variables. The estimated spatial distribution of Culex mosquito abundance ranged from 0 to more than 150 mosquitoes per 900m2. Our model estimated that 87% of the Hanoi area had an abundance of mosquitoes from 0 to 50, whereas approximately 1.2% of the area showed more than 100 mosquitoes, which was mostly in the rural/peri-urban districts. Our findings provide better insight into understanding the spatial distribution of Culex mosquitoes and its associated environmental risk factors. Such information can assist local clinicians and public health policymakers to identify potential areas of risk for JE virus. Risk maps can be an efficient way of raising public awareness about the virus and further preventive measures need to be considered in order to prevent outbreaks and onwards transmission of JE virus., Author summary Our study was to estimate the spatial distribution of Culex mosquitoes in Hanoi, which is one of the most densely populated cities in Vietnam. Our findings may provide better insight into understanding the spatial distribution of Culex mosquitoes and its associated environmental risk factors. Such information can assist local clinicians and public health policymakers to identify the potential areas of risk for JE virus.

This study offers a new perspective on the role of relative humidity in strategies to improve the health and wellbeing of office workers. A lack of studies of sufficient participant size and diversity relating relative humidity (RH) to measured health outcomes has been a driving factor in relaxing thermal comfort standards for RH and removing a lower limit for dry air. We examined the association between RH and objectively measured stress responses, physical activity (PA), and sleep quality. A diverse group of office workers (n = 134) from four well‐functioning federal buildings wore chest‐mounted heart rate variability monitors for three consecutive days, while at the same time, RH and temperature (T) were measured in their workplaces. Those who spent the majority of their time at the office in conditions of 30%‐60% RH experienced 25% less stress at the office than those who spent the majority of their time in drier conditions. Further, a correlational study of our stress response suggests optimal values for RH may exist within an even narrower range around 45%. Finally, we found an indirect effect of objectively measured poorer sleep quality, mediated by stress responses, for those outside this range.

Background. Obtaining tumor specimens and re-evaluating targeted markers is recommended, if possible, in breast cancer patients who relapsed after curative treatment. The biomarker status changes in rebiopsied tumors have been demonstrated to have considerable clinical implications. Objectives. To identify the changes of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status between the primary and recurrent lesions. Materials and Methods. We conducted a study among 67 patients with recurrent breast cancer, recruited from January 2014 to September 2018 in the Vietnam National Cancer Hospital to compare ER, PR, and HER2 status between the primary and recurrent lesions. For each patient, a specimen of their primary tumor and another specimen of recurrent lesions underwent pathological assessment. Immunohistochemistry (IHC) was performed to determine ER, PR, and HER2 status in both specimens. Results. Biomarker status conversion rates (in both directions) between primary and recurrent tumors were 26.9% for ER, 38.8% for PR, and 22.4% for HER2. Overall, IHC subtypes (hormone receptor positive, HER2 amplified, and triple-negative) changed in 25 out of 67 (37.3%) cases. Conversion rates were not statistically significantly different between patients with different recurrent sites and times of recurrence. Eight out of 13 initially triple-negative patients (61.5%) had a change to positive status of either ER, PR, or HER2. Conclusion. A substantial discordance in ER, PR, and HER2 status were observed between primary breast cancer tissues and recurrent lesions. Rebiopsy could bring new therapeutic opportunities in the management of patients with recurrent breast cancer.

Objectives Early diagnosis of tuberculosis (TB) and multidrug-resistant TB (MDR-TB) is a priority for Viet Nam’s National TB Control Programme. In many laboratories, quality systems are weak; few have attained accreditation. We implemented a structured training and mentoring program for TB laboratories and measured impact on quality. Methods Six TB culture laboratories implemented the Strengthening TB Laboratory Management Towards Accreditation (TB SLMTA) program, consisting of three training workshops and on-site mentoring between workshops to support improvement projects. Periodic audits, using standardized checklists, monitored laboratories’ progress toward accreditation readiness. Results At baseline, all six laboratories achieved a zero-star level. At exit, five laboratories attained three stars and another one star. Overall checklist scores increased by 44.2% on average, from 29.8% to 74.0%; improvements occurred across all quality system essentials. Conclusions The program led to improved quality systems. Sites should be monitored to ensure sustainability of improvements and country capacity expanded for national scaleup.

BACKGROUND: Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (

A series of usnic acid benzylidene derivatives (groups I-V) were designed, synthesized and evaluated for their anticancer activity in the search for potentially new anticancer agents. Compounds 1a, 5b, 2b, 2e and 2f exhibited the most potent cytotoxcity against K562 cell line with IC50 values of 10.0 ± 3.6, 5.6 ± 0.4, 8.8 ± 1.0, 4.5 ± 0.1 and 8.4 ± 0.4 μM, respectively. It is noteworthy that compound 2e displayed potent cytotoxicity against K562 cells without any cytotoxic effect on HEK293 normal cell line.

Oxidative stress is elevated in the recipients of allogeneic hematopoietic transplantation (allo-HCT) and likely contributes to the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production and migration of alloreactive donor T cells, and remains a major cause of morbidity and mortality after allo-HCT. Hence, strategies to limit oxidative stress in GVHD are highly desirable. Thioredoxin1 (Trx1) counteracts oxidative stress by scavenging reactive oxygen species (ROS) and regulating other enzymes that metabolize H2O2. The present study sought to elucidate the role of Trx1 in the pathophysiology of GVHD. Using murine and xenograft models of allogeneic bone marrow transplantation (allo-BMT) and genetic (human Trx1-transgenic, Trx1-Tg) as well as pharmacologic (human recombinant Trx1, RTrx1) strategies; we found that Trx1-Tg donor T cells or administration of the recipients with RTrx1 significantly reduced GVHD severity. Mechanistically, we observed RTrx1 reduced ROS accumulation and cytokine production of mouse and human T cells in response to alloantigen stimulation in vitro. In allo-BMT settings, we found that Trx1-Tg or RTrx1 decreased downstream signaling molecules including NFκB activation and T-bet expression, and reduced proliferation, IFN-γ production and ROS accumulation in donor T cells within GVHD target organs. More importantly, administration of RTrx1 did not impair the graft-versus-leukemia (GVL) effect. Taken together, the current work provides a strong rationale and demonstrates feasibility to target the ROS pathway, which can be readily translated into clinic.