The impact of COVID-19 and other factors on the usage status of the biologic drug therapies for rheumatoid arthritis: A study from Vietnam.

OBJECTIVES: To describe the status of using biological Disease Modifying Anti Rheumatic Drugs (bDMARDs) to treat rheumatoid arthritis (RA) and related factors. In addition, the study determined the impact of COVID-19 on the usage of bDMARDs. METHODS: This is a cross-sectional study and included 219 RA patients over 18 years old. The Kaplan-Meier method and the log-rank test (p<0.05) were used to estimate the retention time and compare between different times. Cox regression analysis was used to determine the factors affecting the retention time of biological drugs (p<0.05). RESULTS: Out of 1967 courses of treatment, there were 149 (7.6%) drug discontinuations, 760 (38.6%) doses extensions and 64 (3.3%) drug switch. Moderate disease level and choosing tumor necrosis factor (TNF) inhibitors initially were associated with retention time of COVID-19. Drug discontinuations and dose extensions increased after COVID-19 emergence. The retention time during COVID-19 was significantly different from that of pre-COVID-19. Gender, type of first-used bDMARD, conventional synthetic DMARDs (csDMARDs) and corticoid usage status, disease activity levels were associated with retention time. CONCLUSION: The presence of COVID-19 has a significant effect on usage status of the biologic drug. Further longitudinal studies are needed to clarify the relationship between COVID-19 and drug usage as well as related factors.

The impact of COVID-19 and other factors on the usage status of the biologic drug therapies for rheumatoid arthritis: A study from Vietnam / El impacto de COVID-19 y otros factores en el estado de uso de las terapias farmacológicas biológicas para la artritis reumatoide: un estudio de Vietnam

Objectives: To describe the status of using biological Disease Modifying Anti Rheumatic Drugs (bDMARDs) to treat rheumatoid arthritis (RA) and related factors. In addition, the study determined the impact of COVID-19 on the usage of bDMARDs. Methods: This is a cross-sectional study and included 219 RA patients over 18 years old. The Kaplan–Meier method and the log-rank test (p<0.05) were used to estimate the retention time and compare between different times. Cox regression analysis was used to determine the factors affecting the retention time of biological drugs (p<0.05). Results: Out of 1967 courses of treatment, there were 149 (7.6%) drug discontinuations, 760 (38.6%) doses extensions and 64 (3.3%) drug switch. Moderate disease level and choosing tumor necrosis factor (TNF) inhibitors initially were associated with retention time of COVID-19. Drug discontinuations and dose extensions increased after COVID-19 emergence. The retention time during COVID-19 was significantly different from that of pre-COVID-19. Gender, type of first-used bDMARD, conventional synthetic DMARDs (csDMARDs) and corticoid usage status, disease activity levels were associated with retention time. Conclusion: The presence of COVID-19 has a significant effect on usage status of the biologic drug. Further longitudinal studies are needed to clarify the relationship between COVID-19 and drug usage as well as related factors.(AU)

Objetivos: Describir el estado del uso de fármacos antirreumáticos modificadores de la enfermedad biológica (bDMARD) para tratar la artritis reumatoide (AR) y los factores relacionados. Además, el estudio determinó el impacto de COVID-19 en el uso de bDMARD. Métodos: Este es un estudio transversal que incluyó a 219 pacientes con AR mayores de 18 años. El método Kaplan-Meier y la prueba Log-rank (p<0,05) se usaron para estimar el tiempo de retención y compararlo entre diferentes tiempos. El análisis de regresión de Cox se utilizó para determinar los factores que afectan el tiempo de retención de los medicamentos biológicos (p<0,05). Resultados: De 1.967 cursos de tratamiento, hubo 149 (7,6%) interrupciones del fármaco, 760 (38,6%) extensiones de dosis y 64 (3,3%) cambios de fármaco. Nivel de enfermedad moderado y elección del factor de necrosis tumoral (TNF) inhibidores inicialmente se asociaron con el tiempo de retención de COVID-19. Las discontinuaciones de los medicamentos y las extensiones de las dosis aumentaron después de la aparición de COVID-19. El tiempo de retención durante COVID-19 fue significativamente diferente del pre-COVID-19. Género, tipo de bDMARD de primer uso, convencional DMARD sintéticos (csDMARDs) y el estado de uso de corticoides, los niveles de actividad de la enfermedad se asociaron con el tiempo de retención. Conclusión: La presencia de COVID-19 tiene un efecto significativo en el estado de uso del medicamento biológico. Se necesitan más estudios longitudinales para aclarar la relación entre COVID-19 y el uso de fármacos, así como los factores relacionados.(AU)

RNA therapeutics for metabolic disorders.

The prevalence of metabolic disorders is increasing exponentially and has recently reached epidemic levels. Over the decades, a large number of therapeutic options have been proposed to manage these diseases but still show several limitations. In this circumstance, RNA therapeutics have rapidly emerged as a new hope for patients with metabolic diseases. 57 years have elapsed from the discovery of mRNA, a large number of RNA-based drug candidates have been evaluated for their therapeutic effectiveness and clinical safety under clinical studies. To date, there are seven RNA drugs for treating metabolic disorders receiving official approval and entering the global market. Their targets include hereditary transthyretin-mediated amyloidosis (hATTR), familial chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria type 1 and hypercholesterolemia, which are all related to liver proteins. All of these seven RNA drugs are antisense oligonucleotides (ASO) and small interfering RNA (siRNA). These two types of treatment are both based on oligonucleotides complementary to target RNA through Watson-Crick base-pairing, but their mechanisms of action include different nucleases. Such treatments show greatest potential among all types of RNA therapeutics due to consecutive achievements in chemical modifications. Another method, mRNA therapeutics also promise a brighter future for patients with a handful of drug candidates currently under development.

RNA therapeutics for disorders of excretory system.

The excretory system is responsible for removing wastes from the human body, which plays a crucial role in our lives. Current treatments for diseases related to this system have shown several limitations; therefore, there is a rising need for novel methods. In this circumstance, RNA-based therapeutics have rapidly emerged as new and promising candidates. In fact, to date, a handful of potential drugs have passed the development step and entered the clinical pipeline. Among them, one drug received FDA approval to enter the global market, which is Oxlumo (Lumasiran) for the treatment of primary hyperoxaluria type 1. For other excretory diseases, such as paroxysmal nocturnal hemoglobinuria, urothelial cancer or renal cancer, RNA-based candidates are also being tested under clinical trials. Currently, the most potential types of RNA therapeutics to treat disorders of the excretory system are those based on small interfering RNA (siRNA), antisense oligonucleotides (ASO) and messenger RNA (mRNA), Among them, siRNA therapeutics seem to be the most promising, including Oxlumo and two other developing drug candidates. This chapter will provide a general overview on the application of RNA therapeutics in disorders of the excretory system.

A heparin-based nanogel system for redox and pH dual-responsive delivery of cisplatin.

Heparin recently has been discovered as a novel anti-cancer agent. The combinations of heparin with other agents was reported not only to reduce the undesired effects of free heparin and increase the cellular uptake of the delivered molecules, but also is the basis for the design and development of multi-stimulation response systems to improve their killing cancer cell efficiency at the target positions. This study aimed to design a redox and pH dual-responsive anticancer system based on heparin for cisplatin (CPT) therapy. Heparin was first cross-linked with Poloxamer 407 chains via disulfide bridges to form a redox-sensitive system Hep-P407. CPT was then encapsulated into the Hep-P407 system via the complex of Platin and carboxyl groups to form the redox/pH-responsive system CPT@Hep-P407. The obtained Hep-P407 systems were proved and characterized using specific techniques including1H-NMR, zeta potential, Dynamic Light Scattering (DLS) and Fourier-transform infrared spectroscopy. The dual-responsive behavior to redox and pH of CPT@Hep-P407 was proved through DLS, zeta andin vitrorelease analysis meanwhile its cytotoxicity was investigated using Resazurin assay. The CPT@Hep-P407 system is expected to be a promising redox/pH-responsive anticancer system based on heparin for CPT therapy.

Multidrug resistance plasmids underlie clonal expansions and international spread of Salmonella enterica serotype 1,4,[5],12:i:- ST34 in Southeast Asia.

Salmonella enterica serotype 1,4,[5],12:i:- (Typhimurium monophasic variant) of sequence type (ST) 34 has emerged as the predominant pandemic genotype in recent decades. Despite increasing reports of resistance to antimicrobials in Southeast Asia, Salmonella ST34 population structure and evolution remained understudied in the region. Here we performed detailed genomic investigations on 454 ST34 genomes collected from Vietnam and diverse geographical sources to elucidate the pathogen's epidemiology, evolution and antimicrobial resistance. We showed that ST34 has been introduced into Vietnam in at least nine occasions since 2000, forming five co-circulating major clones responsible for paediatric diarrhoea and bloodstream infection. Most expansion events were associated with acquisitions of large multidrug resistance plasmids of IncHI2 or IncA/C2. Particularly, the self-conjugative IncA/C2 pST34VN2 (co-transferring blaCTX-M-55, mcr-3.1, and qnrS1) underlies local expansion and intercontinental spread in two separate ST34 clones. At the global scale, Southeast Asia was identified as a potential hub for the emergence and dissemination of multidrug resistant Salmonella ST34, and mutation analysis suggests of selection in antimicrobial responses and key virulence factors.

The expression and mutation of BRCA1/2 genes in ovarian cancer: a global systematic study.

INTRODUCTION: This systematic review was designed to summarize the findings on expression and mutation of BRCA1/2 genes in ovarian cancer (OC) patients, focusing on mutation detection technology and taking clinical decisions for better treatment. AREAS COVERED: We conducted a systematic review by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses document selection guidelines for the document selection process and the PICOT standard for developing the keywords to search for. A total of 5729 publications were included, and 50 articles were put into the final screening. The results showed that Next-Generation Sequencing was a breakthrough technology in detecting Breast Cancer 1/2 (BRCA1/2) gene mutations because of its efficacy and affordability. Other technologies are also being applied now for mutation detection. The most prominent associations of BRCA1/2 gene mutations were age, heredity, and family history. Furthermore, mutations of BRCA1/2 could improve survival rate and overall survival. There is no sufficient study available to conclude a systematic analysis for the expression of BRCA1/2 gene in OC. EXPERT OPINION: Research will continue to develop more diagnostic techniques based on the expression and mutation of BCRA1/2 genes for OC in the near future.

Commensal Escherichia coli are a reservoir for the transfer of XDR plasmids into epidemic fluoroquinolone-resistant Shigella sonnei.

Despite the sporadic detection of fluoroquinolone-resistant Shigella in Asia in the early 2000s and the subsequent global spread of ciprofloxacin-resistant (cipR) Shigella sonnei from 2010, fluoroquinolones remain the recommended therapy for shigellosis1-7. The potential for cipR S. sonnei to develop resistance to alternative second-line drugs may further limit future treatment options8. Here, we aim to understand the evolution of novel antimicrobial resistant (AMR) S. sonnei variants after introduction into Vietnam. We found that cipR S. sonnei displaced the resident ciprofloxacin-susceptible (cipS) lineage while rapidly acquiring additional resistance to multiple alternative antimicrobial classes. We identified several independent acquisitions of extensively drug-resistant/multidrug-resistant-inducing plasmids, probably facilitated by horizontal transfer from commensals in the human gut. By characterizing commensal Escherichia coli from Shigella-infected and healthy children, we identified an extensive array of AMR genes and plasmids, including an identical multidrug-resistant plasmid isolated from both S. sonnei and E. coli in the gut of a single child. We additionally found that antimicrobial usage may impact plasmid transfer between commensal E. coli and S. sonnei. These results suggest that, in a setting with high antimicrobial use and a high prevalence of AMR commensals, cipR S. sonnei may be propelled towards pan-resistance by adherence to outdated international treatment guidelines.

South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study.

BACKGROUND: Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei. METHODS AND FINDINGS: We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei. CONCLUSIONS: This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally.

The transfer and decay of maternal antibody against Shigella sonnei in a longitudinal cohort of Vietnamese infants.

BACKGROUND: Shigella sonnei is an emergent and major diarrheal pathogen for which there is currently no vaccine. We aimed to quantify duration of maternal antibody against S. sonnei and investigate transplacental IgG transfer in a birth cohort in southern Vietnam. METHODS AND RESULTS: Over 500-paired maternal/infant plasma samples were evaluated for presence of anti-S. sonnei-O IgG and IgM. Longitudinal plasma samples allowed for the estimation of the median half-life of maternal anti-S. sonnei-O IgG, which was 43 days (95% confidence interval: 41-45 days). Additionally, half of infants lacked a detectable titer by 19 weeks of age. Lower cord titers were associated with greater increases in S. sonnei IgG over the first year of life, and the incidence of S. sonnei seroconversion was estimated to be 4/100 infant years. Maternal IgG titer, the ratio of antibody transfer, the season of birth and gestational age were significantly associated with cord titer. CONCLUSIONS: Maternal anti-S. sonnei-O IgG is efficiently transferred across the placenta and anti-S. sonnei-O maternal IgG declines rapidly after birth and is undetectable after 5 months in the majority of children. Preterm neonates and children born to mothers with low IgG titers have lower cord titers and therefore may be at greater risk of seroconversion in infancy.

The impact of environmental and climatic variation on the spatiotemporal trends of hospitalized pediatric diarrhea in Ho Chi Minh City, Vietnam.

It is predicted that the integration of climate-based early warning systems into existing action plans will facilitate the timely provision of interventions to diarrheal disease epidemics in resource-poor settings. Diarrhea remains a considerable public health problem in Ho Chi Minh City (HCMC), Vietnam and we aimed to quantify variation in the impact of environmental conditions on diarrheal disease risk across the city. Using all inpatient diarrheal admissions data from three large hospitals within HCMC, we developed a mixed effects regression model to differentiate district-level variation in risk due to environmental conditions from the overarching seasonality of diarrheal disease hospitalization in HCMC. We identified considerable spatial heterogeneity in the risk of all-cause diarrhea across districts of HCMC with low elevation and differential responses to flooding, air temperature, and humidity driving further spatial heterogeneity in diarrheal disease risk. The incorporation of these results into predictive forecasting algorithms will provide a powerful resource to aid diarrheal disease prevention and control practices in HCMC and other similar settings.

A laboratory information management system for DNA barcoding workflows.

This paper presents a laboratory information management system for DNA sequences (LIMS) created and based on the needs of a DNA barcoding project at the CBS-KNAW Fungal Biodiversity Centre (Utrecht, the Netherlands). DNA barcoding is a global initiative for species identification through simple DNA sequence markers. We aim at generating barcode data for all strains (or specimens) included in the collection (currently ca. 80 k). The LIMS has been developed to better manage large amounts of sequence data and to keep track of the whole experimental procedure. The system has allowed us to classify strains more efficiently as the quality of sequence data has improved, and as a result, up-to-date taxonomic names have been given to strains and more accurate correlation analyses have been carried out.

Vertically aligned carbon nanofibers: interconnecting solid state electronics with biosystems.

Vertically aligned carbon nanofibers (VACNFs) are grown directly on prefabricated electronic circuits with nanoscale precision. Utilizing the free-standing nanofiber array geometry, we have demonstrated the detection of nucleic acids to construct an ultrasensitive electrochemical sensor. Extending this technology towards in vivo applications, we have modified the free-standing VACNF arrays in order to achieve a multifunctional three dimensional (3-D) matrix that interpenetrates the neuronal network of PC12 cells. We found that PC12 cells cultured on the nanofiber arrays can form an extended neural network upon proper chemical and biochemical modification. The soft 3-D nanofiber array architecture provides a novel platform to fine-tune the topographical, mechanical, chemical, and electrical cues at sub-cellular scales. This biomaterial platform can be used for both fundamental studies of nanomaterial-cell interactions and the development of multifunctional, chronically stable implantable devices. The application of these devices and potential utility as a multifunctional platform for neurophysiology and biochemical studies will be discussed.