High Rates Of Drug Resistance Research Articles

Geospatial and temporal mapping of detectable HIV-1 viral loads amid dolutegravir rollout in KwaZulu-Natal, South Africa.

South Africa rolled out dolutegravir (DTG) as first-line antiretroviral therapy (ART) in December 2019 to overcome high rates of pretreatment non-nucleoside reverse transcriptase inhibitor drug resistance. In the context of transition to DTG-based ART, this study spatiotemporally analysed detectable HIV viral loads (VLs) prior to- and following DTG rollout in public-sector healthcare facilities in KwaZulu-Natal (KZN) province, the epicentre of the HIV epidemic in South Africa. We retrospectively curated a HIV VL database using de-identified routine VL data obtained from the National Health Laboratory Service for the period January 2018 to June 2022. We analysed trends in HIV viraemia and mapped median log10 HIV VLs per facility on inverse distance weighted interpolation maps. We used Getis-Ord Gi* hotspot analysis to identify geospatial HIV hotspots. We obtained 7,639,978 HIV VL records from 736 healthcare facilities across KZN, of which 1,031,171 (13.5%) had detectable VLs (i.e., VLs ≥400 copies/millilitre (mL)). Of those with detectable VLs, we observed an overall decrease in HIV VLs between 2018 and 2022 (median 4.093 log10 copies/mL; 95% confidence interval (CI) 4.087-4.100 to median 3.563 log10 copies/mL; CI 3.553-3.572), p<0.01 (median test). The downward trend in proportion of HIV VLs ≥1000 copies/mL over time was accompanied by an inverse upward trend in the proportion of HIV VLs between 400 and 999 copies/mL. Moreover, specific coastal and northern districts of KZN had persistently higher VLs, with emergent hotspots demonstrating spatial clustering of high median log10 HIV VLs. The overall decrease in HIV VLs over time shows good progress towards achieving UNAIDS 95-95-95 targets in KZN, South Africa. The DTG-transition has been associated with a reduction in VLs, however, there is a need for pre-emptive monitoring of low-level viraemia. Furthermore, our findings highlight that specific districts will need intensified HIV care despite DTG rollout.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

Integrated Proteomics and Protein Co-expression Network Analysis Identifies Novel Epileptogenic Mechanism in Mesial Temporal Lobe Epilepsy.

Over 50 million people worldwide are affected by epilepsy, a common neurological disorder that has a high rate of drug resistance and diverse comorbidities such as progressive cognitive and behavioural disorders, and increased mortality from direct or indirect effects of seizures and therapies. Despite extensive research with animal models and human studies, limited insights have been gained into the mechanisms underlying seizures and epileptogenesis, which has not translated into significant reductions in drug resistance, morbidities, or mortality. To better understand the molecular signaling networks associated with seizures in MTLE patients, we analyzed the proteome of brain samples from MTLE and control cases using an integrated approach that combines mass spectrometry-based quantitative proteomics, differential expression analysis, and co-expression network analysis. Our analyses of 20 human brain tissues from MTLE patients and 20 controls showed the organization of the brain proteome into a network of 9 biologically meaningful modules of co-expressed proteins. Of these, 6 modules are positively or negatively correlated to MTLE phenotypes with hub proteins that are altered in MTLE patients. Our study is the first to employ an integrated approach of proteomics and protein co-expression network analysis to study patients with MTLE. Our findings reveal a molecular blueprint of altered protein networks in MTLE brain and highlight dysregulated pathways and processes including altered cargo transport, neurotransmitter release from synaptic vesicles, synaptic plasticity, proteostasis, RNA homeostasis, ion transport and transmembrane transport, cytoskeleton disorganization, metabolic and mitochondrial dysfunction, blood micro-particle function, extracellular matrix organization, immune response, neuroinflammation, and cell signaling. These insights into MTLE pathogenesis suggest potential new candidates for future diagnostic and therapeutic development.

Deregulation of New Cell Death Mechanisms in Leukemia.

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation.

Targeting Unique Features of Quiescent Cancer Stem Cells to Overcome Resistance and Recurrence in Cancer Therapy: A Review

Quiescent cancer stem cells (QCSC) are non-proliferating cells that survive in the G0 phase and have low ki-67 expression and high p27 expression. QCSCs have the ability to evade most chemotherapy, and some subsequent treatments may result in a higher proportion of quiescent cancer stem cells in the tumor. QCSCs are also associated with cancer recurrence rates because they can re-enter the cell cycle to proliferate when tumor environmental conditions are favorable. QCSCs cause high rates of drug resistance and tumor recurrence, therefore it is necessary to understand the properties of QCSCs. QCSCs have a mechanism that regulates the transition between the proliferative phase and the stationary phase in cancer cells, therefore it is necessary to find new treatments to eliminate QCSCs in tumors. In this review, the authors discuss the mechanisms of QCSCs in inducing drug resistance and tumor recurrence as well as therapies to target QCSCs so that the rate of drug resistance and tumor recurrence can be reduced, including in this review: (i) identifying reactive quiescent cancer cells and eliminating them through anticancer reagents. cell cycle dependent; (ii) modulating the transition from the quiescent to the proliferative phase; and (iii) eliminate QCSC by targeting its unique features. Targeting cancer cells that are in proliferating and stationary phase may ultimately be used as a more effective therapeutic strategy for cancer treatment.

Laboratory tests and analysis of drug resistance in non-tuberculous mycobacteria

BackgroundThis study analyzed the laboratory diagnosis results and drug resistance of patients infected with non-tuberculous mycobacterium (NTM). MethodsWe collected information on patients with positive indicators of NTM infection at the Henan Provincial Chest Hospital from 2020 to 2022. Acid-fast smear, mycobacterium culture, QB-SPOT assay, GeneXpert MTB/RIF assay, immunoglobulin E test, tuberculosis antibody test, and microplate method for drug sensitivity test were analyzed using strain identification as the gold standard. ResultsThe 242 cases of NTM infection were predominantly detected with slow-growing mycobacteria (a detection rate of 87.19%), among which Mycobacterium intracellulare (66.53%), Mycobacterium avium (15.70%), and Mycobacterium chelonei/abscessus complex (11.16%) ranked the top three in terms of the isolation rate. Males patients accounted for a higher proportion (58.26%) than females (41.74%), and the majority of them were over 60 years (50.83%). Among laboratory tests for patients with NTM infection, mycobacterium culture showed a highest detected rate (87.20%) among laboratory tests. The results of the drug sensitivity test demonstrated that the resistance rate of NTM was generally high. Moreover, the Mycobacterium avium complex with the highest isolation rate showed 100% resistant to doxycycline and minocycline, but exhibited relatively high sensitivity to moxifloxacin (a resistance rate of 7.89%) and rifabutin (a resistance rate of 13.16%). The Mycobacterium chelonei/abscessus complex was 100% resistant to doxycycline and relatively sensitive to cefoxitin (29.17%) and clarithromycin (37.50%). ConclusionThe NTM species isolated by the Henan Provincial Chest Hospital is dominated by Mycobacterium intracellulare and the highest positive rate is detected by mycobacterium culture among laboratory tests. NTM infection generally exhibits a high rate of drug resistance. Accordingly, the accurate diagnosis of NTM diseases requires enhanced drug sensitivity testing to provide patients with targeted combination drug treatment.

Molecular characteristics and biofilm formation capacity of nontypeable Haemophilus influenza strains isolated from lower respiratory tract in children

With the widespread introduction of the Hib conjugate vaccine, Nontypeable Haemophilus influenzae (NTHi) has emerged as the predominant strain globally. NTHi presents a significant challenge as a causative agent of chronic clinical infections due to its high rates of drug resistance and biofilm formation. While current research on NTHi biofilms in children has primarily focused on upper respiratory diseases, investigations into lower respiratory sources remain limited. In this study, we collected 54 clinical strains of lower respiratory tract origin from children. Molecular information and drug resistance features were obtained through whole gene sequencing and the disk diffusion method, respectively. Additionally, an in vitro biofilm model was established. All clinical strains were identified as NTHi and demonstrated the ability to form biofilms in vitro. Based on scanning electron microscopy and crystal violet staining, the strains were categorized into weak and strong biofilm-forming groups. We explored the correlation between biofilm formation ability and drug resistance patterns, as well as clinical characteristics. Stronger biofilm formation was associated with a longer cough duration and a higher proportion of abnormal lung imaging findings. Frequent intake of β-lactam antibiotics might be associated with strong biofilm formation. While a complementary relationship between biofilm-forming capacity and drug resistance may exist, further comprehensive studies are warranted. This study confirms the in vitro biofilm formation of clinical NTHi strains and establishes correlations with clinical characteristics, offering valuable insights for combating NTHi infections.

Carbapenemase Genes, Virulence Genes, and Molecular Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae Derived From Bloodstream Infections

To investigate the clinical characteristics and molecular epidemiology of carbapenem-resistant Klebsiella pneumoniae (CRKP) isolated from patients with bloodstream infections in a large tertiary-care general hospital in Southwest China. A total of 131 strains of non-repeating CRKP were collected from the blood cultures of patients who had bloodstream infections in 2015-2019. The strains were identified by VITEK-2, a fully automated microbial analyzer, and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry. The minimum inhibitory concentration (MIC) was determined by microbroth dilution method. The common carbapenemase resistant genes and virulence factors were identified by PCR. Homology analysis was performed by multilocus sequencing typing. Whole genome sequencing was performed to analyze the genomic characteristics of CRKP without carbapenemase. The 131 strains of CRKP showed resistance to common antibiotics, except for polymyxin B (1.6% resistance rate) and tigacycline (8.0% resistance rate). A total of 105 (80.2%) CRKP strains carried the Klebsiella pneumoniae carbapenemase (KPC) resistance gene, 15 (11.4%) strains carried the New Delhi Metallo-β-lactamase (NDM) gene, and 4 (3.1%) isolates carried both KPC and NDM genes. Sequence typing (ST) 11 (74.0%) was the dominant sequence type. High detection rates for mrkD (96.2%), fimH (98.5%), entB (100%), and other virulence genes were reported. One hypervirulent CRKP strain was detected. The seven strains of CRKP that did not produce carbapenemase were shown to carry ESBL or AmpC genes and had anomalies in membrane porins OMPK35 and OMPK36, according to whole genome sequencing. In a large-scale tertiary-care general hospital, CRKP mainly carries the KPC gene, has a high drug resistance rate to a variety of antibiotics, and possesses multiple virulence genes. Attention should be paid to CRKP strains with high virulence.

Anticancer and Antibacterial Properties of Curcumin-Loaded Mannosylated Solid Lipid Nanoparticles for the Treatment of Lung Diseases.

Lung cancer and Mycobacterium avium complex infection are lung diseases associated with high incidence and mortality rates. Most conventional anticancer drugs and antibiotics have certain limitations, including high drug resistance rates and adverse effects. Herein, we aimed to synthesize mannose surface-modified solid lipid nanoparticles (SLNs) loaded with curcumin (Man-CUR SLN) for the effective treatment of lung disease. The synthesized Man-CUR SLNs were analyzed using various instrumental techniques for structural and physicochemical characterization. Loading curcumin into SLNs improved the encapsulation efficiency and drug release capacity, as demonstrated by high-performance liquid chromatography analysis. Furthermore, we characterized the anticancer effect of curcumin using the A549 lung cancer cell line. Cells treated with Man-CUR SLN exhibited an increased cellular uptake and cytotoxicity. Moreover, treatment with free CUR could more effectively reduce cancer migration than treatment with Man-CUR SLNs. Similarly, free curcumin elicited a stronger apoptosis-inducing effect than that of Man-CUR SLNs, as demonstrated by reverse transcription-quantitative PCR analysis. Finally, we examined the antibacterial effects of free curcumin and Man-CUR SLNs against Mycobacterium intracellulare (M.i.) and M.i.-infected macrophages, revealing that Man-CUR SLNs exerted the strongest antibacterial effect. Collectively, these findings indicate that mannose-receptor-targeted curcumin delivery using lipid nanoparticles could be effective in treating lung diseases. Accordingly, this drug delivery system can be used to target a variety of cancers and immune cells.

Whole Genome Sequence-Based Analyses of Drug Resistance Characteristics, Genetic Diversity, and Transmission Dynamics of Drug-Resistant Mycobacterium tuberculosis in Urumqi City.

This study aims to analyze the drug resistance spectrum, genetic diversity, and transmission dynamics to provide a basis for the prevention and control of drug-resistant (DR) tuberculosis (TB) epidemics. This retrospective study is based on routine national drug resistance surveillance. The demographic, epidemiological, and clinical information on DR-TB patients from 2016 to 2021 was collected and used for phenotypic drug susceptibility testing and whole-genome sequencing. It was indicated that L2.2.1 was the dominant lineage in Urumqi. The drug resistance spectrum in Urumqi was narrow, which means more drug combinations can be used for clinical treatment. Furthermore, mutations identification of drug-resistance gene katG, rpoB, embA/B, rrs, rpsL, eis, gyrA/B, folC and tryA are important for clinical drug use. However, mutations in cross-resistance genes rrs have limited guidance for clinical selection of KM, CPM and AK. Moreover, there is an increased risk of cluster transmission of DR-TB, and the difference in clustering rate among L2, L3, and L4 was not statistically significant (χ2 = 2.6410, p = 0.2670). In the Urumqi, DR-TB has a complex prevalence state, a narrow drug resistance spectrum, and a high clustering rate and burden of drug resistance. To reduce the burden of DR-TB, related research should be strengthened, and the development of prevention, control, and treatment strategies should be accelerated.

Natural compounds target programmed cell death (PCD) signaling mechanism to treat ulcerative colitis: a review.

Ulcerative colitis (UC) is a nonspecific inflammatory bowel disease characterized by abdominal pain, bloody diarrhea, weight loss, and colon shortening. However, UC is difficult to cure due to its high drug resistance rate and easy recurrence. Moreover, long-term inflammation and increased disease severity can lead to the development of colon cancer in some patients. Programmed cell death (PCD) is a gene-regulated cell death process that includes apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. PCD plays a crucial role in maintaining body homeostasis and the development of organs and tissues. Abnormal PCD signaling is observed in the pathological process of UC, such as activating the apoptosis signaling pathway to promote the progression of UC. Targeting PCD may be a therapeutic strategy, and natural compounds have shown great potential in modulating key targets of PCD to treat UC. For instance, baicalin can regulate cell apoptosis to alleviate inflammatory infiltration and pathological damage. This review focuses on the specific expression of PCD and its interaction with multiple signaling pathways, such as NF-κB, Nrf2, MAPK, JAK/STAT, PI3K/AKT, NLRP3, GPX4, Bcl-2, etc., to elucidate the role of natural compounds in targeting PCD for the treatment of UC. This review used (ulcerative colitis) (programmed cell death) and (natural products) as keywords to search the related studies in PubMed and the Web of Science, and CNKI database of the past 10years. This work retrieved 72 studies (65 from the past 5years and 7 from the past 10years), which aims to provide new treatment strategies for UC patients and serves as a foundation for the development of new drugs.

Tanshinone IIA inhibits proliferation and migration by downregulation of the PI3K/Akt pathway in small cell lung cancer cells

BackgroundSmall cell lung cancer (SCLC) is the most malignant lung cancer type. Due to the high rates of metastasis and drug resistance, effective therapeutic strategies remain lacking. Tanshinone IIA (Tan IIA) has been reported to exhibit anti-tumor activity. Therefore, this study investigated the ability and underlying mechanism of Tan IIA to inhibit the metastasis and proliferation of SCLC.MethodsH1688 and H446 cells were treated in vitro with Tan IIA (0, 1, 2 and 4 µM) or LY294002 (10 µM) for 24, 48, 72 h. H1688 and H446 cell migration was evaluated in wound healing and transwell migration assays. RNA-sequencing helped assess gene expression. BALB/c nude mice were injected with H1688 cells and treated with the Tan IIA group (10 mg/kg/day) or a control. Expression of E-cadherin, vimentin and PI3K/Akt signaling pathway proteins in tumors and H1688 was investigated by immunohistochemical analysis and western blot.ResultsTan IIA inhibited H1688 and H446 cell proliferation without inducing apoptosis and suppressed H1688 and H446 cell migration. E-cadherin expression was increased, while vimentin expression was reduced after administration of Tan IIA. RNA-sequencing revealed that some genes related with the PI3K/Akt signaling pathway were altered using Tan IIA treatment. Furthermore, western blot helped detect PI3K and p-Akt expression was also reduced by Tan IIA treatment. Tan IIA inhibited tumor growth in vivo. Moreover, Tan IIA increased tumoral expression of E-cadherin accompanied by PI3K and p-Akt downregulation.ConclusionTan IIA suppresses SCLC proliferation and metastasis by inhibiting the PI3K/Akt signaling pathway, thereby highlighting the potential of Tan IIA as a new and relatively safe drug candidate to treat SCLC.

Immune-endocrine network in diabetes-tuberculosis nexus: does latent tuberculosis infection confer protection against meta-inflammation and insulin resistance?

Tuberculosis patients with diabetes, have higher sputum bacillary load, delayed sputum conversion, higher rates of drug resistance, higher lung cavitary involvement and extra-pulmonary TB infection, which is called as "Diabetes-Tuberculosis Nexus". However, recently we have shown a reciprocal relationship between latent tuberculosis infection and insulin resistance, which has not been reported before. In this review, we would first discuss about the immune-endocrine network, which operates during pre-diabetes and incipient diabetes and how it confers protection against LTBI. The ability of IR to augment anti-TB immunity and the immunomodulatory effect of LTBI to quench IR were discussed, under IR-LTB antagonism. The ability of diabetes to impair anti-TB immunity and ability of active TB to worsen glycemic control, were discussed under "Diabetes-Tuberculosis Synergy". The concept of "Fighter Genes" and how they confer protection against TB but susceptibility to IR was elaborated. Finally, we conclude with an evolutionary perspective about how IR and LTBI co-evolved in endemic zones, and have explained the molecular basis of "IR-LTB" Antagonism" and "DM-TB Synergy", from an evolutionary perspective.

Comparison of molecular and microbiological detection rates of Mycobacterium tuberculosis and prevalence of SARS-CoV-2 variants in Monterrey, Mexico

BackgroundTuberculosis (TB) is a severe global health problem, with high drug resistance rates. The emergence of the coronavirus disease 2019 (COVID-19) pandemic caused worldwide setback progress in TB control. Our aim was to compare detection rates of Mycobacterium tuberculosis at different COVID-19 pandemic waves. MethodsPatients (n = 1800) were evaluated using microbiological and molecular assays for mycobacterial detection in a hospital from Monterrey, Mexico. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected by real-time PCR. Data from existing reports of circulating SARS-CoV-2 variants was compared to data of TB prevalence. ResultsThe prevalence of TB was 30.4%. Compared to pre-pandemic, the detection rate of mycobacteria was higher during the first wave. The co-infection of Mycobacterium tuberculosis complex (MTC) and SARS-CoV-2 occurred in seven patients. MTC cases showed several waves which might depend on the prevalence of specific SARS-CoV-2 variants. ConclusionThe COVID-19 pandemic impacted on TB detection on our population, although it is still uncertain if it was mostly due to the influence of specific SARS-CoV-2 variants or to restrictions measures in the region. Public health measures should include the combination of TB and COVID-19 diagnostic screening in TB-endemic settings, such as ours, to restore TB control attempts.

Development of a cell adhesion-based prognostic model for multiple myeloma: Insights into chemotherapy response and potential reversal of adhesion effects.

Multiple myeloma (MM) is a hematologic malignancy notorious for its high relapse rate and development of drug resistance, in which cell adhesion-mediated drug resistance plays a critical role. This study integrated four RNA sequencing datasets (CoMMpass, GSE136337, GSE9782, and GSE2658) and focused on analyzing 1706 adhesion-related genes. Rigorous univariate Cox regression analysis identified 18 key prognosis-related genes, including KIF14, TROAP, FLNA, MSN, LGALS1, PECAM1, and ALCAM, which demonstrated the strongest associations with poor overall survival (OS) in MM patients. To comprehensively evaluate the impact of cell adhesion on MM prognosis, an adhesion-related risk score (ARRS) model was constructed using Lasso Cox regression analysis. The ARRS model emerged as an independent prognostic factor for predicting OS. Furthermore, our findings revealed that a heightened cell adhesion effect correlated with tumor resistance to DNA-damaging drugs, protein kinase inhibitors, and drugs targeting the PI3K/Akt/mTOR signaling pathway. Nevertheless, we identified promising drug candidates, such as tirofiban, pirenzepine, erlotinib, and bosutinib, which exhibit potential in reversing this resistance. In vitro, experiments employing NCIH929, RPMI8226, and AMO1 cell lines confirmed that MM cell lines with high ARRS exhibited poor sensitivity to the aforementioned candidate drugs. By employing siRNA-mediated knockdown of the key ARRS model gene KIF14, we observed suppressed proliferation of NCIH929 cells, along with decreased adhesion to BMSCs and fibronectin. This study presents compelling evidence establishing cell adhesion as a significant prognostic factor in MM. Additionally, potential molecular mechanisms underlying adhesion-related resistance are proposed, along with viable strategies to overcome such resistance. These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM.

Antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae isolates among children in Suzhou, China.

Streptococcus pneumoniae (SP) is responsible for pneumococcal diseases with severe morbidity and mortality. High rates of drug resistance constitute serious public health concerns. Vaccination has proven to be an effective means of reducing disease burden. Epidemiological information of antibiotic susceptibilities and serotype distribution will be of great help to the management of pneumococcal infections. This study reported the serotype distribution and antibiotic resistance pattern of SP in hospitalized children in Suzhou during the years 2017-2018. The aim is to reduce pneumococcal resistance and guide vaccination. The clinical data of hospitalized children with SP were collected and analyzed. A total of 2,446 strains of SP were isolated from these patients. Serotypes were determined using the Quellung reaction. Antibiotic resistance was tested using the E-test diffusion method. The non-susceptible rates of the isolates to penicillin, amoxicillin, and cefotaxime were 9.5%, 27.7%, and 27.2%, respectively. And 97.6% of SP isolates showed multidrug-resistant (MDR). The most common resistance pattern of non-invasive isolates was macrolides + sulfamethoxazole + clindamycin + tetracycline. The major serotypes of this resistance pattern were 6A, 23F, 6B, 19F, 15B. The most extensive resistance pattern of invasive isolates was macrolides + β-lactams + sulfamethoxazole + clindamycin + tetracycline. The most common serotypes of the pattern were 19F, 19A, 6B, 23F, 6A. The most common serotypes were 19F (28.6%), 6B (11.9), 23F (11.2%), 6A (10.6%), and 19A (9.1%). In the isolates with MDR, the first five most common serotypes were 19F, non-vaccine serotype (NVT), 6B, 6A and 23F. Strains belonging to different serotypes exhibited distinct antimicrobial resistance patterns and were found to be associated with different diseases. The coverage rates of pneumococcal conjugate vaccine (PCV)7 and PCV13 in all isolates reached 60.4% (310/513) and 80.9% (415/513), respectively. The main serotypes of SP in Suzhou were 19F, 6B, 23F, 6A, and 19A. The use of PCV13 is beneficial to children in Suzhou.

BIOM-29. FIBRONECTIN TYPE III DOMAIN CONTAINING 3B AS PROGNOSTIC BIOMARKER AND REGULATORY TARGET FOR MALIGNANT BRAIN TUMOR

Abstract Malignant brain tumor (MBT) is an aggressive tumor with high drug-resistance and recurrence rates. Using ‘Oncopression’ big data analysis, we found that a fibronectin-related protein, fibronectin type III domain containing 3B (FNDC3B), was specifically overexpressed in brain tumor patients and conducted a pilot and mechanism study on the role of FNDC3B in MBT. We evaluated the functional significance of FNDC3B in MBT using FNDC3B specific siRNA and performing cell viability assay, real-time qPCR, Western blot, 3D-invasion assay, and wound healing assay. Furthermore, using proteome profiler human phospho-kinase arrays, we investigated the correlated signaling which activated while FNDC3B-mediated MBT cell progression. We found that down-regulation of FNDC3B decreased tumor cell proliferation, migratory and invasiveness properties as well as stemness phenotype which are hallmarks of cancer progression. Furthermore, we demonstrate that PI3K/AKT signaling pathways were involved mainly in FNDC3B-related tumor growth and mesenchymal phenotypes. Although follow-up studies are necessary, the results of this study suggest that FNDC3B is worth investigating as a novel alternative diagnostic and therapeutic target candidate for MBT.

Challenges in management of invasive fungal infections in stem cell transplant.

Invasive fungal infections cause significant morbidity and mortality in hematopoietic stem cell transplant recipients. In order to minimize these infections, prophylaxis has become routine, although the agents used have changed over time. This presents new challenges as we consider an approach to breakthrough infections and recognize the epidemiologic shift toward isolates with higher rates of drug resistance. This review outlines the management of the most common pathogens (Candida, Aspergillus, Mucorales) as well as rarer pathogens that have higher rates of resistance (Trichosporon, Fusarium, Scedosporium, and Lomentospora). We discuss potential approaches to proven or possible breakthrough infections with yeast and pulmonary mold disease. Finally, we outline the role for combination therapy and newer antifungals, acknowledging current knowledge gaps and areas for future exploration.

HIV-1 Disease Progression and Drug Resistance Mutations among Children on First-Line Antiretroviral Therapy in Ethiopia.

Background: High rates of disease progression and HIV drug resistance (HIVDR) among adults taking highly active antiretroviral treatment (HAART) in Sub-Saharan Africa were previously documented. However, children were generally not considered despite their greater risk. Hence, this study was aimed to evaluate HIV-1 disease progression and drug resistance mutation among children on first-line antiretroviral therapy in Ethiopia. Method: A longitudinal study was conducted among 551 HIV-positive children (<15 years old) recruited between 2017 and 2019 at 40 antiretroviral treatment delivery sites in Ethiopia. Disease progression was retrospectively measured over a 12-year (2007-2019) follow-up as the progress towards immunosuppression. Two consecutive viral load (VL) tests were conducted in 6-month intervals to assess virologic failure (VF). For children with VF, HIV-1 genotyping and sequencing was performed for the pol gene region using in-house assay validated at the Chinese Center for Disease Control and Prevention, and the Stanford HIVDB v9.0 algorithm was used for identification of drug resistance mutations. The Kaplan-Meier analysis and Cox proportional hazards regression model were used to estimate the rate and predictors of disease progression, respectively. Results: The disease progression rate was 6.3 per 100 person-years-observation (95% CI = 4.21-8.53). Overall immunosuppression (CD4 count < 200 cells/mm3) during the 12-year follow-up was 11.3% (95% CI = 7.5-15.1). Immunosuppression was significantly increased as of the mean duration of 10.5 (95% CI = 10.1-10.8) years (38.2%) to 67.8% at 12 years (p < 0.001). Overall, 14.5% had resistance to at least one drug, and 6.2% had multi-drug resistance. A resistance of 67.8% was observed among children with VF. Resistance to non-nucleotide reverse transcriptase inhibitors (NNRTI) and nucleotide reverse transcriptase inhibitors (NRTI) drugs were 11.4% and 10.1%, respectively. Mutations responsible for NRTI resistance were M184V (30.1%), K65R (12.1%), and D67N (5.6%). Moreover, NNRTI-associated mutations were K103N (14.8%), Y181C (11.8%), and G190A (7.7%). Children who had a history of opportunistic infection [AHR (95% CI) = 3.4 (1.8-6.2)], vitamin D < 20 ng/mL [AHR (95% CI) = 4.5 (2.1-9.9)], drug resistance [AHR (95% CI) = 2.2 (1.4-3.6)], and VF [AHR (95% CI) = 2.82 (1.21, 3.53)] had a higher hazard of disease progression; whereas, being orphan [AOR (95% CI) = 1.8 (1.2-3.1)], history of drug substitution [(AOR (95% CI) = 4.8 (2.1-6.5), hemoglobin < 12 mg/dL [AOR (95% CI) = 1.2 (1.1-2.1)] had higher odds of developing drug resistance. Conclusions: Immunosuppression was increasing over time and drug resistance was also substantially high. Enhancing routine monitoring of viral load and HIVDR and providing a vitamin-D supplement during clinical management could help improve the immunologic outcome. Limiting HAART substitution is also crucial for children taking HAART in Ethiopia.

Synergistic and Long-Lasting Wound Dressings Promote Multidrug-Resistant Staphylococcus Aureus-Infected Wound Healing.

Multidrug-resistant staphylococcus aureus infected wounds can lead to nonhealing, systemic infections, and even death. Although advanced dressings are effective in protecting, disinfecting, and maintaining moist microenvironments, they often have limitations such as single functionality, inadequate drug release, poor biosafety, or high rates of drug resistance. Here, a novel wound dressing comprising glycyrrhizic acid (GA) and tryptophan-sorbitol carbon quantum dots (WS-CQDs) was developed, which exhibit synergistic and long-lasting antibacterial and anti-inflammatory effects. We investigated the characterization, mechanical properties, synergistic antibacterial effects, sustained-release properties, and cytotoxicity of GA/WS-CQDs hydrogels in vitro. Additionally, we performed transcriptome sequence analysis to elucidate the antibacterial mechanism. Furthermore, we evaluated the biosafety, anti-inflammatory effects, and wound healing ability of GA/WS-CQDs dressings using an in vivo mouse model of methicillin-resistant staphylococcus aureus (MRSA)-infected wounds. The prepared GA/WS-CQDs hydrogels demonstrated superior anti-MRSA effects compared to common antibiotics in vitro. Furthermore, the sustained release of WS-CQDs from GA/WS-CQDs hydrogels lasted for up to 60 h, with a cumulative release of exceeding 90%. The sustained-released WS-CQDs exhibited excellent anti-MRSA effects, with low drug resistance attributed to DNA damage and inhibition of bacterial biofilm formation. Notably, in vivo experiments showed that GA/WS-CQDs dressings reduced the expression of inflammatory factors (TNF-α, IL-1β, and IL-6) and significantly promoted the healing of MRSA-infected wounds with almost no systemic toxicity. Importantly, the dressings did not require replacement during the treatment process. These findings emphasize the high suitability of GA/WS-CQDs dressings for MRSA-infected wound healing and their potential for clinical translation.