Drug Resistance Rate Research Articles

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.

Selenization of Small Molecule Drugs: A New Player on the Board.

There is an urgent need to develop safer and more effective modalities for the treatment of a wide range of pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Throughout the years, selenium (Se) has attracted a great deal of attention due to its important role in human health. Besides, a growing body of work has unveiled that the inclusion of Se motifs into a great number of molecules is a promising strategy for obtaining novel therapeutic agents. In the current Perspective, we have gathered the most recent literature related to the incorporation of different Se moieties into the scaffolds of a wide range of known drugs and their feasible pharmaceutical applications. In addition, we highlight different representative examples as well as provide our perspective on Se drugs and the possible future directions, promises, opportunities, and challenges of this ground-breaking area of research.

Anti-Leishmania major Properties of Nuphar lutea (Yellow Water Lily) Leaf Extracts and Purified 6,6' Dihydroxythiobinupharidine (DTBN).

Cutaneous leishmaniasis (CL) is a zoonotic disease, manifested as chronic ulcers, potentially leaving unattractive scars. There is no preventive vaccination or optimal medication against leishmaniasis. Chemotherapy generally depends upon a small group of compounds, each with its own efficacy, toxicity, and rate of drug resistance. To date, no standardized, simple, safe, and highly effective regimen for treating CL exists. Therefore, there is an urgent need to develop new optimal medication for this disease. Sesquiterpen thio-alkaloids constitute a group of plant secondary metabolites that bear great potential for medicinal uses. The nupharidines found in Nuphar lutea belong to this group of compounds. We have previously published that Nuphar lutea semi-purified extract containing major components of nupharidines has strong anti-leishmanial activity in vitro. Here, we present in vivo data on the therapeutic benefit of the extract against Leishmania major (L. major) in infected mice. We also expanded these observations by establishing the therapeutic effect of the extract-purified nupharidine 6,6'-dihydroxythiobinupharidine (DTBN) in vitro against promastigotes and intracellular amastigotes as well as in vivo in L. major-infected mice. The results suggest that this novel anti-parasitic small molecule has the potential to be further developed against Leishmania.

Exploring the causes of the prevalence of vancomycin-resistant Enterococcus faecalis

BackgroundBacterial drug resistance represents a significant global concern, with vancomycin-resistant Enterococcus faecalis posing a particularly grave threat to contemporary healthcare systems. This study aims to reveal the reasons for the prevalence of VRE in China.MethodsThis study collected data from the China Antimicrobial Resistance Detection System, China Statistical Yearbook, and China Meteorological Network. The collected data are meticulously organized and subjected to both single-factor and multi-factor analyses. An accurate multiple linear regression model was developed by utilizing this comprehensive dataset.ResultsSingle-factor analysis revealed significant regional variations in the resistance rate of vancomycin-resistant Enterococcus faecalis (P = 0.003). Specifically, there were noteworthy disparities observed between regions experiencing temperate and monsoon climates (P = 0.029; P = 0.005). Furthermore, multi-factor regression analysis demonstrated a negative correlation between the drug resistance rate and both rainfall and rGDP, while a positive correlation was observed with nPI.ConclusionWe successfully established a prediction model for the VRE and found that the resistance rate was low in areas with high rainfall and high per capita economic income, but high in areas with many specialized public health institutions. This is critical for public health strategies and helps policymakers and healthcare practitioners tailor antibiotic resistance approaches to local geography, meteorology, economic conditions.

Multicenter Investigation of Drug-Resistance in Burkholderia Cepacia Bloodstream Infections in Hebei Province, China, from 2016 to 2021.

To compare the epidemiological characteristics and drug resistance of Burkholderia cepacia isolated from blood cultures, and to provide data support and a scientific basis for the clinical treatment and detection of hospital infections. The Hebei Province Antimicrobial Surveillance Network received 349 B. cepacia strains isolated from blood cultures reported by 83 hospitals, from 2016 to 2021. These strains were identified by MALDI-TOF MS and, the antibiotic sensitivity tests were carried out using the VITEK 2 COMPACT system. The 2023 Institute of Clinical and Laboratory Standardization drug-susceptibility breakpoints were used for drug susceptibility testing and the data were analyzed using WHONET5.6 software. A total of 349 B. cepacia strains were isolated from 2016 to 2021, including 68 strains from secondary hospitals and 281 strains from tertiary hospitals. The ratios of male: female patients with B. cepacia bloodstream infections in all hospitals, secondary hospitals, and tertiary hospitals were 1.49:1 (209/140), 2.09:1 (46/22), and 1.38:1 (163/118), respectively. Most B. cepacia strains were isolated in intensive care units (ICUs), followed by internal medicine departments, accounting for 49.57% (173/349) and 22.92% (80/349), respectively. Regarding the age distribution, most patients were elderly (>65 years, 57.59%, 201/349), with numbers of patients gradually declining with decreasing of age. The resistance rates for levofloxacin, ceftazidime, and sulfamethoxazole decreased over the 6-year period (P<0.05), while there were no significant changes in the resistance rates for meropenem, chloramphenicol, and minocycline (P>0.05). There was no significant difference in drug-resistance rates between secondary and tertiary hospitals (P>0.05). Attention should be paid to bloodstream infections caused by B. cepacia, especially elderly patients and patients admitted to the ICU. The difficult treatment characteristics of B. cepacia bloodstream infections mean that laboratories and clinicians should pay careful attention to drug resistance to provide a basis for their prevention and empirical treatment.

Identification of novel resistance-associated mutations and discrimination within whole-genome sequences of fluoroquinolone-resistant Mycobacterium tuberculosis isolates.

This study aims to elucidate additional mutation loci associated with fluoroquinolone (FQ) resistance and evaluate the discriminatory capacity of mutation loci and allele mutation frequencies in identifying FQ-resistant Mycobacterium tuberculosis (MTB) isolates. A random selection of isolates was extracted from an ongoing collection. Drug resistance was determined using the resazurin microtiter assay (REMA) as the gold standard. Mutation loci and the burden of mutations in the quinolone resistance-determining region (QRDR) were elucidated through whole-genome sequencing (WGS). Novel amino acid mutations, namely, G520D and G520T, were identified in the gyrB and associated with FQ resistance. In the context of distinguishing FQ-resistant isolates, the AUC for the QRDR mutation frequency burden (0.969) surpassed that of the mutation locus (0.929), and this difference was statistically significant (P = 0.03). Furthermore, using the resistance mutation locus as a reference, setting the QRDR mutation frequency burden threshold at 1.31% resulted in a 3.60% increase in the accuracy of classifying FQ-resistant isolates (NRI = 3.60%, P < 0.001). The QRDR mutation frequency burden appears to offer superior diagnostic efficacy in discriminating FQ-resistant isolates compared to qualitative detection of mutant loci.IMPORTANCEFluoroquinolone (FQ) drugs are recommended as second-line drugs for the treatment of multidrug-resistant tuberculosis. With the massive use of FQ drugs in the clinical treatment of tuberculosis (TB), there is an increasing rate of drug resistance to FQ drugs. In this study, we identified and demonstrated novel amino acid mutations associated with FQ resistance in Mycobacterium tuberculosis (MTB), and we quantified the mutation sites and identified the quinolone resistance-determining region (QRDR) mutation frequency burden as a novel diagnostic method for FQ resistance. We hope that the results of this study will provide data support and a theoretical basis for the rapid diagnosis of FQ-resistant MTB.

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.

Seasonal meropenem resistance in Acinetobacter baumannii and influence of temperature-driven adaptation

BackgroundRecognition of seasonal trends in bacterial infection and drug resistance rates may enhance diagnosis, direct therapeutic strategies, and inform preventive measures. Limited data exist on the seasonal variability of Acinetobacter baumannii. We investigated the seasonality of A. baumannii, the correlation between temperature and meropenem resistance, and the impact of temperature on this bacterium.ResultsMeropenem resistance rates increased with lower temperatures, peaking in winter/colder months. Nonresistant strain detection exhibited temperature-dependent seasonality, rising in summer/warmer months and declining in winter/colder months. In contrast, resistant strains showed no seasonality. Variations in meropenem-resistant and nonresistant bacterial resilience to temperature changes were observed. Nonresistant strains displayed growth advantages at temperatures ≥ 25 °C, whereas meropenem-resistant A. baumannii with β-lactamase OXA-23 exhibited greater resistance to low-temperature (4 °C) stress. Furthermore, at 4 °C, A. baumannii upregulated carbapenem resistance-related genes (adeJ, oxa-51, and oxa-23) and increased meropenem stress tolerance.ConclusionsMeropenem resistance rates in A. baumannii display seasonality and are negatively correlated with local temperature, with rates peaking in winter, possibly linked to the differential adaptation of resistant and nonresistant isolates to temperature fluctuations. Furthermore, due to significant resistance rate variations between quarters, compiling monthly or quarterly reports might enhance comprehension of antibiotic resistance trends. Consequently, this could assist in formulating strategies to control and prevent resistance within healthcare facilities.

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.

Detection of Macrolide-Resistant Streptococcus pneumoniae Genes and Its Clinical Outcomes in a Tertiary Teaching Hospital in Malaysia.

Streptococcus pneumoniae is one of the leading causes of mortality and morbidity worldwide. The dramatic increase in in-vitro resistance of antimicrobial agents, particularly beta-lactams and macrolides, makes pneumococcal infections difficult to treat. The aim of this study was to describe the drug resistance rate, assess the prevalence of macrolide-resistant genes and review the clinical complications of pneumococcal infections among patients presented to Hospital Universiti Sains Malaysia (HUSM), Kelantan, Malaysia. This is a descriptive cross-sectional study. All S. pneumoniae isolates collected from clinical specimens within a 1-year period were subjected to selected antimicrobial susceptibility testing using E-test strips. Polymerase chain reaction (PCR) analysis was conducted to detect macrolide-resistant determinants. The patient's clinical data were obtained from clinical notes. A total of 113 patients with a positive growth of S. pneumoniae were included in the study. The most common predisposing factors among them were bronchopulmonary diseases (15.9%). The penicillin-resistant rate was 7.1%, with minimal inhibitory concentration (MIC) ranging between 0.012 μg/mL and >32 μg/mL, and the erythromycin-resistant rate was 26.5%, with a MIC range of 0.03 μg/mL-> 256 μg/mL. Most of the erythromycin-resistant isolates were found to have the mef(A) gene (50.4%) and the erm(B) gene (20%); 16.7% had a combination of genes mef(A) and erm(B), and 13.3% had none of the two genes. Community-acquired pneumonia is the predominant type of pneumococcal infection. There was no significant association between the presence of macrolide resistance determinants and mortality (P = 0.837) or complications (P > 0.999 for empyema and cardiac complication; P = 0.135 for subdural abscess). The majority of erythromycin-resistant isolates were found to have the mef(A) gene, followed by the erm(B) gene and a combination of genes mef(A) and erm(B).

Whole-Genome Sequencing and Phenotypic Analysis of Streptococcus equi subsp. zooepidemicus Sequence Type 147 Isolated from China.

Streptococcus equi subsp. zooepidemicus (S. zooepidemicus) is one of the important zoonotic and opportunistic pathogens. In recent years, there has been growing evidence that supports the potential role of S. zooepidemicus in severe diseases in horses and other animals, including humans. Furthermore, the clinical isolation and drug resistance rates of S. zooepidemicus have been increasing yearly, leading to interest in its in-depth genomic analysis. In order to deepen the understanding of the S. zooepidemicus characteristics and genomic features, we investigated the genomic islands, mobile genetic elements, virulence and resistance genes, and phenotype of S. zooepidemicus strain ZHZ 211 (ST147), isolated from an equine farm in China. We obtained a 2.18 Mb, high-quality chromosome and found eight genomic islands. According to a comparative genomic investigation with other reference strains, ZHZ 211 has more virulence factors, like an iron uptake system, adherence, exoenzymes, and antiphagocytosis. More interestingly, ZHZ 211 has acquired a mobile genetic element (MGE), prophage Ph01, which was found to be in the chromosome of this strain and included two hyaluronidase (hyl) genes, important virulence factors of the strain. Moreover, two transposons and two virulence (virD4) genes were found to be located in the same genome island of ZHZ 211. In vitro phenotypic results showed that ZHZ 211 grows faster and is resistant to clarithromycin, enrofloxacin, and sulfonamides. The higher biofilm-forming capabilities of ZHZ 211 may provide a competitive advantage for survival in its niche. The results expand our understanding of the genomic, pathogenicity, and resistance characterization of Streptococcus zooepidemicus and facilitate further exploration of its molecular pathogenic mechanism.

Trends in and Risk Factors for Drug Resistance in Mycobacterium tuberculosis in HIV-Infected Patients.

Trends in and risk factors for drug resistance in Mycobacterium tuberculosis (M. tuberculosis) in human immunodeficiency virus (HIV)-infected patients with active tuberculosis were analyzed. The clinical data of M. tuberculosis and HIV-coinfected patients treated at the Shanghai Public Health Clinical Center between 2010 and 2022 were collected. The diagnosis of tuberculosis was confirmed by solid or liquid culture. The phenotypic drug susceptibility test was carried out via the proportional method, and the resistance to first-line and second-line drugs was analyzed. Logistic regression analysis was performed to identify associated risk factors for drug resistance in M. tuberculosis. Of the 304 patients with a M. tuberculosis-positive culture and first-line drug susceptibility test results, 114 (37.5%) were resistant to at least one first-line anti-tuberculosis drug. Of the 93 patients with first-line and second-line drug susceptibility test results, 40 (43%) were resistant to at least one anti-tuberculosis drug, and 20 (21.5%), 27 (29.0%), 19 (20.4%), 16 (17.2%), and 14 (15.1%) were resistant to rifampicin, streptomycin, ofloxacin, levofloxacin, and moxifloxacin, respectively; 17 patients (18.3%) had multidrug-resistant tuberculosis (MDR-TB). Between 2010 and 2021, the rate of resistance to streptomycin and rifampicin ranged from 14.3% to 40.0% and from 8.0% to 26.3%, respectively, showing an increasing trend year by year. From 2016 to 2021, the rate of resistance to quinolones fluctuated between 7.7% and 27.8%, exhibiting an overall upward trend. Logistic regression analysis showed that being aged <60 years old was a risk factor for streptomycin resistance, mono-drug resistance, and any-drug resistance (RR 4.139, p = 0.023; RR 7.734, p = 0.047; RR 3.733, p = 0.009). Retreatment tuberculosis was a risk factor for resistance to rifampicin, ofloxacin, of levofloxacin (RR 2.984, p = 0.047; RR 4.517, p = 0.038; RR 6.277, p = 0.014). The drug resistance rates of M. tuberculosis to rifampicin and to quinolones in HIV/AIDS patients were high and have been increasing year by year. Age and a history of previous anti-tuberculosis treatment were the main factors associated with the development of drug resistance in HIV/AIDS patients with tuberculosis.

Trends and risk factors for drug-resistant tuberculosis among children in Sichuan, China: A 10-year retrospective analysis, 2013-2022.

To investigate the status of the drug-resistant tuberculosis (DR-TB) among children in Sichuan, and to find out the risk factors and high-risk population related to drug resistance among children. The clinical data of tuberculosis patients ≤14 years old with culture-confirmed tuberculosis hospitalized in Chengdu Public Health Clinical Center from January 2013 through December 2022 were collected. Clinical data such as gender, age, ethnicity, history of anti-TB treatment, history of exposure to tuberculosis, nutritional status, and specific drug resistance of the children were collected and recorded. The drug resistance of children in different age groups (0-4 years old, 5-9 years old, 10-14 years old) and different periods (2013-2017 and 2018-2022) were grouped and compared. Logistic regression analysis was to analyze analysis of risk factors of drug resistance in children. A total of 438 children with culture-confirmed tuberculosis were screened. Among them, 26.19% (11/42) were 0 to 4 years old, 33.33% (22/66) were 5 to 9 years old, and 36.67% (121/330) were 10 to 14 years old among the resistant children. There was no statistically significant difference in the resistance rate among the 3 groups (P = .385). The proportions of DR-TB, monoresistant tuberculosis, polydrug-resistant tuberculosis were decreased during 2019 to 2022 compared with 2013 to 2017 (P < .0001). The resistance rates of drug resistant, monoresistant, polydrug-resistant, isoniazid-resistant, and rifampicin resistant during 2018 to 2022 were decreased compared with those from 2013 to 2017 (P < .05), but the multi-drug resistance rate was not decreased (P = .131, without statistical difference). The results of logistic regression analysis showed that male gender OR = 1.566 (95% CI 1.035-2.369), a history of antituberculosis therapy OR = 4.049 (95% CI 1.442-11.367), and pulmonary and extrapulmonary tuberculosis OR = 7.335 (95% CI 1.401-38.392) were risk factors for the development of drug resistance; but fever OR = 0.581 (95% CI 0.355-0.950) was Protective factor. The total drug resistance rate of children in Sichuan showed a downward trend, but the rate of multi-drug-resistant tuberculosis was still at a high level, and the form of drug resistance was still severe. Absence of fever, male, retreatment, and pulmonary concurrent with extrapulmonary tuberculosis are risk factors for DR-TB in children.

Etiological characterization of invasive non-typhoid Salmonella strains in Guangdong Province from 2018 to 2022

Objective: To understand the serotype distribution, drug resistance and molecular characterization of invasive non-typhoid Salmonella (iNTS) in Guangdong Province from 2018 to 2022 and provide scientific evidence for the prevention and treatment of blood flow infection caused by Salmonella. Methods: Serological identification, antimicrobial susceptibility testing, multilocus sequence typing (MLST), and whole genome sequencing were performed on Salmonella isolated from blood and stool samples in Guangdong from 2018 to 2022. Simultaneously, annotated the sequencing results for drug resistance genes and virulence factors by a microbial gene annotation system. Results: The 136 iNTS strains were divided into 25 serotypes, and Salmonella enteritidis accounted for 38.24% (52/136). The OR of other iNTS serotypes were calculated with Salmonella typhimurium as the control. The OR values of Oreninburg, Rysson, and Pomona serotypes were the highest, which were 423.50, 352.92, and 211.75, respectively. The drug resistance rate of iNTS was 0.74%-66.91%, which was lower than that of non-iNTS (3.90%-77.21%). The main iNTS of drug resistance were ampicillin and tetracycline, with resistance rates of 66.91% (91/136) and 50.00% (68/136), respectively, while the resistance rates to ciprofloxacin (5.88%,8/136), ceftazidime (5.88%,8/136), gentamicin (5.13%,7/136) and cefoxitin (0.74%, 1/136) were relatively low. iNTS carried a variety of drug-resistance genes and virulence factors, but no standard virulence factor distribution has been found. MLST cluster analysis showed that iNTS was divided into 26 sequence types, and ST11 accounted for 38.24% (52/136). Conclusions: The iNTS strains in Guangdong were dominated by Salmonella enteritidis, of which three serotypes, Oreninburg, Rison, and Pomona, may be associated with a higher risk of invasive infection during 2018 to 2022. iNTS was sensitive to clinical first-line therapeutic drugs (cephalosporins and fluoroquinolones), with highly diverse sequences and clear phylogenetic branches. ST11 was the local dominant clone group.

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.

Adults with Perinatally Acquired HIV; Emerging Clinical Outcomes and Data Gaps.

In resourced settings, adults living with perinatally acquired HIV are approaching the 5th decade of life. Their clinical and psychological outcomes highlight potential future issues for the much larger number of adolescents growing up with HIV in sub-Saharan Africa, and will inform the development of appropriate healthcare services. Lifelong exposure to HIV, and increasingly to antiretroviral therapy throughout growth and development, contrasts with adults acquiring HIV in later life. This review describes the clinical outcomes for adults living with perinatally acquired HIV including post transition mortality, morbidity and retention in care. Rates of viral suppression, drug resistance and immunological function are explored. Co-morbidities focus on metabolic, cardiovascular, respiratory and bone health with quality-of-life data including neurocognitive functioning and mental health. Sexual and reproductive health including vaccine-preventable disease and the prevention of onward transmission to partners and infants are considered. The data gaps and future research questions to optimise outcomes for this emerging adult cohort are highlighted.

Pathogenic Aspergillus Strains Identification and Antifungal Susceptibility Analysis of 452 Cases with Otomycosis in Jingzhou, China.

To study the distribution of pathogenic Aspergillus strains of otomycosis in central China and the identification of their antifungal sensitivity. We collected external ear canal secretions clinically diagnosed as otomycosis from April 2020 to January 2023 from the Department of Otolaryngology-Head and Neck Surgery in central China. The pathogenic Aspergillus strains were identified through morphological examination and sequencing. The antifungal sensitivity was performed using the broth microdilution method described in the Clinical Laboratory Standard Institute document M38-A3. In the 452 clinical strains isolated from the external ear canal, 284 were identified as Aspergillus terreus (62.83%), 92 as Aspergillus flavus (20.35%), 55 as Aspergillus niger (12.17%). In antifungal susceptibility tests the MIC of Aspergillus strains to bifonazole and clotrimazole was high,all the MIC90 is > 16 ug/mL. However, most Aspergillus isolates show moderate greatly against terbinafine, itraconazole and voriconazole. A. terreus is the most common pathogenic Aspergillus strain in otomycosis in central China. The selected topical antifungal drugs were bifonazole and clotrimazole; the drug resistance rate was approximately 30%. If the infection is persistent and requires systemic treatment, terbinafine and itraconazole can be used. The resistance of Aspergillus in otomycosis to voriconazole should be screened to avoid the systemic spread of infection in immunocompromised people and poor compliance with treatment. However, the pan-azole-resistant strain of Aspergillus should be monitored, particularly in high-risk patients with otomycosis.

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.

Hippo Signaling at the Hallmarks of Cancer and Drug Resistance.

Originally identified in Drosophila melanogaster in 1995, the Hippo signaling pathway plays a pivotal role in organ size control and tumor suppression by inhibiting proliferation and promoting apoptosis. Large tumor suppressors 1 and 2 (LATS1/2) directly phosphorylate the Yki orthologs YAP (yes-associated protein) and its paralog TAZ (also known as WW domain-containing transcription regulator 1 [WWTR1]), thereby inhibiting their nuclear localization and pairing with transcriptional coactivators TEAD1-4. Earnest efforts from many research laboratories have established the role of mis-regulated Hippo signaling in tumorigenesis, epithelial mesenchymal transition (EMT), oncogenic stemness, and, more recently, development of drug resistances. Hippo signaling components at the heart of oncogenic adaptations fuel the development of drug resistance in many cancers for targeted therapies including KRAS and EGFR mutants. The first U.S. food and drug administration (US FDA) approval of the imatinib tyrosine kinase inhibitor in 2001 paved the way for nearly 100 small-molecule anti-cancer drugs approved by the US FDA and the national medical products administration (NMPA). However, the low response rate and development of drug resistance have posed a major hurdle to improving the progression-free survival (PFS) and overall survival (OS) of cancer patients. Accumulating evidence has enabled scientists and clinicians to strategize the therapeutic approaches of targeting cancer cells and to navigate the development of drug resistance through the continuous monitoring of tumor evolution and oncogenic adaptations. In this review, we highlight the emerging aspects of Hippo signaling in cross-talk with other oncogenic drivers and how this information can be translated into combination therapy to target a broad range of aggressive tumors and the development of drug resistance.