Clinical characteristics of neonatal and infant osteomyelitis and septic arthritis: a multicenter retrospective study.

OBJECTIVE: Signs and symptoms of osteomyelitis or septic arthritis in neonates and infants are often nonspecific and early-stage bone infections in infants may often go unnoticed. The objective of this study was to analyze the clinical characteristics of newborns and infants with osteomyelitis and septic arthritis to improve understanding of the disorder and to assist clinicians with diagnosis. METHODS: A retrospective multicenter study was conducted on neonates (0-28 days old, n = 94) and infants (1-12 months old, n = 415) with osteoarticular infections. Data consisting of clinical characteristics, complications, laboratory outcomes, and the pathogenic microorganisms causing osteomyelitis were tabulated. The statistics were further broken down into two regions and the significant differences between neonates and infants were evaluated and compared to the literature. RESULTS: Compared to infants, neonates had significantly lower incidences of fever (p < 0.0001), higher incidences of localized swelling (p = 0.0021), higher rate of infection at the humerus (p = 0.0016), higher percentage of Escherichia coli (p < 0.0001) and Klebsiella pneumoniae (p = 0.0039) infections, lower percentage of Staphylococcus aureus infections (p < 0.0001) and were more likely to develop septic arthritis (p < 0.0001). CONCLUSION: Distinct differences were found between neonatal and infants with osteoarticular infections. Future studies should focus on improving diagnosis and subsequent treatment regimens for younger age groups.

Relationship between biofilm formation and antibiotic resistance of Klebsiella pneumoniae and updates on antibiofilm therapeutic strategies.

Klebsiella pneumoniae is a Gram-negative bacterium within the Enterobacteriaceae family that can cause multiple systemic infections, such as respiratory, blood, liver abscesses and urinary systems. Antibiotic resistance is a global health threat and K. pneumoniae warrants special attention due to its resistance to most modern day antibiotics. Biofilm formation is a critical obstruction that enhances the antibiotic resistance of K. pneumoniae. However, knowledge on the molecular mechanisms of biofilm formation and its relation with antibiotic resistance in K. pneumoniae is limited. Understanding the molecular mechanisms of biofilm formation and its correlation with antibiotic resistance is crucial for providing insight for the design of new drugs to control and treat biofilm-related infections. In this review, we summarize recent advances in genes contributing to the biofilm formation of K. pneumoniae, new progress on the relationship between biofilm formation and antibiotic resistance, and new therapeutic strategies targeting biofilms. Finally, we discuss future research directions that target biofilm formation and antibiotic resistance of this priority pathogen.

Anticancer therapy-induced adverse drug reactions in children and preventive and control measures.

In recent years, considerable achievements have been made in pediatric oncology with the innovation and development of antitumor drugs. However, compared to adults, children as a special group have not yet matured fully in terms of liver and kidney function. Moreover, pediatric patients are prone to more adverse drug reactions (ADRs) from the accumulation of antineoplastic drugs due to their smaller body size and larger body surface area. Chemotherapy-related ADRs have become a non-negligible factor that affects cancer remission. To date, studies on ADRs in pediatric cancer patients have emerged internationally, but few systematic summaries are available. Here, we reviewed the various systemic ADRs associated with antitumor drugs in children and adolescent patients, as well as the advances in strategies to cope with ADRs, which consisted of neurotoxicity, hematological toxicity, cardiotoxicity, ADRs of the respiratory system and gastrointestinal system and urinary system, ADRs of the skin and its adnexa, allergic reactions, and other ADRs. For clinicians and researchers, understanding the causes, symptoms, and coping strategies for ADRs caused by anticancer treatments will undoubtedly benefit more children.

Function and therapeutic prospects of next-generation probiotic Akkermansia muciniphila in infectious diseases.

Akkermansia muciniphila is a gram-negative bacterium that colonizes the human gut, making up 3-5% of the human microbiome. A. muciniphila is a promising next-generation probiotic with clinical application prospects. Emerging studies have reported various beneficial effects of A. muciniphila including anti-cancer, delaying aging, reducing inflammation, improving immune function, regulating nervous system function, whereas knowledge on its roles and mechanism in infectious disease is currently unclear. In this review, we summarized the basic characteristics, genome and phenotype diversity, the influence of A. muciniphila and its derived components on infectious diseases, such as sepsis, virus infection, enteric infection, periodontitis and foodborne pathogen induced infections. We also provided updates on mechanisms how A. muciniphila protects intestinal barrier integrity and modulate host immune response. In summary, we believe that A. muciniphila is a promising therapeutic probiotic that may be applied for the treatment of a variety of infectious diseases.

An APE1 gated signal amplified biosensor driven by catalytic hairpin assembly for the specific imaging of microRNA in situ.

In situ imaging of microRNA (miRNA) content and distribution is valuable for monitoring tumor progression. However, tumor specific in situ imaging remains a challenge due to low miRNA abundance, lack of biological compatibility, and poor specificity. In this study, we designed a DNA tetrahedral framework complex with hairpins (DTF-HPAP) consisting of an apurinic/apyrimidinic site (AP site) that could be specifically recognized and cleaved by apurinic/apyrimidinic endonuclease 1 (APE1). Efficient and specific in situ imaging of miR-21 in tumors was thus achieved through catalytic hairpin assembly (CHA) reaction. In this study, DTF-HPAP was successfully constructed to trigger the cumulative amplification of fluorescence signal in situ. The specificity, sensitivity and serum stability of DTF-HPAP were verified in vitro, and DTF-HPAP could be easily taken up by cells, acting as a biosensor to detect tumors in mice. Furthermore, we verified the ability of DTF-HPAP to specifically image miR-21 in tumors, and demonstrated its capability for tumor-specific imaging in clinical samples.

An efficient and universal In silico screening strategy for acquisition of high-affinity Aptamer and its application in analytical utility.

Numerous aptamers against various targets have been identified through the technology of systematic evolution of ligands by exponential enrichment (SELEX), but the affinity of these aptamers are often insufficient due to the limitations of SELEX. Therefore, a more rational in silico screening strategy (ISS) was developed for efficient screening of high affinity aptamers, which took shape complementarity and thermodynamic stability into consideration. Neuron specific enolase (NSE), a tumor marker, was selected as the target molecule. In the screening process, three aptamer candidates with good shape complementarity, lower ΔG values, and higher ZDOCK scores were produced. The dissociation constant (Kd) of these candidates to NSE was determined to be 10.13 nM, 14.82 nM, and 2.76 nM, respectively. Each of them exhibited higher affinity to NSE than the parent aptamer (Kd = 23.83 nM). Finally, an antibody-free fluorescence aptasensor assay, based on the aptamer with the highest affinity, P-5C8G, was conducted, resulting in a limit of detection (LOD) value of 1.8 nM, which was much lower than the parental aptamer (P, LOD = 12.6 nM). The proposed ISS approach provided an efficient and universal strategy to improve the aptamer to have a high affinity and good analytical utility.

Joint analysis of the metabolomics and transcriptomics uncovers the dysregulated network and develops the diagnostic model of high-risk neuroblastoma.

High-risk neuroblastoma (HR-NB) has a significantly lower survival rate compared to low- and intermediate-risk NB (LIR-NB) due to the lack of risk classification diagnostic models and effective therapeutic targets. The present study aims to characterize the differences between neuroblastomas with different risks through transcriptomic and metabolomic, and establish an early diagnostic model for risk classification of neuroblastoma.Plasma samples from 58 HR-NB and 38 LIR-NB patients were used for metabolomics analysis. Meanwhile, NB tissue samples from 32 HR-NB and 23 LIR-NB patients were used for transcriptomics analysis. In particular, integrative metabolomics and transcriptomic analysis was performed between HR-NB and LIR-NB. A total of 44 metabolites (P < 0.05 and fold change > 1.5) were altered, including 12 that increased and 32 that decreased in HR-NB. A total of 1,408 mRNAs (P < 0.05 and |log2(fold change)|> 1) showed significantly altered in HR-NB, of which 1,116 were upregulated and 292 were downregulated. Joint analysis of both omic data identified 4 aberrant pathways (P < 0.05 and impact ≥ 0.5) consisting of glycerolipid metabolism, retinol metabolism, arginine biosynthesis and linoleic acid metabolism. Importantly, a HR-NB risk classification diagnostic model was developed using plasma circulating-free S100A9, CDK2, and UNC5D, with an area under receiver operating characteristic curve of 0.837 where the sensitivity and specificity in the validation set were both 80.0%. This study presents a novel pioneering study demonstrating the metabolomics and transcriptomics profiles of HR-NB. The glycerolipid metabolism, retinol metabolism, arginine biosynthesis and linoleic acid metabolism were altered in HR-NB. The risk classification diagnostic model based on S100A9, CDK2, and UNC5D can be clinically used for HR-NB risk classification.

Clinical Associations of Bitter Taste Perception and Bitter Taste Receptor Variants and the Potential for Personalized Healthcare.

Bitter taste receptors (T2Rs) consist of 25 functional receptors that can be found in various types of cells throughout the human body with responses ranging from detecting bitter taste to suppressing pathogen-induced inflammation upon activation. Numerous studies have observed clinical associations with genetic or phenotypic variants in bitter taste receptors, most notably that of the receptor isoform T2R38. With genetic variants playing a role in the response of the body to bacterial quorum-sensing molecules, bacterial metabolites, medicinal agonists and nutrients, we examine how T2R polymorphisms, expression levels and bitter taste perception can lead to varying clinical associations. From these genetic and phenotypic differences, healthcare management can potentially be individualized through appropriately administering drugs with bitter masking to increase compliance; optimizing nutritional strategies and diets; avoiding the use of T2R agonists if this pathway is already activated from bacterial infections; adjusting drug regimens based on differing prognoses; or adjusting drug regimens based on T2R expression levels in the target cell type and bodily region.

Global spread of carbapenem-resistant Enterobacteriaceae: Epidemiological features, resistance mechanisms, detection and therapy.

Bacterial drug resistance has become a global public health threat, among which the infection of carbapenem-resistant Enterobacterales (CRE) is one of the top noticeable issues in the global anti-infection area due to limited therapy options. In recent years, the prevalence of CRE transmission around the world has increased, and the transmission of COVID-19 has intensified the situation to a certain extent. CRE resistance can be induced by carbapenemase, porin, efflux pump, penicillin-binding protein alteration, and biofilm production. Deletion, mutation, insertion, and post-transcriptional modification of corresponding coding genes may affect the sensitivity of Enterobacterales bacteria to carbapenems. Clinical and laboratory methods to detect CRE and explore its resistance mechanisms are being developed. Due to the limited options of antibiotics, the clinical treatment of CRE infection also faces severe challenges. The clinical therapies of CRE include single or combined use of antibiotics, and some new antibiotics and treatment methods are also being developed. Hence, this review summarizes the epidemiology, resistance mechanisms, screening and clinical treatments of CRE infection, to provide references for clinical prevention, control and treatment of CRE infection.

Plasma circulating cell-free MYCN gene: A noninvasive and prominent recurrence monitoring indicator of neuroblastoma.

The postoperative recurrence of neuroblastoma (NB) patients is an essential reason for the high mortality of NB due to the lack of early, non-invasive, and dynamic strategies for monitoring NB recurrence. Therefore, whether the plasma circulating cell-free MYCN gene as an indicator for monitoring of NB recurrence was systematically evaluated. The MYCN copy number and NAGK (reference gene) copy number (M/N) ratio in plasma and corresponding tumor tissues of NB patients was detected using an economical, sensitive, and specific single-tube dual RT-PCR approach developed in this study. The plasma M/N ratio of the MYCN gene amplification (MNA) group (N = 25, median M/N ratio = 4.90) was significantly higher than that of the non-MNA group (N = 71, median M/N ratio = 1.22), p < .001. The M/N ratio in NB plasma (N = 60) was positively correlated with the M/N ratio in NB tumor tissue (N = 60), with a correlation coefficient of 0.9496. In particular, the results of dynamic monitoring of postoperative plasma M/N ratio of NB patients showed that an abnormal increase in M/N ratio could be detected 1-2 months before recurrence in NB patients. In summary, the single-tube double RT-PCR approach can be used to quantitatively detect MYCN copy number. The copy number of MYCN in the tissue and plasma of NB patients is consistent with each other. More importantly, the circulating cell-free MYCN gene of NB patients can be used as a monitoring indicator for early, non-invasive, and dynamic monitoring of NB recurrence.

P2Y6R: A Promising New Target in Inflammatory Diseases and Advances in its Antagonists.

P2Y receptors (P2YRs) are G protein-coupled receptors that are activated by extracellular nucleotides. The P2Y6 receptor (P2Y6R) is specifically activated by UDP, causing PKC activation and intracellular calcium ion release through the PLC pathway. Based on receptor tissue distribution and related pathways, several studies have reported that P2Y6R plays a physiological role in mediating inflammation, which suggests that P2Y6R could be a promising molecular target for the treatment of inflammatory diseases. In the past ten years, several P2Y6R antagonists have been discovered as new therapeutic strategies for inflammatory diseases. In this article, we systematically summarize the role of P2Y6R in inflammation and highlight the anti-inflammatory mechanism of a key P2Y6R antagonist, MRS2578. Insight into recent progress on the discovery of P2Y6R antagonists is also discussed.

Efficacy and safety of vancomycin-loaded calcium sulfate versus conventional surgical debridement for pediatric acute osteomyelitis: a retrospective study.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of vancomycin-loaded calcium sulfate beads and negative-pressure wound therapy (NPWT) in treating children with acute hematogenous osteomyelitis (AHOM). METHODS: A retrospective cohort study was conducted from January 2017 to January 2020 examining children (n = 60) with AHOM who were treated with surgical debridement followed by vancomycin-loaded calcium sulfate beads and NPWT (n = 32) and compared to treatment by conventional surgical debridement (n = 28) followed by NPWT. Conventional surgical treatment consisted of fenestration of necrotic infected bone, debridement of surrounding soft tissue, and washing of the medullary canal before the application of NPWT. In the vancomycin group, the antibiotic-loaded beads were implanted after washing the medullary canal and before the application of NPWT. Epidemiological factors, complications during the procedure, outcomes at last follow-up (30.0 ± 11.7 months, range 13-58 months), and laboratory parameters were documented and compared between the two groups. RESULTS: Good outcomes were achieved at last follow-up in 71.4% of the conventional treatment group and 75% of the vancomycin group. In the vancomycin group, it took a mean of 4.8 ± 2.5 days for CRP levels to decrease to 50% of initial inflammatory levels compared to 13 ± 9.6 days for the conventional treatment group (p = 0.001, t-test). The conventional group also had seven patients who underwent four or more surgeries whereas no patients in the vancomycin group underwent more than three surgeries (p = 0.013, chi-square test). CONCLUSION: Localized vancomycin delivery with NPWT effective for treating cases of AHOM that required. No perioperative adverse reactions or complications occurred from this treatment method. Based on the shortened recovery period of CRP levels, prolonged administration of post-operational parenteral antibiotics can possibly be reduced with this treatment method.

Dual isothermal amplification all-in-one approach for rapid and highly sensitive quantification of plasma circulating MYCN gene of neuroblastoma.

A dual isothermal amplification assay with dual fluorescence signal detection strategy, named dual isothermal amplification all-in-one approach, was developed for rapid, one-step, highly sensitive quantification of plasma circulating MYCN copy number of neuroblastoma (NB). The developed strategy consisted of rolling circle amplification (RCA) and loop-mediated isothermal amplification (LAMP) on a real-time PCR system using highly specific probe, molecular beacon (MB), as detection probe. The developed strategy possessing a broad linear dynamic range of 10 aM to 1 pM for both target gene (MYCN) and reference gene (NAGK). The ratio of the MYCN copy number to NAGK copy number (M/N ratio) was detected by the developed approach in cell lines, NB tumor tissues, hepatoblastoma tumor tissues and Wilms' tumor tissues, to which the M/N ratios were consistent with previous reports. In particular, the M/N ratio in NB clinical tissue specimens and NB plasma specimens detected with the developed approach were in keeping with the standard RT-PCR approach. More importantly, the M/N ratio in NB tissue samples and corresponding plasma samples of NB patients were consistent with each other with a correlation coefficient of 0.9690, indicating that plasma circulating MYCN is a promising indicator for the risk classification of NB.

Six-Year Follow-Up of a Rare Bifid Talus and Eight-Toed Central Polydactyly: A Case Report.

Eight-toed central polydactyly is a rare congenital foot deformity and no other case with a bifid talus has been reported in the literature. We present a 6-year follow-up of a male child who had eight-toed central polydactyly with a duplicate cuneiform bone and bifid talus in his right foot. During preoperative planning, CT scans were conducted to evaluate the duplicate tarsals and to assist in reaching surgical decisions. In 2013, when the child was 1 year and 8 months old, the fourth, fifth and sixth phalanges and metatarsals as well as the duplicate cuneiform bone were excised. A portion of the malformed talus was also resected. This case report discusses functional and aesthetic outcomes after 6 years and provides an analysis on relevant reconstructive follow-up practices.

Rapid electrochemical quantification of trace Hg2+ using a hairpin DNA probe and quantum dot modified screen-printed gold electrodes.

Rapid, simple, sensitive and specific approaches for mercury(ii) (Hg2+) detection are essential for toxicology assessment, environmental protection, food analysis and human health. In this study, a ratiometric hairpin DNA probe based electrochemical biosensor, which relies on hairpin DNA probes conjugated with water-soluble and carboxyl functionalized quaternary Zn-Ag-In-S quantum dot (QD) on screen-printed gold electrodes (SPGE), referred to as the HP-QDs-SPGE electrochemical biosensor in this study, was developed for Hg2+ detection. Based on the "turn-off" reaction of a hairpin DNA probe binding with a mismatched target and Hg2+ through the formation of T-Hg2+-T coordination, the HP-QDs-SPGE electrochemical biosensor can rapidly quantify trace Hg2+ with high ultrasensitivity, specificity, repeatability and reproducibility. The conformational change of the hairpin DNA probe caused a significant decrease in electrochemical intensity, which could be used for the quantification of Hg2+. The linear dynamic range and high sensitivity of the HP-QDs-SPGE electrochemical biosensor for the detection of Hg2+ was studied in vitro, with a broad linear dynamic range of 10 pM to 1 µM and detection limits of 0.11 pM. In particular, this HP-QDs-SPGE electrochemical biosensor showed excellent selectivity toward Hg2+ ions in the presence of other metal ions. More importantly, this biosensor has been successfully used to detect Hg2+ in deionized water, tap water, groundwater and urine samples with good recovery rate and small relative standard deviations. In summary, the developed HP-QDs-SPGE electrochemical biosensor exhibited promising potential for further applications in on-site analysis.

Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors.

The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.

A systematic review of Vaccine Breakthrough Infections by SARS-CoV-2 Delta Variant.

Vaccines are proving to be highly effective in controlling hospitalization and deaths associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as shown by clinical trials and real-world evidence. However, a deadly second wave of coronavirus disease 2019 (COVID-19), infected by SARS-CoV-2 variants, especially the Delta (B.1.617.2) variant, with an increased number of post-vaccination breakthrough infections were reported in the world recently. Actually, Delta variant not only resulted in a severe surge of vaccine breakthrough infections which was accompanied with high viral load and transmissibility, but also challenged the development of effective vaccines. Therefore, the biological characteristics and epidemiological profile of Delta variant, the current status of Delta variant vaccine breakthrough infections and the mechanism of vaccine breakthrough infections were discussed in this article. In addition, the significant role of the Delta variant spike (S) protein in the mechanism of immune escape of SARS-CoV-2 was highlighted in this article. In particular, we further discussed key points on the future SARS-CoV-2 vaccine research and development, hoping to make a contribution to the early, accurate and rapid control of the COVID-19 epidemic.

Carbapenem-Resistant Klebsiella pneumoniae Osteomyelitis Treated with Ceftazidime-Avibactam in an Infant: A Case Report.

Increasing cases of carbapenem-resistant Klebsiella pneumoniae (CR-KP) infections have been observed globally where multi-drug resistance to CR-KP can make the infection difficult to treat. In recent years, the ß-lactam/ß-lactamase inhibitor, ceftazidime-avibactam (CAZ-AVI), has been developed to treat complicated urinary tract infections and complicated intra-abdominal infections. CAZ-AVI is approved for children over 3-month old but has yet to be investigated for cases of osteomyelitis. Only three case reports exist in literature on the use of CAZ-AVI for CR-KP osteomyelitis in adults. In this report, we present an infant with primary hematogenous osteomyelitis and septic arthritis in the right shoulder following surgical treatment for a heart murmur. Bacterial isolation revealed a strain of CR-KP, which was successfully treated with CAZ-AVI after initial administration of imipenem-based treatments.

Decreased excitatory drive onto hilar neuronal nitric oxide synthase expressing interneurons in chronic models of epilepsy.

Excitation-inhibition imbalance of GABAergic interneurons is predisposed to develop chronic temporal lobe epilepsy (TLE). We have previously shown that virtually every neuronal nitric oxide synthase (nNOS)-positive cell is a GABAergic inhibitory interneuron in the denate gyrus. The present study was designed to quantify the number of nNOS-containing hilar interneurons using stereology in pilocapine- and kainic acid (KA)-exposed transgenic adult mice that expressed GFP under the nNOS promoter. In addition, we studied the properties of miniature excitatory postsynaptic current (mEPSC) and paired-pulse response ratio (PPR) of evoked EPSC in nNOS interneurons using whole cell recording techniques. Results showed that there were fewer nNOS-immunoreactive interneurons of chronically epileptic animals. Importantly, patch-clamp recordings revealed reduction in mEPSC frequency, indicating diminished global excitatory input. In contrast, PPR of evoked EPSC following the granule cell layer stimulation was increased in epileptic animals suggesting reduced neurotransmitter release from granule cell input. In summary, we propose that impaired excitatory drive onto hippocampal nNOS interneurons may be implicated in the development of refractory epilepsy.

Contact force sensors in minimally invasive catheters: current and future applications.

INTRODUCTION: Advances in catheter design for minimally invasive surgery have brought about the incorporation of contact force (CF) sensors in catheters. Two main approaches to achieve CF sensing at the catheter end-effector consist of fiber optic or magnetic solutions. CF sensing feedback can be used to assist in ablation procedures, mapping cardiac regions, identifying tissue characteristics, and enhancing robotic catheter control. AREAS COVERED: This review covers the technological and clinical aspects of CFS in catheters. Contact force and force-time integral thresholds for ablation procedures, procedural complications, and electroanatomical mapping strategies are discussed. Future applications of improving catheter control, minimizing complications, and enhancing mapping techniques through CF are examined. EXPERT OPINION: Fiber optic CF catheters may be more desirable compared to magnetic modalities due to the lower cost, compactness, and higher accuracy. In ablation procedures, complications due to higher ablation duration, power, contact force, and force time can be reduced through practical experience and informed training for catheter operators. Future prospects consist of the incorporation of CF sensors with remote catheter systems to assist in catheter control. We propose that CF can also be used in machine learning decision-making algorithms to prevent complications or improve tissue characterization.