The photo-based treatment technology simultaneously removes resistant bacteria and resistant genes from wastewater.

Because of the recent widespread usage of antibiotics, the acquisition and dissemination of antibiotic-resistance genes (ARGs) were prevalent in the majority of habitats. Generally, the biological wastewater treatment processes used in wastewater treatment plants have a limited efficiencies of antibiotics resistant bacteria (ARB) disinfection and ARGs degradation and even promote the proliferation of ARGs. Problematically, ARB and ARGs in effluent pose potential risks if they are not further treated. Photocatalytic oxidation is considered a promising disinfection technology, where the photocatalytic process generates many free radicals that enhance the interaction between light and deoxyribonucleic acid (DNA) for ARB elimination and subsequent degradation of ARGs. This review aims to illustrate the progress of photocatalytic oxidation technology for removing antibiotics resistant (AR) from wastewater in recent years. We discuss the sources and transfer of ARGs in wastewater. The overall removal efficiencies of ultraviolet radiation (UV)/chlorination, UV/ozone, UV/H2O2, and UV/sulfate-radical based system for ARB and ARGs, as well as the experimental parameters and removal mechanisms, are systematically discussed. The contribution of photocatalytic materials based on TiO2 and g-C3N4 to the inactivation of ARB and degradation of ARGs is highlighted, producing many free radicals to attack ARB and ARGs while effectively limiting the horizontal gene transfer (HGT) in wastewater. Finally, based on the reviewed studies, future research directions are proposed to realize specific photocatalytic oxidation technology applications and overcome current challenges.

Iron-promoted zirconia-alumina supported Ni catalyst for highly efficient and cost-effective hydrogen production via dry reforming of methane.

Developing cost-effective and high-performance catalyst systems for dry reforming of methane (DRM) is crucial for producing hydrogen (H2) sustainably. Herein, we investigate using iron (Fe) as a promoter and major alumina support in Ni-based catalysts to improve their DRM performance. The addition of iron as a promotor was found to add reducible iron species along with reducible NiO species, enhance the basicity and induce the deposition of oxidizable carbon. By incorporating 1 wt.% Fe into a 5Ni/10ZrAl catalyst, a higher CO2 interaction and formation of reducible "NiO-species having strong interaction with support" was observed, which led to an ∼80% H2 yield in 420 min of Time on Stream (TOS). Further increasing the Fe content to 2wt% led to the formation of additional reducible iron oxide species and a noticeable rise in H2 yield up to 84%. Despite the severe weight loss on Fe-promoted catalysts, high H2 yield was maintained due to the proper balance between the rate of CH4 decomposition and the rate of carbon deposit diffusion. Finally, incorporating 3 wt.% Fe into the 5Ni/10ZrAl catalyst resulted in the highest CO2 interaction, wide presence of reducible NiO-species, minimum graphitic deposit and an 87% H2 yield. Our findings suggest that iron-promoted zirconia-alumina-supported Ni catalysts can be a cheap and excellent catalytic system for H2 production via DRM.

Enhanced anticancer efficacy of TRAIL-conjugated and odanacatib-loaded PLGA nanoparticles in TRAIL resistant cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) demonstrates unique characteristics in anticancer therapies as it selectively induces apoptosis in cancer cells. However, most cancer cells are TRAIL-resistant. Odanacatib (ODN), a cathepsin K inhibitor, is considered a novel sensitizer for cancer treatment. Combination therapy between TRAIL and sensitizers is considered a potent platform that improves TRAIL-based anticancer therapies beyond TRAIL monotherapy. Herein, we developed ODN loaded poly(lactic-co-glycolic) nanoparticles conjugated to GST-TRAIL (TRAIL-ODN-PLGA-NPs) to target and treat TRAIL-resistant cancer. TRAIL-ODN-PLGA-NPs demonstrated a significant increase in cellular uptake via death receptors (DR5 and DR4) on surface of cancer cells. TRAIL-ODN-PLGA-NPs exposure destroyed more TRAIL-resistant cells compared to a single treatment with free drugs. The released ODN decreased the Raptor protein, thereby increasing damage to mitochondria by elevating reactive oxygen species (ROS) generation. Additionally, Bim protein stabilization improved TRAIL-resistant cell sensitization to TRAIL-induced apoptosis. The in vivo biodistribution study revealed that TRAIL-ODN-PLGA-NPs demonstrated high location and retention in tumor sites via the intravenous route. Furthermore, TRAIL-ODN-PLGA-NPs significantly inhibited xenograft tumor models of TRAIL-resistant Caki-1 and TRAIL-sensitive MDA-MB-231 cells.The inhibition was associated with apoptosis activation, Raptor protein stabilizing Bim protein downregulation, Bax accumulation, and mitochondrial ROS generation elevation. Additionally, TRAIL-ODN-PLGA-NPs affected the tumor microenvironment by increasing tumor necrosis factor-α and reducing interleukin-6. In conclusion, we evealed that our formulation demonstrated synergistic effects against TRAIL compared with the combination of free drug in vitro and in vivo models. Therefore, TRAIL-ODN-PLGA-NPs may be a novel candidate for TRAIL-induced apoptosis in cancer treatment.

Antibiotics-free compounds for managing carbapenem-resistant bacteria; a narrative review.

Carbapenem-resistant (CR) Gram-negative bacteria have become a significant public health problem in the last decade. In recent years, the prevalence of CR bacteria has increased. The resistance to carbapenems could result from different mechanisms such as loss of porin, penicillin-binding protein alteration, carbapenemase, efflux pump, and biofilm community. Additionally, genetic variations like insertion, deletion, mutation, and post-transcriptional modification of corresponding coding genes could decrease the susceptibility of bacteria to carbapenems. In this regard, scientists are looking for new approaches to inhibit CR bacteria. Using bacteriophages, natural products, nanoparticles, disulfiram, N-acetylcysteine, and antimicrobial peptides showed promising inhibitory effects against CR bacteria. Additionally, the mentioned compounds could destroy the biofilm community of CR bacteria. Using them in combination with conventional antibiotics increases the efficacy of antibiotics, decreases their dosage and toxicity, and resensitizes CR bacteria to antibiotics. Therefore, in the present review article, we have discussed different aspects of non-antibiotic approaches for managing and inhibiting the CR bacteria and various methods and procedures used as an alternative for carbapenems against these bacteria.

Transmission of multidrug-resistant tuberculosis in Jiangxi, China, and associated risk factors.

In order to effectively combat the urgent threat of multidrug-resistant tuberculosis (MDR-TB), it is imperative to gain a comprehensive understanding of the drug-resistant profiles, transmission dynamics, and associated risk factors. Our study encompassed a population-based retrospective analysis with 130 MDR-TB patients from 2018 to 2021. The research methodology incorporated whole-genome sequencing, drug susceptibility testing , and logistic regression analysis to discern the risk factors of genomic clustering linked to recent transmission. The findings from phenotypic drug resistance assessments revealed notable resistance rates: ethambutol at 62.3% (81/130), streptomycin at 72.3% (94/130), levofloxacin at 51.5% (67/130), and moxifloxacin at 50.0% (65/130). Furthermore, among all patients, 38 individuals (29.23%, 38/130) were found to be part of 17 clusters, indicating instances of recent MDR-TB transmission. The genomic clustering patients were deeply investigated. Lineage 2.2.1 was established as the primary sub-lineage (86.15%, 112/130), followed by lineage 4 (9.23%, 12/130). Moreover, the logistic regression analysis underscored that unemployment, farming occupations, and prior TB treatment were identified as significant risk factors for recent transmission. IMPORTANCE: The high prevalence of multidrug-resistant tuberculosis (MDR-TB) in Jiangxi Province highlights the importance of understanding the genetic background and drug resistance patterns of these strains. This knowledge is crucial for developing effective control methods. Furthermore, in light of the significance of preventing transmission among tuberculosis patients, whole-genome sequencing was utilized to investigate the recent transmission of MDR-TB and identify associated risk factors. The findings revealed that individuals in the farming sector, those who are unemployed, and patients with a history of tuberculosis treatment are at elevated risk. Consequently, targeted public interventions for these at-risk groups are imperative.

Strain-level multidrug-resistant pathogenic bacteria in urban wastewater treatment plants: Transmission, source tracking and evolution.

Wastewater treatment plants (WWTPs) serve as reservoirs for various pathogens and play a pivotal role in safeguarding environmental safety and public health by mitigating pathogen release. Pathogenic bacteria, known for their potential to cause fatal infections, present a significant and emerging threat to global health and remain poorly understood regarding their origins and transmission in the environment. Using metagenomic approaches, we identified a total of 299 pathogens from three full-scale WWTPs. We comprehensively elucidated the occurrence, dissemination, and source tracking of the pathogens across the WWTPs, addressing deficiencies in traditional detection strategies. While indicator pathogens in current wastewater treatment systems such as Escherichia coli are effectively removed, specific drug-resistant pathogens, including Pseudomonas aeruginosa, Pseudomonas putida, and Aeromonas caviae, persist throughout the treatment process, challenging complete eradication efforts. The anoxic section plays a predominant role in controlling abundance but significantly contributes to downstream pathogen diversity. Additionally, evolution throughout the treatment process enhances pathogen diversity, except for upstream transmission, such as A. caviae str. WP8-S18-ESBL-04 and P. aeruginosa PAO1. Our findings highlight the necessity of expanding current biomonitoring indicators for wastewater treatment to optimize treatment strategies and mitigate the potential health risks posed by emerging pathogens. By addressing these research priorities, we can effectively mitigate risks and safeguard environmental safety and public health.

Predictive Factors of Apparent Treatment Resistant Hypertension Among Patients With Hypertension Identified Using Electronic Health Records.

BACKGROUND: Early identification of a patient with resistant hypertension (RH) enables quickly intensified treatment, short-interval follow-up, or perhaps case management to bring his or her blood pressure under control and reduce the risk of complications. OBJECTIVE: To identify predictors of RH among individuals with newly diagnosed hypertension (HTN), while comparing different prediction models and techniques for managing missing covariates using electronic health records data. DESIGN: Risk prediction study in a retrospective cohort. PARTICIPANTS: Adult patients with incident HTN treated in any of the primary care clinics of one health system between April 2013 and December 2016. MAIN MEASURES: Predicted risk of RH at the time of HTN identification and candidate predictors for variable selection in future model development. KEY RESULTS: Among 26,953 individuals with incident HTN, 613 (2.3%) met criteria for RH after 4.7 months (interquartile range, 1.2-11.3). Variables selected by the least absolute shrinkage and selection operator (LASSO), included baseline systolic blood pressure (SBP) and its missing indicator (a dummy variable created if baseline SBP is absent), use of antihypertensive medication at the time of cohort entry, body mass index, and atherosclerosis risk. The random forest technique achieved the highest area under the curve (AUC) of 0.893 (95% CI, 0.881-0.904) and the best calibration with a calibration slope of 1.01. Complete case analysis is not a valuable option (AUC = 0.625). CONCLUSIONS: Machine learning techniques and traditional logistic regression exhibited comparable levels of predictive performance after handling the missingness. We suggest that the variables identified by this study may be good candidates for clinical prediction models to alert clinicians to the need for short-interval follow up and more intensive early therapy for HTN.

Nanocomposites: silver nanoparticles and bacteriocins obtained from lactic acid bacteria against multidrug-resistant Escherichia coli and Staphylococcus aureus.

Drug-resistant bacteria such as Escherichia coli and Staphylococcus aureus represent a global health problem that requires priority attention. Due to the current situation, there is an urgent need to develop new, more effective and safe antimicrobial agents. Biotechnological approaches can provide a possible alternative control through the production of new generation antimicrobial agents, such as silver nanoparticles (AgNPs) and bacteriocins. AgNPs stand out for their antimicrobial potential by employing several mechanisms of action that can act simultaneously on the target cell such as the production of reactive oxygen species and cell wall rupture. On the other hand, bacteriocins are natural peptides synthesized ribosomally that have antimicrobial activity and are produced, among others, by lactic acid bacteria (LAB), whose main mechanism of action is to produce pores at the level of the cell membrane of bacterial cells. However, these agents have disadvantages. Nanoparticles also have limitations such as the tendency to form aggregates, which decreases their antibacterial activity and possible cytotoxic effects, and bacteriocins have a narrow spectrum of action, require high doses to be effective, and can be degraded by proteases. Given these limitations, nanoconjugates of these two agents have been developed that can act synergistically in the control of pathogenic bacteria resistant to antibiotics. This review focuses on knowing relevant aspects of the antibiotic resistance of E. coli and S. aureus, the characteristics of these new generation antibacterial agents, and their effect alone or forming nanoconjugates that are more effective against the multiresistant mentioned bacteria.

Protocol for Cancloz: multicentre randomised, placebo-controlled, double-blind, parallel-group adaptive trial of cannabidiol for clozapine-resistant schizophrenia.

BACKGROUND: Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia (TRS), only 40% of people with TRS respond, and there is limited evidence for augmentation agents. Cannabidiol (CBD) reduces positive symptoms in individuals with schizophrenia, but no trials have specifically examined its efficacy in those with clozapine-resistant schizophrenia. AIMS: To examine the clinical efficacy of CBD augmentation in people with clozapine-resistant schizophrenia. METHOD: This is a 12-week randomised, placebo-controlled, double-blind, parallel-group trial (registration number: ACTRN12622001112752). We will recruit 88 individuals with clozapine-resistant schizophrenia, randomised (1:1) to 1000 mg daily CBD versus placebo. Eligible individuals will be aged between 18 and 64 years, fulfil DSM-IV criteria for schizophrenia or schizoaffective disorder, have a total PANSS (Positive and Negative Syndrome Scale) score ≥60, have received oral clozapine for at least 18 weeks and have a clozapine level of >350 ng/mL. Interim analyses will be conducted at 25, 50 and 75% recruitment; these will also provide an opportunity to reallocate participants dependent on conditional power. The primary endpoint will be the difference in PANSS positive scores at the end of week 12. Secondary endpoints include depression, anxiety, sleep, quality of life, alcohol consumption, change in weight and metabolic syndrome components, and neurocognitive measures, as well as safety and tolerability. DISCUSSION: Novel treatments for clozapine-resistant schizophrenia are urgently needed. If found to be effective, CBD may have a role as a novel and safe adjunct to clozapine.

Clozapine monitoring requirements: is it time for an update?

Oloyede and colleagues advocate for updating haematological monitoring requirements for clozapine, arguing that current protocols overestimate the risk of clozapine-induced agranulocytosis. Their research suggests that stringent monitoring may unnecessarily limit access to clozapine, a crucial treatment for resistant schizophrenia. The editorial supports calls for international consensus to carefully weigh the pros and cons of relaxing monitoring guidelines while ensuring comprehensive care for patients.

Dietary zinc supplementation inhibits bacterial plasmid conjugation in vitro by regulating plasmid replication (rep) and transfer (tra) genes.

Humans use dietary supplements for several intended effects, such as supplementing malnutrition. While these compounds have been developed for host end benefits, their ancillary impact on the gut microbiota remains unclear. The human gut has been proposed as a reservoir for the prevalent lateral transfer of antimicrobial resistance and virulence genes in bacteria through plasmid conjugation. Here, we studied the effect of dietary zinc supplements on the incidence of plasmid conjugation in vitro. Supplement effects were analyzed through standardized broth conjugation assays. The avian pathogenic Escherichia coli (APEC) strain APEC-O2-211 was a donor of the multidrug resistance plasmid pAPEC-O2-211A-ColV, and the human commensal isolate E. coli HS-4 was the plasmid-free recipient. Bacterial strains were standardized and mixed 1:1 and supplemented 1:10 with water, or zinc derived from either commercial zinc supplements or zinc gluconate reagent at varying concentrations. We observed a significant reduction in donors, recipients, and transconjugant populations in conjugations supplemented with zinc, with a dose-dependent relationship. Additionally, we observed a significant reduction (P < 0.05) in log conjugation efficiency in zinc-treated reactions. Upregulation of the mRNA for the plasmid replication initiation gene repA and the subset of transfer genes M, J, E, K, B, P, C, W, U, N, F, Q, D, I, and X was observed. Furthermore, we observed a downregulation of the conjugal propilin gene traA and the entry exclusion gene traS. This study demonstrates the effect of dietary zinc supplements on the conjugal transfer of a multidrug resistance plasmid between pathogenic and commensal bacteria during in vitro conditions.IMPORTANCEThis study identifies dietary zinc supplementation as a potential novel intervention for mitigating the emergence of multidrug resistance in bacteria, thus preventing antibiotic treatment failure and death in patients and animals. Further studies are required to determine the applicability of this approach in an in vivo model.

Evaluation of thyroid profile among children aged 1-15 years with nephrotic syndrome: An observation study.

BACKGROUND: The interaction between the kidney and the thyroid is important for normal function of both organs. In nephrotic syndrome, proteinuria leads to loss of several proteins, which in turn causes hypothyroidism. AIM: To assess the thyroid function in children with nephrotic syndrome. METHODS: This cross-sectional study was conducted in a tertiary center, Bhopal, from February 2020 to January 2021. Consecutive children aged 1-15 years admitted with nephrotic syndrome (first-time diagnosed and all relapse cases) were included in the study. A thyroid profile was sent along with routine investigations, and thyroid hormone status was assessed in nephrotic syndrome children. RESULTS: Of the 70 patients, 39 (55.7%) showed abnormal thyroid profiles; 19 (27.1%) had overt hypothyroidism, and 20 (28.6%) had subclinical hypothyroidism. Overt hypothyroidism was seen in 16.1% of newly diagnosed cases, 40% of second relapses, and 2.7% of frequently relapsed cases (P < 0.001). The mean serum free T3 and free T4 levels in frequent relapses were 2.50 ± 0.39 ng/dL and 0.78 ± 0.12 ng/dL, respectively, which were significantly lower than in newly diagnosed cases (2.77 ± 0.37 ng/dL and 0.91 ± 0.19 ng/dL, respectively). The mean thyroid-stimulating hormone (TSH) level was significantly higher in frequent relapses 5.86 ± 1.56 µIU/mL) and second relapse (5.81 ± 1.78 µIU/mL) than in newly diagnosed cases (4.83 ± 0.76 µIU/mL) and first relapse cases (4.74 ± 1.17 µIU/mL), (P < 0.01). CONCLUSION: An abnormal thyroid profile was commonly observed in children with nephrotic syndrome, and overt hypothyroidism was more common in frequent relapse cases. Therefore, thyroid screening should be a part of the management of nephrotic syndrome so that hypothyroidism can be detected and managed at an early stage.

Combination of the PARPi and ARSi in advanced castration resistant prostate cancer: a review of the recent phase III trials.

Tumors with an impaired ability to repair DNA double-strand breaks by homologous recombination, including those with alterations in breast cancer 1 and 2 (BRCA1 and BRCA2) genes, are very sensitive to blocking DNA single-strand repair by inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a synthetic deadly strategy in the treatment of different types of cancer, such as prostate cancer (PCa). The phase 3 PROfound study was the first to lead to olaparib approval in patients with metastatic castration resistant PCa (mCRPC) and BRCA genes mutations. In recent years, the benefit of combination therapy consisted of a PARP inhibitor (PARPi) plus an androgen receptor signalling inhibitor (ARSi), was evaluated as first-line treatment of mCRPC, regardless of the mutational state of genes, participating in the homologous recombination repair (HRR). This review explores the role of PARPi in PCa and analyses the data of latest clinical trials exploring the PARPi-ARSi combinations, and how these results could change our clinical practice.

Dog Breed and Starch Gelatinisation Correlation in Food Digestibility and Faecal Traits.

Large dog breeds commonly produce unformed faeces. The present study hypothesised that foods for large dog breeds require higher starch gelatinisation (SG) to reduce organic matter flow to colon. Fifteen Rottweilers (Ro; 49.4 ± 6.12 kg), 18 Beagles (Be; 12.13 ± 1.75 kg) and 20 Shih-Tzus (ST; 4.62 ± 1.15 kg) were fed one of three diets, all based on the same sorghum formulation, processed to obtain three levels of SG: SG90 (91.8% SG), SG50 (50.7% SG) and SG30 (27.4% SG). Foods were provided for 23 days, and the coefficient of total tract apparent digestibility (CTTAD) of nutrients, faecal production and fermentation products, Na, K and Cl apparent absorption and gastrointestinal transit time (GTT) were evaluated. Results were submitted to analysis of variance considering SG, breed and their interactions, and means compared by the Tukey test (p < 0.05). All dogs promptly ate the foods. Faeces scores were lower for Ro than for Be and ST, and lower for SG30 than SG90 (p < 0.05). Faeces pH was higher, and total short-chain fatty acids were lower for SG90 than for SG50 and SG30 (p < 0.01), regardless of breed. No diet effect was observed for GTT (p > 0.05), but it was lower for Ro (41.7 ± 6.2 h) than for ST (48.7 ± 8.6 h). The CTTAD of nutrients was lower for SG30, intermediary for SG50 and higher for SG90 (p < 0.05), and among breeds CTTAD was higher for Be than ST and Ro (p < 0.05), which did not differ from each other, except for crude protein CTTAD which was lower for Ro (p < 0.05). The apparent absorption of Na and K was higher for the SG90 treatment, and for Be in comparison with Ro and ST (p < 0.05). Food SG had a remarkable influence on Ro faeces formation and on the CTTAD in all breeds. Greater fermentation in the colon and lower protein CTTAD may be involved in Ro unformed faeces formation.

Long-term trends in total administered radiation dose from brain [18F]FDG-PET in children with drug-resistant epilepsy.

PURPOSE: To assess the trends in administered 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) doses, computed tomography (CT) radiation doses, and image quality over the last 15 years in children with drug-resistant epilepsy (DRE) undergoing hybrid positron emission tomography (PET) brain scans. METHODS: We retrospectively analyzed data from children with DRE who had [18F]FDG-PET/CT or magnetic resonance scans for presurgical evaluation between 2005 and 2021. We evaluated changes in injected [18F]FDG doses, administered activity per body weight, CT dose index volume (CTDIvol), and dose length product (DLP). PET image quality was assessed visually by four trained raters. Conversely, CT image quality was measured using region-of-interest analysis, normalized by signal-to-noise (SNR) and contrast-to-noise ratio (CNR). RESULTS: We included 55 children (30 male, mean age: 9 ± 6 years) who underwent 61 [18F]FDG-PET scans (71% as PET/CT). Annually, the injected [18F]FDG dose decreased by ~ 1% (95% CI: 0.92%-0.98%, p < 0.001), with no significant changes in administered activity per body weight (p = 0.51). CTDIvol and DLP decreased annually by 16% (95% CI: 9%-23%) and 15% (95% CI: 8%-21%, both p < 0.001), respectively. PET image quality improved by 9% year-over-year (95% CI: 6%-13%, p < 0.001), while CT-associated SNR and CNR decreased annually by 7% (95% CI: 3%-11%, p = 0.001) and 6% (95% CI: 2%-10%, p = 0.008), respectively. CONCLUSION: Our findings indicate stability in [18F]FDG administered activity per body weight alongside improvements in PET image quality. Conversely, CT-associated radiation doses reduced. These results reaffirm [18F]FDG-PET as an increasingly safer and higher-resolution auxiliary imaging modality for children with DRE. These improvements, driven by technological advancements, may enhance the diagnostic precision and patient outcomes in pediatric epilepsy surgery.

Clinical experience with ceftazidime/avibactam for the treatment of extensively drug-resistant or pandrug-resistant Klebsiella pneumoniae in neonates and children.

PURPOSE: Klebsiella pneumoniae is a significant cause of healthcare-associated infections, resulting in high morbidity and mortality rates due to limited treatment options. In this study, we aimed to evaluate the treatment outcomes and the safety of Ceftazidime-avibactam in infections caused by extensively drug-resistant or pandrug-resistant Klebsiella pneumoniae in pediatric patients. METHODS: This study included pediatric patients who received ceftazidime-avibactam treatment due to extensively drug-resistant or pandrug-resistant Klebsiella pneumoniae infections, monitored in the pediatric intensive care, neonatal intensive care, and pediatric wards of Cukurova University Faculty of Medicine between 2022 and 2023. Patients' microbiological responses, clinical responses, medication side effects, and 30-day survival rates were evaluated. RESULTS: Eleven pediatric patients were included in the study, of whom nine were male (81.8%). The median age at the initiation of ceftazidime-avibactam treatment was 15 months (range: 14 days-183 months). Sepsis was diagnosed in 9 patients (81.8%). Two premature infants (27 and 35 weeks) were admitted to the neonatal ICU. Regarding the Klebsiella pneumoniae strains, 10 (91%) were extensively drug-resistant (XDR), and 1 (9%) was pandrug-resistant (PDR). Eight strains (72.7%) were carbapenem-resistant, and 9 (81.8%) were colistin-resistant. Microbiological response was noted in 8 patients (72.7%), clinical response was evident in 6 patients (54.5%). The 30-day survival rate was 54.5%, with six patients surviving. CONCLUSION: In our study, ceftazidime-avibactam has been identified as a significant treatment option for resistant Klebsiella pneumoniae infection in critically ill children and premature infants with sepsis and organ failure, and it has been found to be well tolerated.

Navigating the Current Treatment Landscape of Metallo-ß-Lactamase-Producing Gram-Negative Infections: What are the Limitations?

The spread of carbapenemase-producing gram-negative pathogens, especially those producing metallo-ß-lactamases (MBLs), has become a major health concern. MBLs are molecularly the most diverse carbapenemases, produced by a wide spectrum of gram-negative organisms, including the Enterobacterales, Pseudomonas spp., Acinetobacter baumannii, and Stenotrophomonas maltophilia, and can hydrolyze most ß-lactams using metal ion cofactors in their active sites. Over the years, the prevalence of MBL-carrying isolates has increased globally, particularly in Asia. MBL infections are associated with adverse clinical outcomes including longer length of hospital stay, ICU admission, and increased mortality across the globe. The optimal treatment for MBL infections not only depends on the pathogen but also on the underlying resistance mechanisms. Currently, there are only few drugs or drug combinations that can efficiently offset MBL-mediated resistance, which makes the treatment of MBL infections challenging. The rising concern of MBLs along with the limited treatment options has led to the need and development of drugs that are specifically targeted towards MBLs. This review discusses the prevalence of MBLs, their clinical impact, and the current treatment options for MBL infections and their limitations. Furthermore, this review will discuss agents currently in the pipeline for treatment of MBL infections.

Psychiatrists' views on clozapine prescribing in Ireland.

INTRODUCTION: Despite proven effectiveness in refractory schizophrenia, clozapine remains underutilised, and it is important to understand potential reasons for this. This study's aim was to examine in a National sample of Consultant Psychiatrists their knowledge of, attitudes and perceived barriers to clozapine use. METHODS: A novel questionnaire was designed and distributed by email to 275 Consultant Psychiatrists in Republic of Ireland. RESULTS: Twenty-eight percent (n = 77) completed the survey, with 55% of respondents practicing for 15 or more years. Clinicians expressed confidence in managing clozapine treatment and side effects and were well aware of clozapine's clinical effectiveness and guideline-based use. A majority indicated insufficient experience managing rechallenge and half expressed insufficient experience managing adverse events. Perceived patient factors were highlighted as barriers with 69% of respondents reporting patients' concern about effectiveness and 50% regarding tolerability. Sixty-four percent (n = 40) indicated that a specialised/tertiary clozapine service would facilitate initiation, with 57% (n = 36) reporting less frequent blood monitoring would aid clozapine prescribing. A majority identified that access to dedicated staff (81%, n = 51) and dedicated day hospital services (84%, n = 53) would facilitate community initiation. CONCLUSION: Consultants are familiar with clozapine use and related guidelines. Dedicated staff and facilities for clozapine use is one identified structural change to enhance clozapine prescribing in Ireland. Tertiary service or clinical advice service would assist in clozapine rechallenge cases or in managing significant adverse events. More structured patient education regarding clozapine effectiveness and professional development programmes focused on managing side effects and rechallenge may promote clozapine use.

The enhanced antibacterial and antibiofilm properties of titanium dioxide nanoparticles biosynthesized by multidrug-resistant Pseudomonas aeruginosa.

The emergence of Multidrug-resistant (MDR) bacteria are becoming a major worldwide health concern, encouraging the development effective alternatives to conventional antibiotics. The study identified P. aeruginosa and assessed its antimicrobial sensitivity using the Vitek-2 system. Carbapenem-resistant genes were detected through Polymerase chain reaction (PCR). MDR- P. aeruginosa isolates were used to biosynthesize titanium dioxide nanoparticles (TiO2NPs) and characterized using X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM). A study involving 78 P. aeruginosa isolates revealed that 85.8% were MDR, with meropenem and amikacin showing effectiveness against 70% of the isolates. The most prevalent carbapenemase gene was blaOXA-48, present in 83% of the isolates. Majority of the isolates formed biofilms, and biosynthesized TiO2NPs were able to reduce biofilm formation by 94%. TiO2NPs exhibited potent antibacterial action against MDR-Gram-negative bacilli pathogens and showed synergistic activity with antibiotics, particularly piperacillin, with a significant fold increase in areas (283%). A new local strain of P. aeruginosa, identified as ON678251 in the World GenBank, was found capable of producing TiO2NPs. Our findings demonstrate the potential of biosynthesized TiO2NPs to manage antibiotic resistance and regulate the formation of biofilms. This presents a promising direction for the creation of novel antimicrobial agents or substitutes for use in clinical settings, particularly in the management of isolates capable of resisting multiple drugs.

Efficacy and safety of shorter multidrug-resistant or rifampicin-resistant tuberculosis regimens: a network meta-analysis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) remains a threat to public health. Shorter regimens have been proposed as potentially valuable treatments for multidrug or rifampicin resistant tuberculosis (MDR/RR-TB). We undertook a systematic review and network meta-analysis to evaluate the efficacy and safety of shorter MDR/RR-TB regimens. METHODS: We searched PubMed/MEDLINE, Cochrane Center for Clinical Trials (CENTRAL), Scopus, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, US Food and Drug Administration, and Chinese Clinical Trial Registry for primary articles published from 2013 to July 2023. Favorable (cured and treatment completed) and unfavorable (treatment failure, death, loss to follow-up, and culture conversion) outcomes were assessed as the main efficacy outcomes, while adverse events were assessed as the safety outcomes. The network meta-analysis was performed using R Studio version 4.3.1 and the Netmeta package. The study protocol adhered to the PRISMA-NMA guidelines and was registered in PROSPERO (CRD42023434050). RESULT: We included 11 eligible studies (4 randomized control trials and 7 cohorts) that enrolled 3,548 patients with MDR/RR-TB. Treatment with a 6-month combination of BdqLzdLfxZTrd/Eto/H had two times more favorable outcomes [RR 2.2 (95% CI 1.22, 4.13), P = 0.0094], followed by a 9-11 month combination of km/CmMfx/LfxPtoCfzZEHh [RR1.67 (95% CI 1.45, 1.92), P < 0.001] and a 6-month BdqPaLzdMfx [RR 1.64 (95% CI 1.24, 2.16), P < 0.0005] compared to the standard longer regimens. Treatment with 6 months of BdqPaLzdMfx [RR 0.33 (95% CI 0.2, 0.55), P < 0.0001] had a low risk of severe adverse events, followed by 6 months of BdqPaLzd [RR 0.36 (95% CI 0.22, 0.59), P ≤ 0.001] and BdqPaLzdCfz [RR 0.54 (95% CI 0.37, 0.80), P < 0.0001] than standard of care. CONCLUSION: Treatment of patients with RR/MDR-TB using shorter regimens of 6 months BdqLzdLfxZTrd/Eto/H, 9-11 months km/CmMfx/LfxPtoCfzZEHh, and 6 months BdqPaLzdMfx provides significantly higher cure and treatment completion rates compared to the standard longer MDR/RR-TB. However, 6BdqPaLzdMfx, 6BdqPaLzd, and 6BdqPaLzdCfz short regimens are significantly associated with decreased severity of adverse events. The findings are in support of the current WHO-recommended 6-month shorter regimens.