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Despite significant global progress in reducing neonatal mortality, bacterial sepsis remains a major cause of neonatal deaths. Klebsiella pneumoniae (K. pneumoniae) is the leading pathogen globally underlying cases of neonatal sepsis and is frequently resistant to antibiotic treatment regimens recommended by the World Health Organization (WHO), including first-line therapy with ampicillin and gentamicin, second-line therapy with amikacin and ceftazidime, and meropenem. Maternal vaccination to prevent neonatal infection could reduce the burden of K. pneumoniae neonatal sepsis in low- and middle-income countries (LMICs), but the potential impact of vaccination remains poorly quantified. We estimated the potential impact of such vaccination on cases and deaths of K. pneumoniae neonatal sepsis and project the global effects of routine immunization of pregnant women with the K. pneumoniae vaccine as antimicrobial resistance (AMR) increases. We developed a Bayesian mixture-modeling framework to estimate the effects of a hypothetical K. pneumoniae maternal vaccine with 70% efficacy administered with coverage equivalent to that of the maternal tetanus vaccine on neonatal sepsis infections and mortality. To parameterize our model, we used data from 3 global studies of neonatal sepsis and/or mortality-with 2,330 neonates who died with sepsis surveilled from 2016 to 2020 undertaken in 18 mainly LMICs across all WHO regions (Ethiopia, Kenya, Mali, Mozambique, Nigeria, Rwanda, Sierra Leone, South Africa, Uganda, Brazil, Italy, Greece, Pakistan, Bangladesh, India, Thailand, China, and Vietnam). Within these studies, 26.95% of fatal neonatal sepsis cases were culture-positive for K. pneumoniae. We analyzed 9,070 K. pneumoniae genomes from human isolates gathered globally from 2001 to 2020 to quantify the temporal rate of acquisition of AMR genes in K. pneumoniae isolates to predict the future number of drug-resistant cases and deaths that could be averted by vaccination. Resistance rates to carbapenems are increasing most rapidly and 22.43% [95th percentile Bayesian credible interval (CrI): 5.24 to 41.42] of neonatal sepsis deaths are caused by meropenem-resistant K. pneumoniae. Globally, we estimate that maternal vaccination could avert 80,258 [CrI: 18,084 to 189,040] neonatal deaths and 399,015 [CrI: 334,523 to 485,442] neonatal sepsis cases yearly worldwide, accounting for more than 3.40% [CrI: 0.75 to 8.01] of all neonatal deaths. The largest relative benefits are in Africa (Sierra Leone, Mali, Niger) and South-East Asia (Bangladesh) where vaccination could avert over 6% of all neonatal deaths. Nevertheless, our modeling only considers country-level trends in K. pneumoniae neonatal sepsis deaths and is unable to consider within-country variability in bacterial prevalence that may impact the projected burden of sepsis. A K. pneumoniae maternal vaccine could have widespread, sustained global benefits as AMR in K. pneumoniae continues to increase.

Purpose The purpose of this exploratory study is to investigate the significance of self-efficacy and knowledge acquisition among micro businesses operating in challenging economic environments. The study uses social cognitive theory (SCT) and the knowledge-based theory of the firm (KBTF), and it proposes a refinement of these theoretical frameworks in the context of the study. Design/methodology/approach A case method was chosen, and face-to-face interviews with 14 owners of firms in island and rural regions of Greece and Spain were conducted. Findings Content analysis identified the importance of self-efficacy, primarily illustrated by entrepreneurs’ determination and self-motivation, propensity to take risks and ability to anticipate consequences of their actions. Acquisition and accumulation of explicit knowledge, particularly through generational or mentoring processes, and subsequent wealth of tacit knowledge, also emerged as very significant in preparing and guiding entrepreneurs. Various links between the adopted theories and findings emerged, particularly regarding forethought, vicarious learning (SCT) and specialisation in knowledge acquisition (KBTF). Originality/value The proposed theoretical refinement based on the SCT and KBTF paradigms allows for a more rigorous, in-depth reflection on the links between cognitive elements present in the participating micro entrepreneurs and knowledge-based attributes on their ability to increase organisational resilience. The study also contributes toward the micro business literature and addresses a knowledge gap, particularly, in that contemporary research has not explored entrepreneurial motivations among small firm entrepreneurs. Finally, the practical implications emerging from the findings provide a platform for various stakeholders (associations, government agencies) to appreciate and support entrepreneurs’ needs, notably, of acquiring, increasing and sharing knowledge.

The adherence of Proteus mirabilis to the surface of urinary catheters leads to colonization and eventual blockage of the catheter lumen by unique crystalline biofilms produced by these opportunistic pathogens, making P. mirabilis one of the leading causes of catheter-associated urinary tract infections. The Proteus biofilms reduce efficiency of antibiotic-based treatment, which in turn increases the risk of antibiotic resistance development. Bacteriophages and their enzymes have recently become investigated as alternative treatment options. In this study, a novel Proteus bacteriophage (vB_PmiS_PM-CJR) was isolated from an environmental sample and fully characterized. The phage displayed depolymerase activity and the subsequent genome analysis revealed the presence of a pectate lyase domain in its tail spike protein. The protein was heterologously expressed and purified; the ability of the purified tail spike to degrade Proteus biofilms was tested. We showed that the application of the tail spike protein was able to reduce the adherence of bacterial biofilm to plastic pegs in a MBEC (minimum biofilm eradication concentration) assay and improve the survival of Galleria mellonella larvae infected with Proteus mirabilis. Our study is the first to successfully isolate and characterize a biofilm depolymerase from a Proteus phage, demonstrating the potential of this group of enzymes in treatment of Proteus infections.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

This exploratory study investigates the impact of family firms as a product of their contributions, and proposes a framework, which associates these with the adopted social capital theory. Interviews with owners of six firms operating in three different South American countries not only revealed the more familiar contributions of creating employment and instilling values, but also through business opportunities, growth, a sense of community and increasing knowledge. Aligned with various dimensions of social capital theory, several observable premises emerged, for instance, through the creation of value gained from developing links between individuals, developing local niches, or reciprocity.

Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aβ42 (ROC > 0.8), and spermidine significantly correlated with Aβ42 (pearson r = −0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aβ42, and this requires further investigation.

Purpose The purpose of this study is to ascertain factors that enable micro- and small firms (MSFs) to cope with the effects of a long-term crisis and develop a model which guides conceptual understanding. This study’s setting is represented by the global financial crisis and by Cyprus and Greece, two nations severely affected. Design/methodology/approach On-site, unstructured, face-to-face interviews were conducted among 135 MSF leaders. Findings Sixteen different coping factors were identified as central to participants, resulting in the emergence of four key dimensions. Three dimensions, self-initiative, financial acumen and human attributes, are associated with entrepreneurs’ skills, initiatives, passion and networks, whereas one dimension, individual-firm advantage, considers firms’ and individuals’ valuable assets and resources, namely, image/reputation, quality or location. Almost two-thirds of participants recognised a lack of collaboration beyond their suppliers within their industry. Several intergroup differences were revealed, including Cypriot participants’ higher optimism concerning their firms’ future. Originality/value This study responds to calls for research that illuminates the understanding of firms’ ability to overcome inadequacies imposed by the socio-economic environment in which they operate. To this end, a theoretical framework emphasising the vital significance of four dimensions is proposed. Apart from their conceptual insightfulness, the dimensions identify clear associations with resilience and coping and can therefore be of practical value to micro–small-sized firms and their respective industry.

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. High levels of extended spectrum beta-lactamase (ESBL) and carbapenemase encoding genes were detected in bacterial isolates causing neonatal sepsis in LMICs. Authors assess the in vitro activity of three antibiotics (fosfomycin, flomoxef and amikacin) in combination against ESBL-producing Klebsiella pneumoniae and Escherichia coli isolates.

Bacterial biofilm infections account for a major proportion of chronic and medical device associated infections in humans, yet our ability to control them is compromised by their inherent tolerance to antimicrobial agents. Cold atmospheric plasma (CAP) represents a promising therapeutic option. CAP treatment of microbial biofilms represents the convergence of two complex phenomena: the production of a chemically diverse mixture of reactive species and intermediates, and their interaction with a heterogeneous 3D interface created by the biofilm extracellular polymeric matrix. Therefore, understanding these interactions and physiological responses to CAP exposure are central to effective management of infectious biofilms. We review the unique opportunities and challenges for translating CAP to the management of biofilms. Biofilms are implicated in around 65% of all chronic human infections, including those associated with indwelling medical devices such as catheters and prostheses. Biofilm infections are often asymptomatic between exacerbations and challenging to detect and effectively treat using conventional antibiotics and antimicrobial agents. CAP provides an effective multimodal, multitarget approach for controlling microbial biofilms. Biofilms express a complex extracellular matrix of polymeric substances that may attenuate the antimicrobial efficacy of CAP via interactions with CAP-generated RONS. Biofilm tolerance to CAP is variable between species and between strains of the same species, which may be due to production of EPS, RONS-detoxifying enzymes, or acquired tolerance to physiological RONS during chronic infections.

Antimicrobial resistance (AMR) has developed into a huge threat to global health, and reducing it is an urgent priority for public health authorities. The importance of a healthy and balanced gut microbiome has been identified as a key protective factor against AMR development, but this can be significantly affected by antibiotic therapy, resulting in dysbiosis and reduction of taxonomic richness. The way in which antibiotics are administered could form an important part of future antimicrobial stewardship strategies, where drug delivery is ideally placed to play a key role in the fight against AMR. This review focuses on drug delivery strategies for antibiotic administration, including avoidance of the gut microbiome and targeted delivery approaches, which may reduce AMR. Avoiding antibiotic exposure of the gut microbiota may help to reduce the enrichment for antimicrobial resistance genes and the subsequent emergence of antimicrobial resistance.Drug delivery modality should be considered in any antimicrobial resistance stewardship strategy, and formulation, route of administration, and targeted antibiotic delivery all play key roles.The use of nanoparticle-based formulations for antibiotic delivery has resulted in increased efficacy against intracellular pathogens compared with free drug, as well as reductions in effective antibiotic doses.Novel and emerging drug delivery technologies, including molecularly imprinted polymers and enhanced transdermal delivery platforms such as microneedles, could be employed in targeted antibiotic delivery systems.