Cost-effectiveness analysis of the management of distal ureteral stones in children

Objective To determine the most cost-effective approach to the management of distal ureteral stones in children given the potential for recurrent renal colic during a trial of passage versus potential stent discomfort and complications of ureteroscopy. Methods We developed a decision tree to project costs and clinical outcomes associated with observation, medical explusive therapy (MET), and ureteroscopy for the management of an index patient with a 4mm distal ureteral stone. We determined which strategy would be least costly and offer the most pain-free days within 30 days of diagnosis. We performed a one-way sensitivity analysis on the probability of successful stone passage with MET. We obtained probabilities from the literature and costs from the 2016 Pediatric Health Information System Database. Results Ureteroscopywas the costliest strategy but maximized the number of pain-free days within 30 days of diagnosis ($5,282/29 pain-free days). MET was less costly than ureteroscopybut also less effective ($615/21.8 pain-free days). Observation cost more than MET and was also less effective ($2,139/15.5 pain-free days). The one-way sensitivity analysis on the probability of successful stone passage with MET demonstrated that ureteroscopyalways has the highest net monetary benefits value and is therefore the recommended strategy given a fixed WTP. Discussion Using a rigorous decision-science approach, we found that ureteroscopy is the recommended strategy in children with small distal ureteral stones. Although it cost more than MET, it resulted in more pain-free days in the first 30 days following diagnosis given the faster resolution of the stone episode

Is surgical antibiotic prophylaxis necessary for pediatric orchiopexy?

Introduction Surgeons frequently use surgical antibiotic prophylaxis (SAP), despite limited evidence to support its efficacy. Potential adverse events associated with antibiotic use include allergic reaction (including anaphylaxis), Clostridium difficile infection, and selecting for resistant bacteria. Surgical site infections (SSI) are very rare in patients undergoing clean pediatric urologic procedures. Current guidelines are unclear about the efficacy of surgical antibiotic prophylaxis for prevention of SSI in the pediatric population. Objective It was hypothesized that children who received SAP prior to orchiopexy would have no reduction in surgical site infection (SSI) risk but an increased risk of antibiotic-associated adverse events. Methods A retrospective cohort study was conducted of all males aged between 30 days and 18 years who underwent an orchiopexy (ICD-9 CM 62.5) in an ambulatory or observation setting from 2004 to 2015 using the Pediatric Health Information System database. Inpatients and those with concomitant procedures were excluded. Chi-squared or Fisher's exact tests were used to determine the association between SAP and allergic reaction (defined as a charge for epinephrine or ICD-9 diagnosis code for allergic reaction on the date of surgery) and any of the following within 30 days: SSI, hospital readmission or any repeat hospital encounter. Mixed effects logistic regression was performed, controlling for age, race, and insurance, and clustering of similar practice patterns by hospital. Results A total of 71,767 patients were included: median age was 4.6 years, 61.4% were white, and 49.3% had public insurance; 33.5% received SAP. Of these participants, 996/71,767 (1.4%) had a perioperative allergic reaction and <0.1% were diagnosed with an SSI. On mixed effects logistic regression, those who received SAP had 1.2 times the odds of a perioperative allergic reaction compared with those who did not receive SAP ( P = 0.005). Surgical antibiotic prophylaxis was not associated with decreased rates of SSI, lower hospital readmission, nor a lower chance of a repeat encounter within 30 days. Conclusions In patients undergoing orchiopexy, it was found that SAP did not reduce the risk of postoperative SSI, readmissions, or hospital visits. Patients who received SAP had significantly increased odds of perioperative allergic reaction. This demonstrated that the risks of SAP outweigh the benefits in children undergoing orchiopexy

Genomic landscape of extended-spectrum β-lactamase resistance in Escherichia coli from an urban African setting

Objectives: Efforts to treat Escherichia coli infections are increasingly being compromised by the rapid, global spread of antimicrobial resistance (AMR). Whilst AMR in E. coli has been extensively investigated in resource-rich settings, in sub-Saharan Africa molecular patterns of AMR are not well described. In this study, we have begun to explore the population structure and molecular determinants of AMR amongst E. coli isolates from Malawi. Methods: Ninety-four E. coli isolates from patients admitted to Queen’s Hospital, Malawi, were whole-genome sequenced. The isolates were selected on the basis of diversity of phenotypic resistance profiles and clinical source of isolation (blood, CSF and rectal swab). Sequence data were analysed using comparative genomics and phylogenetics. Results: Our results revealed the presence of five clades, which were strongly associated with E. coli phylogroups A, B1, B2, D and F. We identified 43 multilocus STs, of which ST131 (14.9%) and ST12 (9.6%) were the most common. We identified 25 AMR genes. The most common ESBL gene was blaCTX-M-15 and it was present in all five phylogroups and 11 STs, and most commonly detected in ST391 (4/4 isolates), ST648 (3/3 isolates) and ST131 [3/14 (21.4%) isolates]. Conclusions: This study has revealed a high diversity of lineages associated with AMR, including ESBL and fluoroquinolone resistance, in Malawi. The data highlight the value of longitudinal bacteraemia surveillance coupled with detailed molecular epidemiology in all settings, including low-income settings, in describing the global epidemiology of ESBL resistance

The mTOR regulated RNA-binding protein LARP1 requires PABPC1 for guided mRNA interaction.

The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, integrating multiple signalling cues and pathways. Key among the downstream activities of mTOR is the control of the protein synthesis machinery. This is achieved, in part, via the co-ordinated regulation of mRNAs that contain a terminal oligopyrimidine tract (TOP) at their 5'ends, although the mechanisms by which this occurs downstream of mTOR signalling are still unclear. We used RNA-binding protein (RBP) capture to identify changes in the protein-RNA interaction landscape following mTOR inhibition. Upon mTOR inhibition, the binding of LARP1 to a number of mRNAs, including TOP-containing mRNAs, increased. Importantly, non-TOP-containing mRNAs bound by LARP1 are in a translationally-repressed state, even under control conditions. The mRNA interactome of the LARP1-associated protein PABPC1 was found to have a high degree of overlap with that of LARP1 and our data show that PABPC1 is required for the association of LARP1 with its specific mRNA targets. Finally, we demonstrate that mRNAs, including those encoding proteins critical for cell growth and survival, are translationally repressed when bound by both LARP1 and PABPC1

Gathering opinion leader data for a tailored implementation intervention in secondary healthcare: a randomised trial

Background: Health professionals’ behaviour is a key component in compliance with evidence-based recommendations. Opinion leaders are an oft-used method of influencing such behaviours in implementation studies, but reliably and cost effectively identifying them is not straightforward. Survey and questionnaire based data collection methods have potential and carefully chosen items can – in theory – both aid identification of opinion leaders and help in the design of an implementation strategy itself. This study compares two methods of identifying opinion leaders for behaviour-change interventions. Methods: Healthcare professionals working in a single UK mental health NHS Foundation Trust were randomly allocated to one of two questionnaires. The first, slightly longer questionnaire, asked for multiple nominations of opinion leaders, with specific information about the nature of the relationship with each nominee. The second, shorter version, asked simply for a list of named “champions” but no more additional information. We compared, using Chi Square statistics, both the questionnaire response rates and the number of health professionals likely to be influenced by the opinion leaders (i.e. the “coverage” rates) for both questionnaire conditions. Results: Both questionnaire versions had low response rates: only 15% of health professionals named colleagues in the longer questionnaire and 13% in the shorter version. The opinion leaders identified by both methods had a low number of contacts (range of coverage, 2–6 each). There were no significant differences in response rates or coverage between the two identification methods. Conclusions: The low response and population coverage rates for both questionnaire versions suggest that alternative methods of identifying opinion leaders for implementation studies may be more effective. Future research should seek to identify and evaluate alternative, non-questionnaire based, methods of identifying opinion leaders in order to maximise their potential in organisational behaviour change interventions

Genomic analysis of Klebsiella pneumoniae isolates from Malawi reveals acquisition of multiple ESBL determinants across diverse lineages

Objectives ESBL-producing Klebsiella pneumoniae (KPN) pose a major threat to human health globally. We carried out a WGS study to understand the genetic background of ESBL-producing KPN in Malawi and place them in the context of other global isolates. Methods We sequenced genomes of 72 invasive and carriage KPN isolates collected from patients admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi. We performed phylogenetic and population structure analyses on these and previously published genomes from Kenya (n = 66) and from outside sub-Saharan Africa (n = 67). We screened for presence of antimicrobial resistance (AMR) genetic determinants and carried out association analyses by genomic sequence cluster, AMR phenotype and time. Results Malawian isolates fit within the global population structure of KPN, clustering into the major lineages of KpI, KpII and KpIII. KpI isolates from Malawi were more related to those from Kenya, with both collections exhibiting more clonality than isolates from the rest of the world. We identified multiple ESBL genes, including blaCTX-M-15, several blaSHV, blaTEM-63 and blaOXA-10, and other AMR genes, across diverse lineages of the KPN isolates from Malawi. No carbapenem resistance genes were detected; however, we detected IncFII and IncFIB plasmids that were similar to the carbapenem resistance-associated plasmid pNDM-mar. Conclusions There are multiple ESBL genes across diverse KPN lineages in Malawi and plasmids in circulation that are capable of carrying carbapenem resistance. Unless appropriate interventions are rapidly put in place, these may lead to a high burden of locally untreatable infection in vulnerable populations

Extracellular Superoxide Dismutase Protects Histoplasma Yeast Cells from Host-Derived Oxidative Stress

In order to establish infections within the mammalian host, pathogens must protect themselves against toxic reactive oxygen species produced by phagocytes of the immune system. The fungal pathogen Histoplasma capsulatum infects both neutrophils and macrophages but the mechanisms enabling Histoplasma yeasts to survive in these phagocytes have not been fully elucidated. We show that Histoplasma yeasts produce a superoxide dismutase (Sod3) and direct it to the extracellular environment via N-terminal and C-terminal signals which promote its secretion and association with the yeast cell surface. This localization permits Sod3 to protect yeasts specifically from exogenous superoxide whereas amelioration of endogenous reactive oxygen depends on intracellular dismutases such as Sod1. While infection of resting macrophages by Histoplasma does not stimulate the phagocyte oxidative burst, interaction with polymorphonuclear leukocytes (PMNs) and cytokine-activated macrophages triggers production of reactive oxygen species (ROS). Histoplasma yeasts producing Sod3 survive co-incubation with these phagocytes but yeasts lacking Sod3 are rapidly eliminated through oxidative killing similar to the effect of phagocytes on Candida albicans yeasts. The protection provided by Sod3 against host-derived ROS extends in vivo. Without Sod3, Histoplasma yeasts are attenuated in their ability to establish respiratory infections and are rapidly cleared with the onset of adaptive immunity. The virulence of Sod3-deficient yeasts is restored in murine hosts unable to produce superoxide due to loss of the NADPH-oxidase function. These results demonstrate that phagocyte-produced ROS contributes to the immune response to Histoplasma and that Sod3 facilitates Histoplasma pathogenesis by detoxifying host-derived reactive oxygen thereby enabling Histoplasma survival

Long-term genetic consequences of mammal reintroductions into an Australian conservation reserve

Available online 05 January 2018Reintroduction programs aim to restore self-sustaining populations of threatened species to their historic range. However, demographic restoration may not reflect genetic restoration, which is necessary for the long-term persistence of populations. Four threatened Australian mammals, the greater stick-nest rat (Leporillus conditor), greater bilby (Macrotis lagotis), burrowing bettong (Bettongia lesueur) and western barred bandicoot (Perameles bougainville), were reintroduced at Arid Recovery Reserve in northern South Australia over the last 18 years. These reintroductions have been deemed successful based on population growth and persistence, however the genetic consequences of the reintroductions are not known. We generated large single nucleotide polymorphism (SNP) datasets for each species currently at Arid Recovery and compared them to samples collected from founders. We found that average genetic diversity in all populations at the Arid Recovery Reserve are close to, or exceeding, the levels measured in the founders. Increased genetic diversity in two species was achieved by admixing slightly diverged and inbred source populations. Our results suggest that genetic diversity in translocated populations can be improved or maintained over relatively long time frames, even in small conservation reserves, and highlight the power of admixture as a tool for conservation management.Lauren C. White, Katherine E. Moseby, Vicki A. Thomson, Stephen C. Donnellan, Jeremy J. Austi

Newborn and child-like molecular signatures in older adults stem from TCR shifts across human lifespan

CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158–66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αβ signatures. Suboptimal TCRαβ signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment