Antibiotic review kit for hospitals (ARK-Hospital): a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: Strategies to reduce antibiotic overuse in hospitals depend on prescribers taking decisions to stop unnecessary antibiotic use. There is scarce evidence for how to support these decisions. We evaluated a multifaceted behaviour change intervention (ie, the antibiotic review kit) designed to reduce antibiotic use among adult acute general medical inpatients by increasing appropriate decisions to stop antibiotics at clinical review. METHODS: We performed a stepped-wedge, cluster (hospital)-randomised controlled trial using computer-generated sequence randomisation of eligible hospitals in seven calendar-time blocks in the UK. Hospitals were eligible for inclusion if they admitted adult non-elective general or medical inpatients, had a local representative to champion the intervention, and could provide the required study data. Hospital clusters were randomised to an implementation date occurring at 1-2 week intervals, and the date was concealed until 12 weeks before implementation, when local preparations were designed to start. The intervention effect was assessed using data from pseudonymised routine electronic health records, ward-level antibiotic dispensing, Clostridioides difficile tests, prescription audits, and an implementation process evaluation. Co-primary outcomes were monthly antibiotic defined daily doses per adult acute general medical admission (hospital-level, superiority) and all-cause mortality within 30 days of admission (patient level, non-inferiority margin of 5%). Outcomes were assessed in the modified intention-to-treat population (ie, excluding sites that withdrew before implementation). Intervention effects were assessed by use of interrupted time series analyses within each site, estimating overall effects through random-effects meta-analysis, with heterogeneity across prespecified potential modifiers assessed by use of meta-regression. This trial is completed and is registered with ISRCTN, ISRCTN12674243. FINDINGS: 58 hospital organisations expressed an interest in participating. Three pilot sites implemented the intervention between Sept 25 and Nov 20, 2017. 43 further sites were randomised to implement the intervention between Feb 12, 2018, and July 1, 2019, and seven sites withdrew before implementation. 39 sites were followed up for at least 14 months. Adjusted estimates showed reductions in total antibiotic defined daily doses per acute general medical admission (-4·8% per year, 95% CI -9·1 to -0·2) following the intervention. Among 7 160 421 acute general medical admissions, the ARK intervention was associated with an immediate change of -2·7% (95% CI -5·7 to 0·3) and sustained change of 3·0% (-0·1 to 6·2) in adjusted 30-day mortality. INTERPRETATION: The antibiotic review kit intervention resulted in sustained reductions in antibiotic use among adult acute general medical inpatients. The weak, inconsistent intervention effects on mortality are probably explained by the onset of the COVID-19 pandemic. Hospitals should use the antibiotic review kit to reduce antibiotic overuse. FUNDING: UK National Institute for Health and Care Research.

Determining normal values for lower trachea and bronchi size in children by computed tomography (CT).

BACKGROUND: Normative data for central airway dimensions are a prerequisite to objectively assess large airway pathologies. Studies with computed tomography (CT) measurements of normal trachea and bronchi size in children are scarce. OBJECTIVE: The purpose of this study is to establish normal values of central airway dimensions in children by CT. METHODS: The study included chest CT studies from children aged 0-18 years. Any condition that predisposed the patient to have an abnormal tracheal or bronchial size was excluded. Airway diameters and cross-sectional area (CSA) were measured using double oblique reconstructions at five levels: proximal trachea, mid-trachea, distal trachea, right main bronchus, and left main bronchus. RESULTS: The inclusion criteria were met by 110 subjects (mean age, 10.8 years; SD, 5.2 years). Various regression models that considered the relationship between patient demographics and anteroposterior (AP) diameter, transverse diameter, and CSA at each of the five levels were assessed. R2 was utilized to select the best model. Multiple formulae (using patient age) were developed to calculate expected normal dimensions for five levels in the central airways on the natural log scale. Finally, z-scores were obtained for central airway dimensions at these five levels. CONCLUSION: Normative data in pediatric central airways are crucial to identify large airway pathologies. We propose using the formulae devised in our study to calculate the predicted dimensions of central airways and their z-scores in pediatric patients. Normative data from our study will aid in objective quantification of central airways, increase clinician confidence, and provide appropriate patient care.

The Cost-Effectiveness of Anterior Cruciate Ligament Reconstruction in Competitive Athletes.

BACKGROUND: Competitive athletes value the ability to return to competitive play after the treatment of anterior cruciate ligament (ACL) injuries. ACL reconstruction has high success rates for return to play, but some studies indicate that patients may do well with nonoperative physical therapy treatment. PURPOSE: To evaluate the cost-effectiveness of the treatment of acute ACL tears with either initial surgical reconstruction or physical therapy in competitive athletes. STUDY DESIGN: Economic and decision analysis; Level of evidence, 2. METHODS: The incremental cost, incremental effectiveness, and incremental cost-effectiveness ratio (ICER) of ACL reconstruction compared with physical therapy were calculated from a cost-effectiveness analysis of ACL reconstruction compared with physical therapy for the initial management of acute ACL injuries in competitive athletes. The ACL reconstruction strategy and the physical therapy strategy were represented as Markov models. Costs and quality-adjusted life-years (QALYs) were evaluated over a 6-year time horizon and were analyzed from a societal perspective. Quality of life and probabilities of clinical outcomes were obtained from the peer-reviewed literature, and costs were compiled from a large academic hospital in the United States. One-way, 2-way, and probabilistic sensitivity analyses were used to assess the effect of uncertainty in variables on the ICER of ACL reconstruction. RESULTS: The ICER of ACL reconstruction compared with physical therapy was $22,702 per QALY gained. The ICER was most sensitive to the quality of life of returning to play or not returning to play, costs, and duration of follow-up but relatively insensitive to the rates and costs of complications, probabilities of return to play for both operative and nonoperative treatments, and discount rate. CONCLUSION: ACL reconstruction is a cost-effective strategy for competitive athletes with an ACL injury.

Bacteriophage Can Prevent Encrustation and Blockage of Urinary Catheters by Proteus mirabilis.

Proteus mirabilis forms dense crystalline biofilms on catheter surfaces that occlude urine flow, leading to serious clinical complications in long-term catheterized patients, but there are presently no truly effective approaches to control catheter blockage by this organism. This study evaluated the potential for bacteriophage therapy to control P. mirabilis infection and prevent catheter blockage. Representative in vitro models of the catheterized urinary tract, simulating a complete closed drainage system as used in clinical practice, were employed to evaluate the performance of phage therapy in preventing blockage. Models mimicking either an established infection or early colonization of the catheterized urinary tract were treated with a single dose of a 3-phage cocktail, and the impact on time taken for catheters to block, as well as levels of crystalline biofilm formation, was measured. In models of established infection, phage treatment significantly increased time taken for catheters to block (∼ 3-fold) compared to untreated controls. However, in models simulating early-stage infection, phage treatment eradicated P. mirabilis and prevented blockage entirely. Analysis of catheters from models of established infection 10 h after phage application demonstrated that phage significantly reduced crystalline biofilm formation but did not significantly reduce the level of planktonic cells in the residual bladder urine. Taken together, these results show that bacteriophage constitute a promising strategy for the prevention of catheter blockage but that methods to deliver phage in sufficient numbers and within a key therapeutic window (early infection) will also be important to the successful application of phage to this problem.

Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations.

OBJECTIVES: To develop a population model to describe the pharmacokinetics (PK) of intravenous meropenem in adult patients with severe burns and investigate potential relationships between dosage regimens and antimicrobial efficacy. PATIENTS AND METHODS: A dose of 1 g every 8 h was administered to adult patients with total body surface area burns of ≥15%. Doses for subsequent courses were determined using results from the initial course and the patient's clinical condition. Five plasma meropenem concentrations were typically measured over the dosage interval on one to four occasions. An open, two-compartment PK model was fitted to the meropenem concentrations using NONMEM and the effect of covariates on meropenem PK was investigated. Monte Carlo simulations investigated dosage regimens to achieve a target T>MIC for ≥40%, ≥60% or ≥80% of the dose interval. RESULTS: Data comprised 113 meropenem concentration measurements from 20 dosage intervals in 12 patients. The parameters were CL (L/h) = 0.196 L/h/kg × [1 - 0.023 × (age - 46)] × [1 - 0.049 × (albumin - 15)], V1 = 0.273 L/kg × [1 - 0.049 × (albumin - 15)], Q = 0.199 L/h/kg and V2 = 0.309 L/kg × [1 - 0.049 × (albumin - 15)]. For a target of ≥80% T>MIC, the breakpoint was 8 mg/L for doses of 1 g every 4 h and 2 g every 8 h given over 3 h, but only 4 mg/L if given over 5 min. CONCLUSIONS: Although 1 g 8 hourly should be effective against Escherichia coli and CoNS, higher doses, ideally with a longer infusion time, would be more appropriate for empirical therapy, mixed infections and bacteria with MIC values ≥4 mg/L.

Effects of Continuous Irrigation During Burring on Thermal Necrosis and Fusion Strength in a Rabbit Arthrodesis Model.

BACKGROUND: High-speed burring used to prepare bony surfaces during arthrodesis procedures can increase heat generation that may impede healing and fusion. Irrigation during burring has the potential to improve early healing of burred bone surfaces and result in a stronger fusion mass. The purpose of this study was to determine the effects of continuous irrigation during burring on thermal necrosis and fusion strength in an in vivo arthrodesis animal model. METHODS: A small joint rabbit ulnohumeral arthrodesis model was developed and utilized in 16 New Zealand white rabbits. Joints were prepared and contoured using a high-speed cutting burr and fixed in compression with crossed screws to obtain fusion. Prepared bony surfaces were either irrigated (n = 8) with chilled 6°C (43°F) saline or not irrigated (n = 8). Specimens were harvested, radiographed, mechanically tested for torque to failure and stiffness, and evaluated for histology. RESULTS: Fusion rate was 100% (8/8) when joints were irrigated during burring and 75% (6/8) when joints were not irrigated (P = .45). Mechanical testing showed a mean torque to failure of 0.85 Nm and 0.72 Nm in irrigated and nonirrigated specimens, respectively (P = .57). Histology showed evidence of less mature osseous formation in nonirrigated specimens compared to irrigated specimens. CONCLUSION: There was an overall trend toward decreased fusion rate and lower fusion mass strength in nonirrigated fusion specimens compared with those treated with chilled irrigation during bone preparation. CLINICAL RELEVANCE: Continuous chilled irrigation during bone preparation with burring may have a positive effect on fusion rate and fusion mass strength for arthrodesis procedures.

Emergence of MD type infectious hematopoietic necrosis virus in Washington State coastal steelhead trout.

Infectious hematopoietic necrosis virus (IHNV) occurs in North America as 3 major phylogenetic groups designated U, M, and L. In coastal Washington State, IHNV has historically consisted of U genogroup viruses found predominantly in sockeye salmon Oncorhynchus nerka. M genogroup IHNV, which has host-specific virulence for rainbow and steelhead trout O. mykiss, was detected only once in coastal Washington prior to 2007, in an epidemic among juvenile steelhead trout in 1997. Beginning in 2007 and continuing through 2011, there were 8 IHNV epidemics in juvenile steelhead trout, involving 7 different fish culture facilities in 4 separate watersheds. During the same time period, IHNV was also detected in asymptomatic adult steelhead trout from 6 coastal watersheds. Genetic typing of 283 recent virus isolates from coastal Washington revealed that the great majority were in the M genogroup of IHNV and that there were 2 distinct waves of viral emergence between the years 2007 and 2011. IHNV type mG110M was dominant in coastal steelhead trout during 2007 to 2009, and type mG139M was dominant between 2010 and 2011. Phylogenetic analysis of viral isolates indicated that all coastal M genogroup viruses detected in 1997 and 2007 to 2011 were part of the MD subgroup and that several novel genetic variants related to the dominant types arose in the coastal sites. Comparison of spatial and temporal incidence of coastal MD viruses with that of the rest of the Pacific Northwest indicated that the likely source of the emergent viruses was Columbia River Basin steelhead trout.

Imaging and percutaneous treatment of secondarily infected hepatic infarctions.

OBJECTIVE: The objective of our study was to describe the imaging features and success rate of percutaneously treated infected hepatic infarctions. MATERIALS AND METHODS: Three hundred ninety-two patients had percutaneous liver abscess aspiration and drainage or aspiration and intraoperative débridement at our institution between 1990 and 2003. One hundred fifty-one of these patients underwent CT at least 2 days before the drainage procedure and immediately before the procedure. Retrospective review of the imaging and medical records identified 13 patients with microbiologically documented liver abscesses who had liver lesions consistent with hepatic infarction on the baseline CT. RESULTS: Twenty-one hepatic infarctions in 13 patients were documented on baseline CT, 15 of which became secondarily infected. Ten of 15 patients with infected infarctions had undergone either hepatic transplantation or the Whipple procedure. Although the left lobe was slightly more commonly infarcted than the right lobe (54% vs 46%, respectively), right lobe infarctions were more commonly superinfected than left lobe infarctions (61% vs 39%); however, neither of these distinctions was statistically significant. Twelve of 13 patients underwent percutaneous drainage. The duration of catheter drainage was significantly longer in patients in whom catheter drainage was complicated by biliary communication than those without biliary communication (61 vs 19 days, respectively). Eleven of 12 patients (92%) responded to drainage such that they survived to discharge from the hospital. CONCLUSION: Patients with hepatic infarctions are at risk for secondary infection, particularly those patients having undergone surgery involving the porta hepatis. Percutaneous abscess drainage can be performed safely with excellent technical and clinical outcomes in this complex patient population.

Palliative Care Partnership: a successful model of primary/secondary integration.

The health reforms of the 1990s and early 21st century have seen unheralded change in the delivery of health services in New Zealand, and the concept of integration of primary and specialist or secondary services into a seamless health delivery service is one of the key planks of national and regional healthcare planning in New Zealand. This paper reports on a successful primary secondary integration project. Starting with commentary on the historical difficulties that acted as a catalyst to this initiative, it reports on the development process, how the model works in practice, and outlines some initial evaluation work done as part of its quality improvement component. Given the collaborative nature of this project and its scope across primary and specialist care sectors, the authors believe this model has implications and relevance across a wide spectrum of the New Zealand health service.

The role of AEBP1 in sex-specific diet-induced obesity.

Obesity is an important risk factor for heart disease, diabetes, and certain cancers, but the molecular basis for obesity is poorly understood. The transcriptional repressor AEBP1, which functions as a negative regulator of PTEN through a protein-protein interaction, is highly expressed in the stromal compartment of adipose tissues, including proliferative preadipocytes, and its expression is abolished in terminally differentiated, nonproliferative adipocytes. Here we show that transgenic overexpression of AEBP1 during adipogenesis coupled with a high-fat diet (HFD) resulted in massive obesity in female transgenic (AEBP1(TG)) mice via adipocyte hyperplasia. AEBP1 levels dynamically changed with aging, and HFD induced AEBP1 expression in females. Thus, HFD-fed AEBP1(TG) females display hyperinduction of AEBP1 and a marked reduction of PTEN level with concomitant hyperactivation of the survival signal in white adipose tissue. Our results suggest that AEBP1 plays a key functional role in in vivo modulation of adiposity via fat-cell proliferation and is involved in a sex-specific susceptibility to diet-induced obesity by the estrogen signaling pathway.

Deletion of N-terminal amino acids from human lecithin:cholesterol acyltransferase differentially affects enzyme activity toward alpha- and beta-substrate lipoproteins.

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for generation of the majority of the cholesteryl esters (CE) in human plasma. Although most plasma cholesterol esterification occurs on high-density lipoprotein (HDL), via alpha-LCAT activity, esterification also occurs on low-density lipoprotein (LDL) via the beta-activity of the enzyme. Computer threading techniques have provided a three-dimensional model for use in the structure-function analysis of the core and catalytic site of the LCAT protein, but the model does not extend to the N-terminal region of the enzyme, which may mediate LCAT interaction with lipoprotein substrates. In the present study, we have examined the functional consequences of deletion of the highly conserved hydrophobic N-terminal amino acids (residues 1-5) of human LCAT. Western blot analysis showed that the mutant proteins (Delta 1-Delta 5) were synthesized and secreted from transfected COS-7 cells at levels approximately equivalent to those of wild-type hLCAT. The secreted proteins had apparent molecular weights of 67 kDa, indicating that they were correctly processed and glycosylated during cellular transit. However, deletion of the first residue of the mature LCAT protein (Delta 1 mutant) resulted in a dramatic loss of alpha-LCAT activity (5% of wild type using reconstituted HDL substrate, rHDL), although this mutant retained full beta-LCAT activity (108% of wild-type using human LDL substrate). Removal of residues 1 and 2 (Delta 2 mutant) abolished alpha-LCAT activity and reduced beta-LCAT activity to 12% of wild type. Nevertheless, LCAT Delta 1 and Delta 2 mutants retained their ability to bind to rHDL and LDL lipoprotein substrates. The dramatic loss of enzyme activity suggests that the N-terminal residues of LCAT may be involved in maintaining the conformation of the lid domain and influence activation by the alpha-LCAT cofactor apoA-I (in Delta 1) and/or loss of enzyme activity (in Delta 1-Delta 5). Since the Delta 1 and Delta 2 mutants retain their ability to bind substrate, other factor(s), such as decreased access to the substrate binding pocket, may be responsible for the loss of enzyme activity.

Is the screening portable pelvis film clinically useful in multiple trauma patients who will be examined by abdominopelvic CT? Experience with 397 patients.

The multiple trauma patient is usually initially imaged with a portable "trauma series" consisting of a lateral cervical spine film, a portable chest film, and a portable pelvis film (PPF). An investigation was performed to determine whether the screening PPF could be eliminated for multiple trauma patients being examined by abdominopelvic CT scan (APCT). A retrospective investigation analyzed all patients evaluated in our level I trauma center from 1 January to 31 December 2000 who were examined with a "trauma series" followed by an APCT scan within 8 h. The numbers and types of fractures diagnosed by PPF and by APCT were compared and correlated with clinical follow-up. Of 397 patients imaged by both PPF and APCT, 43 patients were diagnosed with 109 individual fractures by CT scan. The PPF did not detect 51 of the 109 individual fractures (47%) and failed to diagnose 9 of the 43 patients (21%) with a pelvic fracture. The PPF most often failed to detect sacral and iliac fractures. The four cases in which the PPF reported a fracture not listed in the APCT report were due to reporting errors or film artifacts. No soft tissue injuries were seen by PPF that were not also seen by APCT. We conclude that the screening PPF appears to be an unnecessary exam in multiple trauma patients about to be imaged by APCT scan.