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Background: Estimates of inappropriate prescribing can highlight key target areas for antimicrobial stewardship (AMS) and inform national targets., Objectives: To (1) define and (2) produce estimates of inappropriate antibiotic prescribing levels within acute hospital trusts in England., Methods: The 2016 national Healthcare-Associated Infections (HAI), Antimicrobial Use (AMU) and AMS point prevalence survey (PPS) was used to derive estimates of inappropriate prescribing, focusing on the four most reported community-acquired antibiotic indications (CAIs) in the PPS and surgical prophylaxis. Definitions of appropriate antibiotic therapy for each indication were developed through the compilation of national treatment guidelines. A Likert-scale system of appropriateness coding was validated and refined through a two-stage expert review process., Results: Antimicrobial usage prevalence data were collected for 25,741 individual antibiotic prescriptions, representing 17,884 patients and 213 hospitals in England. 30.4% of prescriptions for the four CAIs of interest were estimated to be inappropriate (2054 prescriptions). The highest percentage of inappropriate prescribing occurred in uncomplicated cystitis prescriptions (62.5%), followed by bronchitis (48%). For surgical prophylaxis, 30.8% of prescriptions were inappropriate in terms of dose number, and 21.3% in terms of excess prophylaxis duration., Conclusions: The 2016 prevalence of inappropriate antibiotic prescribing in hospitals in England was approximated to be 30.4%; this establishes a baseline prevalence and provided indication of where AMS interventions should be prioritized. Our definitions appraised antibiotic choice, treatment duration and dose number (surgical prophylaxis only); however, they did not consider other aspects of appropriateness, such as combination therapy - this is an important area for future work., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Objectives: To determine whether MDR occurs more frequently in nitrofurantoin-resistant Escherichia coli urinary isolates in England, compared with nitrofurantoin-susceptible isolates., Methods: Using routine E. coli urine isolate antibiotic susceptibility laboratory surveillance data for England, 2015-19 inclusive, the percentage of MDR or XDR phenotype was estimated for nitrofurantoin-susceptible and nitrofurantoin-resistant laboratory-reported urinary tract samples by region, patient sex and age group., Results: Resistance to nitrofurantoin among E. coli urinary samples decreased slightly year on year from 2.9% in 2015 to 2.3% in 2019. Among E. coli UTIs tested for nitrofurantoin susceptibility and  ≥3 additional antibiotics, the percentage that were MDR was consistently 15%-20% percentage points higher for nitrofurantoin-resistant isolates compared with nitrofurantoin-susceptible isolates. Similarly, the percentage of isolates with an XDR phenotype was higher among nitrofurantoin-resistant versus -susceptible isolates (8.7% versus 1.4%, respectively, in 2019); this disparity was greater in male patients, although variation was seen by age group in both sexes. Regional variation was also noted, with the highest MDR percentage amongst nitrofurantoin-resistant E. coli urinary samples in the London region (36.7% in 2019); the lowest was in the North East (2019: 16.9%)., Conclusions: MDR and XDR phenotypes occur more frequently in nitrofurantoin-resistant E. coli urinary isolates in England, compared with nitrofurantoin-susceptible isolates. However, nitrofurantoin resistance is low (<3%) overall. This latest study provides important insights into trends in nitrofurantoin resistance and MDR, which is of particular concern for patients ≥75 years old and those who are male. It also emphasises geographical heterogeneities within England in nitrofurantoin resistance and MDR., (© Crown copyright 2023.)

Background: Point prevalence surveys are an important surveillance method for determining the burden of healthcare-associated infections (HCAIs)., Aim: To outline the key results of two point prevalence surveys in England (2011 and 2016)., Methods: All National Health Service and independent sector hospitals in England were eligible to participate. Data were collected between September and November in both 2011 and 2016 based on the protocol and codebook devised by the European Centre for Disease Prevention and Control. Analysis was performed using Stata Version 13 and SAS Version 9.3. A mixed-effects model was applied, which allowed estimation of organization-specific means and accounted for the heterogeneity in the responses from different organizations., Findings: A total of 100,755 case records were included (52,433 in 2011 and 48,312 in 2016). The estimated prevalence of HCAIs was slightly higher in 2016 [6.89%, 95% confidence interval (CI) 6.21-7.57%] than in 2011 (6.41%, 95% CI 5.75-7.06%). In both surveys, the prevalence of HCAIs was highest in adult intensive care units (23.1% in 2011, 21.2% in 2016), and pneumonia/lower respiratory tract infections was the most common cause of HCAIs (22.7% in 2011 vs 29.2% in 2016). Inpatients in acute hospitals were older and had higher risk of dying in 2016 compared with 2011; however, the proportion of inpatients with HCAIs or on antibiotics did not differ significantly., Conclusion: The burden of HCAIs in English hospitals increased slightly between 2011 and 2016. However, the proportion of inpatients with HCAIs or on antibiotics did not differ significantly., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

In prior research, perceived low neighborhood social cohesion (nSC) has been associated with prevalence of type 2 diabetes mellitus (T2DM); however, few studies have investigated the nSC-T2DM relationship among a large, racially/ethnically diverse, and nationally representative sample of the U.S. population. We used National Health Interview Survey (2013-2018) data to determine overall, age-, sex/gender-, and racial/ethnic-specific associations between nSC and T2DM among 170,432 adults. Self-reported nSC was categorized as low, medium, and high. T2DM was determined by participants being told they had diabetes by a health professional. We used Poisson regression with robust variance to estimate prevalence ratios (PRs) and 95% confidence intervals (CI) while adjusting for confounders. Mean age was 47.4 ± 0.1 years, 52% were women, and 69% self-identified as Non-Hispanic (NH)-White. Low vs. high nSC was associated with a higher prevalence of T2DM (PR = 1.22 [95% CI: 1.16-1.27]), after adjustment. A higher prevalence of T2DM was observed among participants 31-49 years old who perceived low vs. high nSC (PR = 1.36 [95% CI: 1.20-1.54]) and among participants ≥50 years old (PR = 1.18 [95% CI: 1.13-1.24]). Hispanic/Latinx women 18-30 years old in neighborhoods with low vs. high social cohesion had a higher prevalence of T2DM (PR = 3.70 [95% CI: 1.40-9.80]), whereas NH-Black women 18-30 years old in neighborhoods with medium vs. high social cohesion had a lower prevalence of T2DM (PR = 0.35 [95% CI: 0.14-0.89]). Our findings support the literature by demonstrating an association between neighborhood environment and T2DM as well as extend it by identifying determinants for intervention for T2DM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Introduction: Acquired carbapenemase-producing Gram-negative bacteria are an increasing public health concern globally and have been mandatory to report in England since October 2020. However, in light of the COVID-19 (SARS-CoV-2) pandemic, the Royal College of Pathologists (RCPath) released new guidance "for reducing the need for screening of CRE (carbapenem-resistant Enterobacterales) […] in low-risk areas", without defining "low risk"., Methods: To assess the impact of the RCPath recommendations on screening of carbapenemase-producing Enterobacterales (CPE), an online Select Survey was sent to all NHS acute hospitals in England. The initial survey distribution was between March and April 2021 and the survey was relaunched between November 2021 and March 2022., Results: In total, 54 hospitals completed the survey, representing 39.1% of 138 eligible Trusts. All hospitals had a CPE screening policy in place, and the majority of these reflect UKHSA's Framework of actions to contain CPE. Of the 23 hospitals who reported a reduction in CPE screening, only three (13.0%) indicated that this was due to the RCPath recommendations, with 21 (91.3%) indicating that there had been a natural reduction in the number of patients admitted to the Trust who would have previously been screened due to the COVID-19 pandemic., Conclusion: For most surveyed hospitals, CPE screening was not reduced due to the RCPath recommendations. However, the results highlighted that there is a large amount of individual variation in CPE screening practices and diagnostic testing between hospitals., (Crown Copyright © 2023 Published by Elsevier Ltd on behalf of The Healthcare Infection Society.)

Increases in invasive group A streptococcal (iGAS) infection and associated deaths, particularly in children, above seasonally expected levels are being seen this season (772 notifications reported in weeks 37 to 48 in 2022) across England. Diagnoses of iGAS infection from lower respiratory tract specimens in children under 15 years increased to 28% in November 2022. Medical practitioners have been alerted to the exceptional increase in incidence, including unusual numbers of children presenting with pulmonary empyema.

Vaccines are a key part of the global strategy to tackle antimicrobial resistance (AMR) since prevention of infection should reduce antibiotic use. England commenced national rollout of a live attenuated influenza vaccine (LAIV) programme for children aged 2-3 years together with a series of geographically discrete pilot areas for primary school age children in 2013 extending to older children in subsequent seasons. We investigated vaccine programme impact on community antibiotic prescribing rates. Antibiotic prescribing incidence rates for respiratory (RTI) and urinary tract infections (UTI; controls) were calculated at general practice (GP) level by age category (children<=10 years/adults) and season for LAIV pilot and non-pilot areas between 2013/14 and 2015/16. To estimate the LAIV (primary school age children only) intervention effect, a random effects model was fitted. A multivariable random-effects Poisson regression investigated the association of antibiotic prescribing rates in children with LAIV uptake (2-3-year-olds only) at GP practice level. RTI antibiotic prescribing rates for children <=10 years and adults showed clear seasonal trends and were lower in LAIV-pilot and non-pilot areas after the introduction of the LAIV programme in 2013. The reductions for RTI prescriptions (children) were similar (within 3%) in all areas, which coincided with the start the UK AMR strategy. Antibiotic prescribing was significantly (p < 0.0001) related to LAIV uptake in 2-3-year-olds with antibiotic prescribing reduced by 2.7% (95% CI: 2.1% to 3.4%) for every 10% increase in uptake. We found no evidence the LAIV programme for primary school age children resulted in reductions in RTI antibiotic prescribing, however we detected a significant inverse association between increased vaccine uptake in pre-school age children and antibiotic prescribing at GP level. The temporal association of reduced RTI and UTI antibiotic prescribing with the launch of the UK's AMR Strategy in 2013 highlights the importance of a multifaceted approach to tackle AMR., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Transcription initiation is highly regulated by promoter sequence, transcription factors, and ligands. All known transcription inhibitors, an important class of antibiotics, act in initiation. To understand regulation and inhibition, the biophysical mechanisms of formation and stabilization of the "open" promoter complex (OC), of synthesis of a short RNA-DNA hybrid upon nucleotide addition, and of escape of RNA polymerase (RNAP) from the promoter must be understood. We previously found that RNAP forms three different OC with λP R promoter DNA. The 37 °C RNAP-λP R OC (RP O ) is very stable. At lower temperatures, RP O is less stable and in equilibrium with an intermediate OC (I 3 ). Here, we report step-by-step rapid quench-flow kinetic data for initiation and growth of the RNA-DNA hybrid at 25 and 37 °C that yield rate constants for each step of productive nucleotide addition. Analyzed together, with previously published data at 19 °C, our results reveal that I 3 and not RP O is the productive initiation complex at all temperatures. From the strong variations of rate constants and activation energies and entropies for individual steps of hybrid extension, we deduce that contacts of RNAP with the bubble strands are disrupted stepwise as the hybrid grows and translocates. Stepwise disruption of RNAP-strand contacts is accompanied by stepwise bubble collapse, base stacking, and duplex formation, as the hybrid extends to a 9-mer prior to disruption of upstream DNA-RNAP contacts and escape of RNAP from the promoter., Competing Interests: The authors declare no competing interest.

Introduction: Antibiotic resistance poses a threat to public health and healthcare systems. Escherichia coli causes more bacteraemia episodes in England than any other bacterial species. This study aimed to estimate the burden of E. coli bacteraemia and associated antibiotic resistance in the secondary care setting., Materials and Methods: This was a retrospective cohort study, with E. coli bacteraemia as the main exposure of interest. Adult hospital in-patients, admitted to acute NHS hospitals between July 2011 and June 2012 were included. English national surveillance and administrative datasets were utilised. Cox proportional hazard, subdistribution hazard and multistate models were constructed to estimate rate of discharge, rate of in-hospital death and excess length of stay, with a unit bed day cost applied to the latter to estimate cost burden from the healthcare system perspective., Results: 14,042 E. coli bacteraemia and 8,919,284 non-infected inpatient observations were included. E. coli bacteraemia was associated with an increased rate of in-hospital death across all models, with an adjusted subdistribution hazard ratio of 5.88 (95% CI: 5.62-6.15). Resistance was not found to be associated with in-hospital mortality once adjusting for patient and hospital covariates. However, resistance was found to be associated with an increased excess length of stay. This was especially true for third generation cephalosporin (1.58 days excess length of stay, 95% CI: 0.84-2.31) and piperacillin/tazobactam resistance (1.23 days (95% CI: 0.50-1.95)). The annual cost of E. coli bacteraemia was estimated to be £14,346,400 (2012 £), with third-generation cephalosporin resistance associated with excess costs per infection of £420 (95% CI: 220-630)., Conclusions: E. coli bacteraemia places a statistically significant burden on patient health and the hospital sector in England. Resistance to front-line antibiotics increases length of stay; increasing the cost burden of such infections in the secondary care setting., Competing Interests: The authors have declared that no competing interests exist.

Objective: To estimate the incidence of laboratory-confirmed, invasive bacterial infections (IBIs) by week of age in infants over a 7-year period., Design: Analysis of prospective national surveillance data for England., Setting: National Health Service hospitals in England., Patients: Infants aged <1 year who were hospitalised with IBI., Main Outcome Measures: IBI incidence by week of age, incidence rate ratio (IRR) at 8, 12 and 16 weeks compared with the first week of life, and the main pathogens responsible for IBI., Results: There were 22 075 IBI episodes between 2010/2011 and 2016/2017. The lowest annual cases were in 2011/2012 (n=2 799; incidence, 412/100 000 population), increasing year-on-year to 3 698 cases in 2016/2017 (incidence, 552/100 000 population). The incidence was highest in the first week of life and then declined rapidly. In 2016/2017, compared with the first week of life, weekly IBI incidence was 92% lower at 8 weeks (IRR 0.08; 95% CI 0.06 to 0.10) and 96% lower at 16 weeks of age (IRR 0.04; 95% CI 0.03 to 0.06). In 2016/2017, Escherichia coli was the most prevalent pathogen responsible for IBI (n=592, 16.0%), followed by group B Streptococci (n=493, 13.3%), Staphylococcus aureus (n=400, 10.8%) and Enterococci (n=304, 8.2%). The other pathogens were individually responsible for <5% of total cases. There were differences in age distribution of the pathogens with increasing age., Conclusion: IBI incidence declines rapidly after the first week of life, such that infants have a very low risk of IBI by the time they are eligible for their routine immunisations from 8 weeks of age., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Hospital performance is often measured using self-reported statistics, such as the incidence of hospital-transmitted micro-organisms or those exhibiting antimicrobial resistance (AMR), encouraging hospitals with high levels to improve their performance. However, hospitals that increase screening efforts will appear to have a higher incidence and perform poorly, undermining comparison between hospitals and disincentivising testing, thus hampering infection control. We propose a surveillance system in which hospitals test patients previously discharged from other hospitals and report observed cases. Using English National Health Service (NHS) Hospital Episode Statistics data, we analysed patient movements across England and assessed the number of hospitals required to participate in such a reporting scheme to deliver robust estimates of incidence. With over 1.2 million admissions to English hospitals previously discharged from other hospitals annually, even when only a fraction of hospitals (41/155) participate (each screening at least 1000 of these admissions), the proposed surveillance system can estimate incidence across all hospitals. By reporting on other hospitals, the reporting of incidence is separated from the task of improving own performance. Therefore the incentives for increasing performance can be aligned to increase (rather than decrease) screening efforts, thus delivering both more comparable figures on the AMR problems across hospitals and improving infection control efforts., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: All authors declare no support from any organisation for the submitted work; NW has received research grants from Wockhardt, Merck Sharp & Dohme Corp, Roche, Meiji Seika, Enigma Diagnostics, Bio-Rad, Biomerieux, Accelerate, BD Diagnostics, Astrazeneca, Check points, GlaxoSmithKline, Kalidex, Malinta, Momentum, Norgine, Rempex, Rotikan, Smith&Nephew, Venato Rx Pharmaceuticals, and Basilea for research projects or contracted evaluations. There were no other relationships or activities that could appear to have influenced the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

To determine the step-by-step kinetics and mechanism of transcription initiation and escape by E. coli RNA polymerase from the λP R promoter, we quantify the accumulation and decay of transient short RNA intermediates on the pathway to promoter escape and full-length (FL) RNA synthesis over a wide range of NTP concentrations by rapid-quench mixing and phosphorimager analysis of gel separations. Experiments are performed at 19 °C, where almost all short RNAs detected are intermediates in FL-RNA synthesis by productive complexes or end-products in nonproductive (stalled) initiation complexes and not from abortive initiation. Analysis of productive-initiation kinetic data yields composite second-order rate constants for all steps of NTP binding and hybrid extension up to the escape point (11-mer). The largest of these rate constants is for incorporation of UTP into the dinucleotide pppApU in a step which does not involve DNA opening or translocation. Subsequent steps, each of which begins with reversible translocation and DNA opening, are slower with rate constants that vary more than 10-fold, interpreted as effects of translocation stress on the translocation equilibrium constant. Rate constants for synthesis of 4- and 5-mer, 7-mer to 9-mer, and 11-mer are particularly small, indicating that RNAP-promoter interactions are disrupted in these steps. These reductions in rate constants are consistent with the previously determined ∼9 kcal cost of escape from λP R . Structural modeling and previous results indicate that the three groups of small rate constants correspond to sequential disruption of in-cleft, -10, and -35 interactions. Parallels to escape by T7 RNAP are discussed.

Background: To describe the clinical characteristics and risk factors associated with poor outcome in infants <90 days of age with bacterial meningitis., Methods: Prospective, enhanced, national population-based active surveillance for infants <90 days of age with bacterial meningitis in the United Kingdom and Ireland between July 2010 and July 2011. Infants were identified through the British Paediatric Surveillance Unit, laboratory surveillance and meningitis charities., Results: Clinical details was available for 263 of 298 (88%) infants where a bacterium was identified, 184 (70%) were born at term. Fever was reported in 143 (54%), seizures in 73 (28%), bulging fontanelle in 58 (22%), coma in 15 (6%) and neck stiffness in 7 (3%). Twenty-three (9%) died and 56/240 (23%) of the survivors had serious central nervous system complications at discharge. Temperature instability [odds ratio (OR), 2.99; 95% confidence interval (CI): 1.21-7.41], seizures (OR, 7.06; 95% CI: 2.80-17.81), cerebrospinal fluid protein greater than the median concentration (2275 mg/dL; OR, 2.62; 95% CI: 1.13-6.10) and pneumococcal meningitis (OR, 4.83; 95% CI: 1.33-17.58) were independently associated with serious central nervous system complications while prematurity (OR, 5.84; 95% CI: 2.02-16.85), low birthweight (OR, 8.48; 95% CI: 2.60-27.69), coma at presentation (OR, 31.85; 95% CI: 8.46-119.81) and pneumococcal meningitis (OR, 4.62; 95% CI: 1.19-17.91) were independently associated with death., Conclusions: The classic features of meningitis were uncommon. The presentation in young infants is often nonspecific, and only half of cases presented with fever. A number of clinical and laboratory factors were associated with poor outcomes; further research is required to determine how knowledge of these risk factors might improve clinical management and outcomes.

Taurine/α-ketoglutarate (αKG) dioxygenase (TauD) is an E. coli nonheme Fe 2+ - and αKG-dependent metalloenzyme that catalyzes the hydroxylation of taurine, leading to the production of sulfite. The metal-dependent active site in TauD is formed by two histidine and one aspartate that coordinating to one face of an octahedral coordination geometry, known as the 2-His-1-carboxylate facial triad. This motif is found in many nonheme Fe 2+ proteins, but there is limited information on the thermodynamic parameters that govern metal-ion binding to this site. Here, we report data from calorimetry and related biophysical techniques to generate complete thermodynamic profiles of Mn 2+ and Co 2+ binding to TauD, and these values are compared to the Fe 2+ data reported earlier Henderson et al. (Inorg Chem 54: 2278-2283, 2015). The buffer-independent binding constants (K) were measured to be 1.6 × 10 6 , 2.4 × 10 7 , and 1.7 × 10 9 , for Mn 2+ , Fe 2+ , and Co 2+ , respectively. The corresponding ΔG° values were calculated to be - 8.4, - 10.1, and - 12.5 kcal/mol, respectively. The metal-binding enthalpy changes (ΔH) for these binding events are - 11.1 (± 0.1), - 12.2 (± 0.1), and - 16.0 (± 0.6) kcal/mol, respectively. These data are fully consistent with the Irving-Williams series, which show an increasing affinity for transition metal ions across the periodic table. It appears that the periodic increase in affinity, however, is a result of a complicated summation of enthalpy terms (including favorable metal-ion coordination processes and unfavorable ionization events) and related entropy terms.

Objectives: To evaluate the association between use of different antibiotics and trimethoprim resistance at the population level., Methods: Monthly primary care prescribing data were obtained from NHS Digital. Positive Enterobacteriaceae records from urine samples from patients between April 2014 and January 2016 in England were extracted from PHE's Second Generation Surveillance System (SGSS). Elastic net regularization and generalized boosted regression models were used to evaluate associations between antibiotic prescribing and trimethoprim resistance, both measured at Clinical Commission Group level., Results: In total, 2 487 635 (99%) of 2 513 285 urine Enterobacteriaceae samples from 1 667 839 patients were tested for trimethoprim resistance. Using both elastic net regularization and generalized boosted regression models, geographical variation in trimethoprim resistance among Enterobacteriaceae urinary samples could be partly explained by geographical variation in use of trimethoprim (relative risk = 1.14, 95% CI = 1.02-1.75; relative influence = 4.1) and penicillins with extended spectrum (mainly amoxicillin/ampicillin in England) (relative risk = 1.19, 95% CI = 1.11-1.30; relative influence = 7.4). Nitrofurantoin use was associated with lower trimethoprim resistance levels (relative risk = 0.83, 95% CI =  0.57-0.96; relative influence = 9.2)., Conclusions: Use of amoxicillin/ampicillin explained more of the variance in trimethoprim resistance than trimethoprim use, suggesting that co-selection by these antibiotics is an important driver of trimethoprim resistance levels at the population level. Nitrofurantoin use was consistently associated with lower trimethoprim resistance levels, indicating that trimethoprim resistance levels could be lowered if trimethoprim use is replaced by nitrofurantoin.

Background: After decades of decreasing scarlet fever incidence, a dramatic increase was seen in England beginning in 2014. Investigations were launched to assess clinical and epidemiological patterns and identify potential causes., Methods: In this population-based surveillance study, we analysed statutory scarlet fever notifications held by Public Health England from 1911 to 2016 in England and Wales to identify periods of sudden escalation of scarlet fever. Characteristics of cases and outbreaks in England including frequency of complications and hospital admissions were assessed and compared with the pre-upsurge period. Isolates from throat swabs were obtained and were emm typed., Findings: Data were retrieved for our analysis between Jan 1, 1911, and Dec 31, 2016. Population rates of scarlet fever increased by a factor of three between 2013 and 2014 from 8·2 to 27·2 per 100 000 (rate ratio [RR] 3·34, 95% CI 3·23-3·45; p<0·0001); further increases were observed in 2015 (30·6 per 100 000) and in 2016 (33·2 per 100 000), which reached the highest number of cases (19 206) and rate of scarlet fever notifcation since 1967. The median age of cases in 2014 was 4 years (IQR 3-7) with an incidence of 186 per 100 000 children under age 10 years. All parts of England saw an increase in incidence, with 620 outbreaks reported in 2016. Hospital admissions for scarlet fever increased by 97% between 2013 and 2016; one in 40 cases were admitted for management of the condition or potential complications. Analysis of strains (n=303) identified a diversity of emm types with emm3 (43%), emm12 (15%), emm1 (11%), and emm4 (9%) being the most common. Longitudinal analysis identified 4-yearly periodicity in population incidence of scarlet fever but of consistently lower magnitude than the current escalation., Interpretation: England is experiencing an unprecedented rise in scarlet fever with the highest incidence for nearly 50 years. Reasons for this escalation are unclear and identifying these remains a public health priority., Funding: None., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hospital networks, formed by patients visiting multiple hospitals, affect the spread of hospital-associated infections, resulting in differences in risks for hospitals depending on their network position. These networks are increasingly used to inform strategies to prevent and control the spread of hospital-associated pathogens. However, many studies only consider patients that are received directly from the initial hospital, without considering the effect of indirect trajectories through the network. We determine the optimal way to measure the distance between hospitals within the network, by reconstructing the English hospital network based on shared patients in 2014-2015, and simulating the spread of a hospital-associated pathogen between hospitals, taking into consideration that each intermediate hospital conveys a delay in the further spread of the pathogen. While the risk of transferring a hospital-associated pathogen between directly neighbouring hospitals is a direct reflection of the number of shared patients, the distance between two hospitals far-away in the network is determined largely by the number of intermediate hospitals in the network. Because the network is dense, most long distance transmission chains in fact involve only few intermediate steps, spreading along the many weak links. The dense connectivity of hospital networks, together with a strong regional structure, causes hospital-associated pathogens to spread from the initial outbreak in a two-step process: first, the directly surrounding hospitals are affected through the strong connections, second all other hospitals receive introductions through the multitude of weaker links. Although the strong connections matter for local spread, weak links in the network can offer ideal routes for hospital-associated pathogens to travel further faster. This hold important implications for infection prevention and control efforts: if a local outbreak is not controlled in time, colonised patients will appear in other regions, irrespective of the distance to the initial outbreak, making import screening ever more difficult.

Background: TauD is a nonheme iron(II) and α-ketoglutarate (αKG) dependent dioxygenase, and a member of a broader family of enzymes that oxidatively decarboxylate αKG to succinate and carbon dioxide thereby activating O 2 to perform a range of oxidation reactions. However before O 2 activation can occur, these enzymes bind both substrate and cofactor in an effective manner. Here the thermodynamics associated with substrate and cofactor binding to FeTauD are explored., Methods: Thermal denaturation of TauD and its enzyme-taurine, enzyme-αKG, and enzyme-taurine-αKG complexes are explored using circular dichroism (CD) spectroscopy and differential scanning calorimetry (DSC)., Results: Taurine binding is endothermic (+26kcal/mol) and entropically driven that includes burial of hydrophobic surfaces to close the lid domain. Binding of αKG is enthalpically favorable and shows cooperativity with taurine binding, where the change in enthalpy associated with αKG binding (δΔH cal ) increases from -30.1kcal/mol when binding to FeTauD to -65.2kcal/mol when binding to the FeTauD-taurine complex., Conclusions: The intermolecular interactions that govern taurine and αKG binding impact the global stability of TauD and its complexes, with clear and dramatic cooperativity between substrate and cofactor., General Significance: Thermal denaturation of TauD and its enzyme-taurine, enzyme-αKG, and enzyme-taurine-αKG complexes each exhibited increased temperature stability over the free enzyme. Through deconvolution of the energetic profiles for all species studied, a thermodynamic cycle was generated that shows significant cooperativity between substrate and cofactor binding which continues to clarity the events leading up O 2 activation., (Copyright © 2017. Published by Elsevier B.V.)

Background: To combat the spread of antimicrobial resistance (AMR), hospitals are advised to screen high-risk patients for carriage of antibiotic-resistant bacteria on admission. This often includes patients previously admitted to hospitals with a high AMR prevalence. However, the ability of such a strategy to identify introductions (and hence prevent onward transmission) is unclear, as it depends on AMR prevalence in each hospital, the number of patients moving between hospitals, and the number of hospitals considered 'high risk'., Methods: We tracked patient movements using data from the National Health Service of England Hospital Episode Statistics and estimated differences in regional AMR prevalences using, as an exemplar, data collected through the national reference laboratory service of Public Health England on carbapenemase-producing Enterobacteriaceae (CPE) from 2008 to 2014. Combining these datasets, we calculated expected CPE introductions into hospitals from across the hospital network to assess the effectiveness of admission screening based on defining high-prevalence hospitals as high risk., Results: Based on numbers of exchanged patients, the English hospital network can be divided into 14 referral regions. England saw a sharp increase in numbers of CPE isolates referred to the national reference laboratory over 7 years, from 26 isolates in 2008 to 1649 in 2014. Large regional differences in numbers of confirmed CPE isolates overlapped with regional structuring of patient movements between hospitals. However, despite these large differences in prevalence between regions, we estimated that hospitals received only a small proportion (1.8%) of CPE-colonised patients from hospitals outside their own region, which decreased over time., Conclusions: In contrast to the focus on import screening based on assigning a few hospitals as 'high risk', patient transfers between hospitals with small AMR problems in the same region often pose a larger absolute threat than patient transfers from hospitals in other regions with large problems, even if the prevalence in other regions is orders of magnitude higher. Because the difference in numbers of exchanged patients, between and within regions, was mostly larger than the difference in CPE prevalence, it would be more effective for hospitals to focus on their own populations or region to inform control efforts rather than focussing on problems elsewhere.

To investigate roles of the discriminator and open complex (OC) lifetime in transcription initiation by Escherichia coli RNA polymerase (RNAP; α 2 ββ'ωσ 70 ), we compare productive and abortive initiation rates, short RNA distributions, and OC lifetime for the λP R and T7A1 promoters and variants with exchanged discriminators, all with the same transcribed region. The discriminator determines the OC lifetime of these promoters. Permanganate reactivity of thymines reveals that strand backbones in open regions of long-lived λP R -discriminator OCs are much more tightly held than for shorter-lived T7A1-discriminator OCs. Initiation from these OCs exhibits two kinetic phases and at least two subpopulations of ternary complexes. Long RNA synthesis (constrained to be single round) occurs only in the initial phase (<10 s), at similar rates for all promoters. Less than half of OCs synthesize a full-length RNA; the majority stall after synthesizing a short RNA. Most abortive cycling occurs in the slower phase (>10 s), when stalled complexes release their short RNA and make another without escaping. In both kinetic phases, significant amounts of 8-nt and 10-nt transcripts are produced by longer-lived, λP R -discriminator OCs, whereas no RNA longer than 7 nt is produced by shorter-lived T7A1-discriminator OCs. These observations and the lack of abortive RNA in initiation from short-lived ribosomal promoter OCs are well described by a quantitative model in which ∼1.0 kcal/mol of scrunching free energy is generated per translocation step of RNA synthesis to overcome OC stability and drive escape. The different length-distributions of abortive RNAs released from OCs with different lifetimes likely play regulatory roles.

Study Objective: A substantial proportion of antipsychotic (AP) use in veterans is for nonapproved indications (i.e., off-label prescribing). Not all off-label use is necessarily detrimental to patients, however, and in certain situations, off-label prescribing could be considered justifiable. The objective of this study was to determine the extent to which off-label AP prescribing in a veteran population was potentially appropriate., Design: Expert panel and retrospective analysis., Data Source: Veterans Health Administration (VHA) Corporate Data Warehouse., Patients: A total of 69,823 veterans who had at least one pharmacy record for an AP medication during fiscal years 2005-2012., Measurements and Main Results: An expert panel was convened to determine if agreement exists on the appropriateness of AP use in various scenarios. The panel consisted of 10 experts in the field of psychiatry: nine physicians with various specialties, and one pharmacist. We used a modified RAND appropriateness method approach to identify potentially appropriate, uncertain, and inappropriate cases of AP use. The use of six second-generation APs was examined individually, and the use of first-generation APs was examined as a class. Based on data previously collected quantifying VHA AP use, the panel was given disease state scenarios for the most commonly occurring off-label diagnoses for AP prescriptions. Disease states were coupled with scenario modifiers that the expert panel considered potentially significant clinical factors. Among the four disease states-anxiety, dementia, insomnia, and posttraumatic stress disorder-29 scenarios were investigated for each AP. None of the scenarios were judged by the expert panel to be appropriate for the use of APs. Of the 203 scenarios for all APs, 60% were judged to be inappropriate by the expert panel, and the remaining 40% were considered uncertain. Of the AP medications, risperidone (72%) and olanzapine (62%) were the most likely to be seen as uncertain, whereas first-generation APs (86%) were the most likely to be considered inappropriate in a given scenario. Widespread off-label use of APs outside of the approved indications of treatment of schizophrenia and bipolar disorder, or adjunctive treatment of major depressive disorder, may not be an appropriate treatment option. According to this expert panel, no examined situations were considered appropriate for the use of APs., Conclusion: The consensus of our expert panel was that off-label AP use is uncertain at best and more likely, even in complicated cases, inappropriate. These findings strengthen the case for stronger control of APs in integrated health care settings such as the VHA, as well as better education and information for practitioners who provide care for patients with anxiety, dementia, insomnia, or posttraumatic stress disorder., (© 2017 Pharmacotherapy Publications, Inc.)

Background: Extradiol dioxygenases are a family of nonheme iron (and sometimes manganese) enzymes that catalyze an O2-dependent ring-opening reaction in a biodegradation pathway of aromatic compounds. Here we characterize the thermodynamics of two substrates binding in homoprotocatechuate 2,3-dioxygenase (HPCD) prior to the O2 activation step., Methods: This study uses microcalorimetry under an inert atmosphere to measure thermodynamic parameters associated with catechol binding to nonheme metal centers in HPCD. Several stopped-flow rapid mixing experiments were used to support the calorimetry experiments., Results: The equilibria constant for 4-nitrocatechol and homoprotocatechuate binding to the iron(II) and manganese(II) forms of HPCD range from 2×10(4) to 1×10(6), suggesting there are distinctive differences in how the enzyme-substrate complexes are stabilized. Further experiments in multiple buffers allowed us to correct the experimental ΔH for substrate ionization and to fully derive the pH and buffer independent thermodynamic parameters for substrate binding to HPCD. Fewer protons are released from the iron(II) dependent processes than their manganese(II) counterparts., Conclusions: Condition independent thermodynamic parameters for 4-nitrocatechol and homoprotocatechuate binding to HPCD are highly consistent with each other, suggesting these enzyme-substrate complexes are more similar than once thought, and the ionization state of metal coordinated waters may be playing a role in tuning redox potential and in governing reactivity., General Significance: Substrate binding to HPCD is a complex set of equilibria that includes ionization of substrate and water release, yet it is also the key step in O2 activation., (Copyright © 2015. Published by Elsevier B.V.)

Background: The human telomere contains tandem repeat of (TTAGG) capable of forming a higher order DNA structure known as G-quadruplex. Porphyrin molecules such as TMPyP4 bind and stabilize G-quadruplex structure., Methods: Isothermal titration calorimetry (ITC), circular dichroism (CD), and mass spectroscopy (ESI/MS), were used to investigate the interactions between TMPyP4 and the Co(III), Ni(II), Cu(II), and Zn(II) complexes of TMPyP4 (e.g. Co(III)-TMPyP4) and a model human telomere G-quadruplex (hTel22) at or near physiologic ionic strength ([Na(+)] or [K(+)]≈0.15M)., Results: The apo-TMPyP4, Ni(II)-TMPyP4, and Cu(II)-TMPyP4 all formed complexes having a saturation stoichiometry of 4:1, moles of ligand per mole of DNA. Binding of apo-TMPyP4, Ni(II)-TMPyP4, and Cu(II)-TMPyP4 is described by a "four-independent-sites model". The two highest-affinity sites exhibit a K in the range of 10(8) to 10(10)M(-1) with the two lower-affinity sites exhibiting a K in the range of 10(4) to 10(5)M(-1). Binding of Co(III)-TMPyP4, and Zn(II)-TMPyP4, is best described by a "two-independent-sites model" in which only the end-stacking binding mode is observed with a K in the range of 10(4) to 10(5)M(-1)., Conclusions: In the case of apo-TMPyP4, Ni(II)-TMPyP4, and Cu(II)-TMPyP4, the thermodynamic signatures for the two binding modes are consistent with an "end stacking" mechanism for the higher affinity binding mode and an "intercalation" mechanism for the lower affinity binding mode. In the case of Co(III)-TMPyP4 and Zn(II)-TMPyP4, both the lower affinity for the "end-stacking" mode and the loss of the intercalative mode for forming the 2:1 complexes with hTel22 are attributed to the preferred metal coordination geometry and the presence of axial ligands., General Significance: The preferred coordination geometry around the metal center strongly influences the energetics of the interactions between the metallated-TMPyP4 and the model human telomeric G-quadruplex., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: The objective of this study was to evaluate the ability of weighted-incidence syndromic combination antibiograms (WISCAs) to inform the selection of empirical antibiotic regimens for suspected paediatric bloodstream infections (BSIs) by comparing WISCAs derived using data from single hospitals and from a multicentre surveillance dataset., Methods: WISCAs were developed by estimating the coverage of five empirical antibiotic regimens for childhood BSI using a Bayesian decision tree. The study used microbiological data on ∼2000 bloodstream isolates collected over 2 years from 19 European hospitals. We evaluated the ability of a WISCA to show differences in regimen coverage at two exemplar hospitals. For each, a WISCA was first calculated using only their local data; a second WISCA was calculated using pooled data from all 19 hospitals., Results: The estimated coverage of the five regimens was 72%-86% for Hospital 1 and 79%-94% for Hospital 2, based on their own data. In both cases, the best regimens could not be definitively identified because the differences in coverage were not statistically significant. For Hospital 1, coverage estimates derived using pooled data gave sufficient precision to reveal clinically important differences among regimens, including high coverage provided by a narrow-spectrum antibiotic combination. For Hospital 2, the hospital and pooled data showed signs of heterogeneity and the use of pooled data was judged not to be appropriate., Conclusions: The Bayesian WISCA provides a useful approach to pooling information from different sources to guide empirical therapy and could increase confidence in the selection of narrow-spectrum regimens., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Non-melanoma skin cancer and other epithelial tumors overexpress cyclooxygenase-2 (COX-2), differentiating them from normal cells. COX-2 metabolizes arachidonic acid to prostaglandins including, the J-series prostaglandins, which induce apoptosis by mechanisms including endoplasmic reticulum (ER) stress. Arachidonoyl-ethanolamide (AEA) is a cannabinoid that causes apoptosis in diverse tumor types. Previous studies from our group demonstrated that AEA was metabolized by COX-2 to J-series prostaglandins. Thus, the current study examines the role of COX-2, J-series prostaglandins, and ER stress in AEA-induced apoptosis. In tumorigenic keratinocytes that overexpress COX-2, AEA activated the PKR-like ER kinase (PERK), inositol requiring kinase-1 (IRE1), and activating transcription factor-6 (ATF6) ER stress pathways and the ER stress apoptosis-associated proteins, C/EBP homologous protein-10 (CHOP10), caspase-12, and caspase-3. Using an ER stress inhibitor, it was determined that ER stress was required for AEA-induced apoptosis. To evaluate the role of COX-2 in ER stress-apoptosis, HaCaT keratinocytes with low endogenous COX-2 expression were transfected with COX-2 cDNA or an empty vector and AEA-induced ER stress-apoptosis occurred only in the presence of COX-2. Moreover, LC-MS analysis showed that the novel prostaglandins, 15-deoxyΔ(12,14) PGJ2 -EA and Δ(12) PGJ2 /PGJ2-EA, were synthesized from AEA. These findings suggest that AEA will be selectively toxic in tumor cells that overexpress COX-2 due to the metabolism of AEA by COX-2 to J-series prostaglandin-ethanolamides (prostamides). Hence, AEA may be an ideal topical agent for the elimination of malignancies that overexpress COX-2., (© 2015 Wiley Periodicals, Inc.)

Isothermal titration calorimetry (ITC) can be used to study the thermodynamics of enzyme substrate binding or the kinetics of substrate turnover (or both). Substrate-binding interactions are observed in a typical ITC titration experiment in which the heat change for the addition of an aliquot of substrate to a solution containing the enzyme is determined for a number of titrant (i.e., substrate) injections and the data fit for the thermodynamic parameters (ΔG, ΔH, and -TΔS) for substrate binding. Of course, these measurements must be made under conditions where the substrate binds but does not turnover. In the ITC "kinetics" experiment, the power change observed after injection of an excess of substrate into a solution of the enzyme is a direct measure of the rate at which substrate is converted to product, and the ITC data can be analyzed for the kinetic parameters (Vmax, kcat, KM, and kcat/KM). The ITC technique is particularly versatile in that it can be applied to systems where there might not be a change in a spectroscopic signal for either substrate binding or the reaction of the substrate to form product. A complication is that if there are competing reactions, for example, buffer protonation, or product binding, to name just two, the enthalpy change measured for either substrate binding or for substrate turnover will be a summation of all of the reaction heats. Enzyme studies are typically done in buffered solutions at constant pH. The general, and often incorrect, assumption is that the buffer components are simply spectators and not participants in either substrate binding or substrate turnover. This chapter describes how we have used ITC measurements to identify problem buffers that impact the kinetics for an enzyme catalyzed reaction. Herein, we show the effects of several buffers on the steady-state kinetics for the conversion of the substrate, 3,4-dihydroxyphenyl acetate (homoprotocatechuate), to the ring-opened product, 5-carboxymethyl-2-hydroxymuconic semialdehyde by the nonheme iron(II) metalloenzyme, homoprotocatechuate 2,3-dioxygenase. Several buffers were observed to engage in buffer/enzyme interactions within the active site pocket. These enzyme-buffer interactions were shown to inhibit substrate turnover and to contribute additional enthalpy terms to the overall heat of reaction observed for substrate turnover (and for substrate binding)., (© 2016 Elsevier Inc. All rights reserved.)

Background: Hospital-acquired bloodstream infection (HA-BSI) is associated with substantial morbidity, mortality, and healthcare costs in all patient populations. Young children have been shown to have a high rate of healthcare-associated infections compared with the adult population. We aimed to quantify the excess mortality and length of stay in pediatric patients from HA-BSI., Methods: We analyzed data collected retrospectively from a probabilistically linked national database of pediatric (aged 1 month-18 years) in-patients with a microbiologically confirmed HA-BSI in England between January and March 2009. A time-dependent Cox regression model was fit to determine the presence of any effect. Furthermore, a multistate model, adjusted for the time to onset of HA-BSI, was used to compare outcomes in patients with HA-BSI to those without HA-BSI. We further adjusted for patients' characteristics as recorded in hospital admission data., Results: The dataset comprised 333 605 patients, with 214 cases of HA-BSI. After adjustment for time to HA-BSI and comorbidities, the hazard for discharge (dead or alive) from hospital for patients with HA-BSI was 0.9 times (95% confidence interval [CI], .8-1.1) that of noninfected patients. Excess length of stay associated with all-cause HA-BSI was 1.6 days (95% CI, .2-3.0), although this duration varied by pathogen. Patients with HA-BSI had a 3.6 (95% CI, 1.3-10.4) times higher hazard for in-hospital death than noninfected patients., Conclusions: Hospital-acquired bloodstream infection increased the length of stay and mortality of pediatric inpatients. The results of this study provide an evidence base to judge the health and economic impact of programs to prevent and control HA-BSI in children., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Paediatricians recognize that using the time-dependent community-acquired vs. hospital-acquired bloodstream infection (BSI) dichotomy to guide empirical treatment no longer distinguishes between causative pathogens due to the emergence of healthcare-associated BSIs. However, paediatric epidemiological evidence of the aetiology of BSIs in relation to hospital admission in England is lacking. For 12 common BSI-causing pathogens in England, timing of laboratory reports of positive paediatric (3 months to 5 years) bacterial blood isolates were linked to in-patient hospital data and plotted in relation to hospital admission. The majority (88·6%) of linked pathogens were isolated <2 days after hospital admission, including pathogens widely regarded as hospital acquired: Enterococcus spp. (67·2%) and Klebsiella spp. (88·9%). Neisseria meningitidis, Streptococcus pneumoniae, group A streptococcus and Salmonella spp. were unlikely to cause hospital-acquired BSI. Pathogens commonly associated with hospital-acquired BSI are being isolated <2 days after hospital admission alongside pathogens commonly associated with community-acquired BSI. We confirm that timing of blood samples alone does not differentiate between bacterial pathogens. Additional factors including clinical patient characteristics and healthcare contact should be considered to help predict the causative pathogen and guide empirical antibiotic therapy.

The thermodynamic properties of Fe(2+) binding to the 2-His-1-carboxylate facial triad in α-ketoglutarate/taurine dioxygenase (TauD) were explored using isothermal titration calorimetry. Direct titrations of Fe(2+) into TauD and chelation experiments involving the titration of ethylenediaminetetraacetic acid into Fe(2+)-TauD were performed under an anaerobic environment to yield a binding equilibrium of 2.4 (±0.1) × 10(7) (Kd = 43 nM) and a ΔG° value of -10.1 (±0.03) kcal/mol. Further analysis of the enthalpy/entropy contributions indicates a highly enthalpic binding event, where ΔH = -11.6 (±0.3) kcal/mol. Investigations into the unfavorable entropy term led to the observation of water molecules becoming organized within the Fe(2+)-TauD structure.

Background: Bacterial meningitis remains a major cause of morbidity and mortality in young infants. Understanding the epidemiology and burden of disease is important., Methods: Prospective, enhanced, national population-based active surveillance was undertaken to determine the incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United Kingdom and Ireland., Results: During July 2010-July 2011, 364 cases were identified (annual incidence, 0.38/1000 live births; 95% confidence interval [CI], .35-.42). In England and Wales, the incidence of confirmed neonatal bacterial meningitis was 0.21 (n = 167; 95% CI, .18-.25). A total of 302 bacteria were isolated in 298 (82%) of the cases. The pathogens responsible varied by route of admission, gestation at birth, and age at infection. Group B Streptococcus (GBS) (150/302 [50%]; incidence, 0.16/1000 live births; 95% CI, .13-.18) and Escherichia coli (41/302 [14%]; incidence, 0.04/1000; 95% CI, .03-.06) were responsible for approximately two-thirds of identified bacteria. Pneumococcal (28/302 [9%]) and meningococcal (23/302 [8%]) meningitis were rare in the first month, whereas Listeria meningitis was seen only in the first month of life (11/302 [4%]). In hospitalized preterm infants, the etiology of both early- and late-onset meningitis was more varied. Overall case fatality was 8% (25/329) and was higher for pneumococcal meningitis (5/26 [19%]) than GBS meningitis (7/135 [5%]; P = .04) and for preterm (15/90 [17%]) compared with term (10/235 [4%]; P = .0002) infants., Conclusions: The incidence of bacterial meningitis in young infants remains unchanged since the 1980s and is associated with significant case fatality. Prevention strategies and guidelines to improve the early management of cases should be prioritized., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Historically, bacterial infections were categorized as either community-acquired (CA) or hospital-acquired (HA). However, the CA/HA dichotomy no longer adequately reflects patterns of emerging healthcare-associated (HCA) infections in complex patients managed between hospital and the community. Studies trying to define this evolving epidemiology often excluded children., Aim: To identify what criteria have been used to distinguish between CA, HCA and HA bloodstream infections (BSIs) in children, and the proportional distribution of CA, HCA and HA among total BSIs and by organism., Methods: We systematically reviewed published literature from PubMed, UK Department of Health and US Centers for Disease Control and Prevention websites., Findings: Results from 23 studies and the websites highlighted the use of inconsistent criteria. There were 13 and 15 criteria variations for CA and HA BSI respectively, although a 48h cut-off for cultures sampled post admission was most commonly reported. Five studies used variable clinical criteria to define HCA. The mean proportion of paediatric CA BSI in nine studies was 50%. Only four BSI organisms from five studies were predominantly CA (Streptococcus pneumoniae, Salmonella spp.) or HA (coagulase-negative staphylococci, Enterococcus spp.), whereas Pseudomonas spp., Klebsiella spp. and Enterobacter spp. did not clearly fit into either category., Conclusions: Our study reveals inconsistent use of criteria, and a lack of evidence upon which to base them, to distinguish between CA, HCA and HA BSI in children. Criteria for CA, HCA and HA BSI need to be developed using population-based studies that consider patients' clinical characteristics, recent healthcare exposure as well as isolated organism species., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Background: Few cross-population studies examining the epidemiology of invasive group B streptococcal (GBS) disease have been undertaken. To identify longitudinal trends in the burden and characteristics of infections, national surveillance data on diagnoses in England and Wales from 1991 to 2010 were analyzed., Methods: A parallel review of laboratory-confirmed invasive GBS infection surveillance reports and isolates submitted to the national reference laboratory was undertaken. Cases were defined as GBS isolated from a normally sterile site., Results: A total of 21 386 reports of invasive GBS infection were made between 1991 and 2010. The annual rate of reports doubled over the 20 years from 1.48 to 2.99 per 100 000 population. Significant increases were seen in all age groups but most pronounced in adults. Rates of early-onset (0-6 days) infant disease fluctuated but showed a general rise between 2000 and 2010 from 0.28 to 0.41 per 1000 live births. Rates of late-onset (7-90 days) disease increased steadily between 1991 and 2010 from 0.11 to 0.29 per 1000 live births. Resistance to erythromycin increased markedly from 2.5% in 1991 to 15% in 2010. The distribution of serotypes varied according to patient age and over time with type III increasing among early-onset cases and decreasing in adults., Conclusions: Although risk of invasive GBS infection remains highest within the first few days of life, the relative burden of disease is shifting toward adults. The rise in incidence and antibiotic resistance makes development of an effective and safe vaccine all the more pressing.

After an increase in the number of reported cases of Pneumocystis jirovecii pneumonia in England, we investigated data from 2000-2010 to verify the increase. We analyzed national databases for microbiological and clinical diagnoses of P. jirovecii pneumonia and associated deaths. We found that laboratory-confirmed cases in England had increased an average of 7% per year and that death certifications and hospital admissions also increased. Hospital admissions indicated increased P. jirovecii pneumonia diagnoses among patients not infected with HIV, particularly among those who had received a transplant or had a hematologic malignancy. A new risk was identified: preexisting lung disease. Infection rates among HIV-positive adults decreased. The results confirm that diagnoses of potentially preventable P. jirovecii pneumonia among persons outside the known risk group of persons with HIV infection have increased. This finding warrants further characterization of risk groups and a review of P. jirovecii pneumonia prevention strategies.

Background: Hospital-acquired bloodstream infection (HA-BSI) requires immediate effective antibiotic treatment. However, there are no published national data for England that describe the pathogen profile and antibiotic resistance rates of HA-BSI in children., Methods: Probabilistic matching methods were used to link national data on microbiologically confirmed BSI to hospital in-patient admissions data for the period of January 2009-March 2010. HA-BSI was defined as a positive blood culture drawn from a child aged 1 month-18 years 2 or more days after admission (and before discharge)., Results: A total of 8718 episodes of BSI was reported during the study period. Linkage allowed 82% of records to be matched, of which 23% (1734) were HA-BSI, giving a rate of 4.74 per 1000 admissions. The median age of infection was 1 year, and 54% of infections were in males. Methicillin resistance was seen in 83% and 17% of coagulase-negative staphylococci and Staphylococcus aureus, respectively. Penicillin resistance was rare in pyogenic streptococci but more common in viridans streptococci (39%). Among Gram-positive organisms, only 3% were vancomycin-resistant. The overall proportion of Gram-negative bacteria resistant to recommended empirical antibiotics (meropenem or piperacillin/tazobactam) was 5% and 16%, respectively, but <4% of isolates were resistant when either of these drugs were combined with gentamicin., Conclusions: This study provides the first national estimates of the proportion of pediatric BSI that is hospital-acquired and describes the antimicrobial resistance of organisms causing infection. Pediatric HA-BSI remains unacceptably high; interventions must focus on identifying effective means of preventing HA-BSI, fostering antibiotic stewardship, and improving surveillance., (© The Author 2012. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Homoprotocatechuate 2,3-dioxygenase (HPCD) is a member of the extradiol dioxygenase family of non-heme iron enzymes. These enzymes catalyze the ring-cleavage step in the aromatic degradation pathway commonly found in soil bacteria. In this study, isothermal titration calorimetry (ITC) is used to measure the equilibrium constant (K = 1.1 ± 0.6 × 10(6)) and enthalpy change (ΔH = -17.0 ± 1.7 kcal/mol) associated with homoprotocatechuate binding to HPCD. The ITC data are consistent with the release of approximately 2.6 protons upon binding of the substrate to HPCD. These results raise new questions regarding the relationships between substrate, protein, and the oxygen activation mechanism for this class of non-heme metalloenzymes.

Objective: To examine the experiences of veterans (mostly middle-aged and elderly men) prescribed antidepressants, specifically with regard to different types of nonadherence, reasons for nonadherence, and side effects., Method: A mixed-methods analysis of Department of Veterans Affairs primary care patients (N = 395) with depression (9-item depression scale of the Patient Health Questionnaire criteria) enrolled in a randomized collaborative care trial was conducted. Adherence was measured from patient self-report and pharmacy data. Qualitative interviews elicited in-depth information regarding adherence. The study was conducted from April 2003 to September 2005., Results: The intervention significantly improved self-reported adherence at 6 months (OR = 2.1; 95% CI, 1.0-4.4; P = .04) and 12 months (OR = 2.7; 95% CI, 1.4-5.4; P < .01), as well as medication possession at 12 months (OR = 1.82; 95% CI, 1.0-3.2; P = .04). The most common type of nonadherence at 6 months was discontinuation (12.2%), followed by not taking as prescribed (10.9%) and never took (4.8%). For patients discontinuing their antidepressant in the first 6 months, the most common and important reason was that it was not helping. Only 19.4% of patients with self-reported adherence ≥ 80% responded to treatment by 6 months. Side effects were also a commonly reported reason for discontinuation at 6 months, with 82% reporting experiencing side effects. One-third (31.4%) reported difficulty with sexual activity at 6 months, with 66.1% reporting that it was severe. Qualitative interviews supported the finding that side effects, and generally not feeling like oneself, are important adherence barriers., Conclusions: In this sample of mostly middle-aged and elderly men with depression, treatment nonresponse and side effects were the rule rather than the exception. These findings suggest that nonadherence may have resulted primarily from patients' negative experiences with antidepressants rather than structural barriers or noncompliant behaviors., Trial Registration: Clinicaltrials.gov Identifier: NCT00105690., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Objectives: To use national laboratory surveillance data to determine whether pathogens responsible for neonatal bacteraemia were sensitive to nationally recommended antibiotic regimens., Design: All reports of neonatal bacteraemia received by the Health Protection Agency's voluntary surveillance scheme in England and Wales from January 2006 until March 2008, were extracted from the database. Organisms were ranked by frequency, and proportions susceptible to antimicrobials recommended for empirical treatment of neonatal sepsis were determined., Results: There were 1516 reports of bacteraemia for neonates <48 h old (early-onset) and 3482 reports for neonates 2-28 days old (late-onset). For early-onset bacteraemia, group B streptococcus (GBS) was the most frequent pathogen (31%) followed by coagulase-negative staphylococci (CoNS; 22%), non-pyogenic streptococci (9%) and Escherichia coli (9%). For late-onset bacteraemia, CoNS were isolated most frequently (45%), followed by Staphylococcus aureus (13%), Enterobacteriaceae (9%), E coli (7%) and GBS (7%). More than 94% of organisms (early-onset) were susceptible to regimens involving combinations of penicillin with either gentamicin or amoxicillin, amoxicillin combined with cefotaxime or cefotaxime monotherapy. More than 95% of organisms (late-onset) were susceptible to gentamicin with either flucloxacillin or amoxicillin and amoxicillin with cefotaxime, but only 79% were susceptible to cefotaxime monotherapy., Conclusions: Current guidelines for empirical therapy in neonates with sepsis are appropriate. However, gentamicin-based regimens should be used in preference to cefotaxime-based treatments, because of lower levels of susceptibility to cefotaxime and the need to avoid exerting selective pressure for resistance. Surveillance data linked to clinical data should further inform rational antibiotic prescribing in neonatal units.

Bacteraemia in children is a potentially life-threatening condition. The objective of this study was to determine trends in the aetiology of bacteraemia in children aged 1 month-15 years in England and Wales by collecting data voluntarily reported by National Health Service hospital microbiology laboratories. Over the 10-year period 1998-2007, a total of 51 788 bacteraemia cases involving 105 genera/species of bacteria were reported. Total annual reports of bacteraemia increased from 4125 to 6916, with a mean increase of 6.5 % per year (95 % CI: 1.3-12.1 %). In 2007, just over half the cases were accounted for by four groups of organisms: coagulase-negative staphylococci (28 %), Staphylococcus aureus (10 %), non-pyogenic streptococci (9 %) and Streptococcus pneumoniae (7 %). These organisms along with a further 13 species/genera accounted for 90 % of the cases. The commonest Gram-negative organisms were Neisseria meningitidis and Escherichia coli, which each accounted for 5 % of total bacteraemia reports in 2007. There was a significant decrease in reports of bacteraemia due to the three vaccine-preventable pathogens Haemophilus influenzae, N. meningitidis and Strep. pneumoniae, following the introduction of each vaccine programme or catch-up campaign. This study identified the commonest causes of bacteraemia in children in England and Wales, and highlighted the shifts in trends observed over time.

Atrazine is a well-known contaminant of surface waters and has been implicated in point-source pollution at agrochemical dealerships in the Midwest. Although the fate of atrazine has been well documented in soil and water, little is known about the fate of this contaminant and its metabolites within a grassed system. In the present study, [U-ring-14C]atrazine was added to soil in closed systems to determine the fate of the parent compound and its metabolites in soil, including degradation and movement into plants and air. Soil was treated with 25 mg/kg [14C]labeled atrazine and allowed to age for 5 d. Four systems then were amended with a mixture of prairie grasses, and the remaining four chambers were maintained as unvegetated controls. Dissipation and distribution of parent compound and metabolites were recorded for 21 d. Plant uptake of [14C]residue was less than 0.5% of applied radioactivity. Approximately 2% of total applied [14C]atrazine was mineralized to [14C]CO2, with no differences between vegetated and unvegetated systems. Mass balance recoveries were 76% for grassed systems and 77.5% for unvegetated controls. Approximately 40% of applied radioactivity remained bound to the soil following extraction. The most prevalent extractable compound detected in the soil was the parent, atrazine; major metabolites in soil were deethylatrazine (DEA) and didealkylatrazine (DDA). Leaf tissue contained concentrations of atrazine and key metabolites, i.e., DEA, DDA, and deisopropylatrazine (DIA), above those allowed in forage grasses by the U.S. Environmental Protection Agency; another key metabolite, hydroxyatrazine, was the most prevalent compound identified in both leaf and root tissue.

Background: Evidence-based practices designed for large urban clinics are not necessarily portable into smaller isolated clinics. Implementing practice-based collaborative care for depression in smaller primary care clinics presents unique challenges because it is often not feasible to employ on-site psychiatrists., Objective: The purpose of the Telemedicine Enhanced Antidepressant Management (TEAM) study was to evaluate a telemedicine-based collaborative care model adapted for small clinics without on-site psychiatrists., Design: Matched sites were randomized to the intervention or usual care., Participants: Small VA Community-based outpatient clinics with no on-site psychiatrists, but access to telepsychiatrists. In 2003-2004, 395 primary care patients with PHQ9 depression severity scores > or = 12 were enrolled, and followed for 12 months. Patients with serious mental illness and current substance dependence were excluded., Measures: Medication adherence, treatment response, remission, health status, health-related quality of life, and treatment satisfaction., Results: The sample comprised mostly elderly, white, males with substantial physical and behavioral health comorbidity. At baseline, subjects had moderate depression severity (Hopkins Symptom Checklist, SCL-20 = 1.8), 3.7 prior depression episodes, and 67% had received prior depression treatment. Multivariate analyses indicated that intervention patients were more likely to be adherent at both 6 (odds ratio [OR] = 2.1, p = .04) and 12 months (OR = 2.7, p = .01). Intervention patients were more likely to respond by 6 months (OR = 2.0, p = .02), and remit by 12 months (OR = 2.4, p = .02). Intervention patients reported larger gains in mental health status and health-related quality of life, and reported higher satisfaction., Conclusions: Collaborative care can be successfully adapted for primary care clinics without on-site psychiatrists using telemedicine technologies.

Metolachlor is a point-source pollutant at agrochemical dealerships in the Midwest, as well as a non point-source contaminant of surface waters caused by runoff. Prairie grasses have been used in filter strips to control runoff and are also useful for phytoremediation; however, little is known about the fate of metolachlor and its metabolites within a grassed system. Effects of uptake by prairie grasses on the formation and fate of degradation products are not known. In this study, [U-ring-14C]metolachlor was added to enclosed systems to determine the fate of the parent compound and its metabolites in soil and plants. Mineralization and volatilization were monitored over the 97 day study and found to be 1.05 and 0.2%, respectively, for vegetated systems. At the end of the study, soil and plant material was evaluated for the presence of parent metolachlor and selected metabolites, as well as bound residues. Metolachlor ethane sulfonic acid was the dominant metabolite in soil and plant tissue. Over 7% of applied radioactivity was taken up by the grasses, and plant uptake/metabolism appeared to be the main mechanism for phytoremediation of metolachlor. Vegetation significantly reduced the amount of metolachlor in soil by 9%, indicating potential success as a remediation tool.