Regional differences in presence of Shiga toxin-producing Escherichia coli virulence-associated genes in the environment in the North West and East Anglian regions of England.

Shiga toxin-producing Escherichia coli is carried in the intestine of ruminant animals, and outbreaks have occurred after contact with ruminant animals or their environment. The presence of STEC virulence genes in the environment was investigated along recreational walking paths in the North West and East Anglia regions of England. In all, 720 boot sock samples from walkers' shoes were collected between April 2013 and July 2014. Multiplex PCR was used to detect E. coli based on the amplification of the uidA gene and investigate STEC-associated virulence genes eaeA, stx1 and stx2. The eaeA virulence gene was detected in 45·5% of the samples, where stx1 and/or stx2 was detected in 12·4% of samples. There was a difference between the two regions sampled, with the North West exhibiting a higher proportion of positive boot socks for stx compared to East Anglia. In univariate analysis, ground conditions, river flow and temperature were associated with positive boot socks. The detection of stx genes in the soil samples suggests that STEC is present in the English countryside and individuals may be at risk for infection after outdoor activities even if there is no direct contact with animals. SIGNIFICANCE AND IMPACT OF THE STUDY: Several outbreaks within the UK have highlighted the danger of contracting Shiga toxin-producing Escherichia coli from contact with areas recently vacated by livestock. This is more likely to occur for STEC infections compared to other zoonotic bacteria given the low infectious dose required. While studies have determined the prevalence of STEC within farms and petting zoos, determining the risk to individuals enjoying recreational outdoor activities that occur near where livestock may be present is less researched. This study describes the prevalence with which stx genes, indicative of STEC bacteria, were found in the environment in the English countryside.

An agent-based model about the effects of fake news on a norovirus outbreak.

BACKGROUND: Concern about health misinformation is longstanding, especially on the Internet. METHODS: Using agent-based models, we considered the effects of such misinformation on a norovirus outbreak, and some methods for countering the possible impacts of "good" and "bad" health advice. The work explicitly models spread of physical disease and information (both online and offline) as two separate but interacting processes. The models have multiple stochastic elements; repeat model runs were made to identify parameter values that most consistently produced the desired target baseline scenario. Next, parameters were found that most consistently led to a scenario when outbreak severity was clearly made worse by circulating poor quality disease prevention advice. Strategies to counter "fake" health news were tested. RESULTS: Reducing bad advice to 30% of total information or making at least 30% of people fully resistant to believing in and sharing bad health advice were effective thresholds to counteract the negative impacts of bad advice during a norovirus outbreak. CONCLUSION: How feasible it is to achieve these targets within communication networks (online and offline) should be explored.

Facile Conversion of Bis-Silylene to Cyclic Silylene Isomers: Unexpected C-N and C-H Bond Cleavage.

Reaction of thiolate 1 with carbene-stabilized diiodo-bis-silylene (2) (in a 2:1 ratio) in THF unexpectedly gives both the first five-membered, sulfur-containing, zwitterionic silylene ring (3) via insertion of the "SiI2" unit of 2 into the olefinic C-H bond of the imidazole ring of 1 and four-membered cyclic silylene (4) via insertion of a silicon(I) atom of 2 into the Cphenyl-N bond of the carbene ligand. The parallel reaction in toluene only gives 3 as the major product. The nature of the bonding in isomeric 3 and 4 was probed by experimental and theoretical methods.

A Stable Anionic Dithiolene Radical.

Sulfurization of anionic N-heterocyclic dicarbene, [:C{[N(2,6-Pri2C6H3)]2CHCLi}]n (2), with elemental sulfur (in a 1:2 ratio) in Et2O at low temperature gives 3 by inserting two sulfur atoms into the Li-C (i.e., C2 and C4) bonds in polymeric 2. Further reaction of 3 with 2 equiv of elemental sulfur in THF affords 4• via unexpected C-H bond activation, which represents the first anionic dithiolene radical to be structurally characterized in the solid state. Alternatively, 4• may also be synthesized directly by reaction of 1 with sulfur (in a 1:4 ratio) in THF. Reaction of 4• with GeCl2·dioxane gives an anionic germanium(IV)-bis(dithiolene) complex (5). The nature of the bonding in 4• and 5 was probed by experimental and theoretical methods.

Mild Cognitive Impairment and Exposure to General Anesthesia for Surgeries and Procedures: A Population-Based Case-Control Study.

BACKGROUND: To examine whether exposure to general anesthesia for procedures at age ≥40 years is associated with prevalent mild cognitive impairment (MCI) in the elderly. METHODS: A case-control study nested within a population-based cohort. Olmsted County, Minnesota, residents, aged 70-91 years, underwent baseline evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychologic testing. Individuals identified with MCI (cases) at enrollment were matched 1:2 on age, sex, education, and apolipoprotein genotype with participants who were cognitively normal at the time of the index visit. Medical records from age 40 years until the index visit were reviewed to determine exposures to general anesthesia. Conditional logistic regression, taking into account the matched set study design and adjusting for MCI risk factors, was used to assess whether exposure to anesthesia after the age of 40 years was associated with prevalent MCI. RESULTS: A total of 387 Mayo Clinic Study of Aging participants (219 males, 168 females) were diagnosed with MCI at enrollment with mean age of 81 ± 5 years. Exposure to general anesthesia after the age of 40 years was not significantly associated with prevalent MCI when analyzed as a dichotomous variable (any versus none, adjusted odds ratio, 0.97 [95% confidence interval, 0.68-1.40]) or the number of exposures (odds ratio, 1.13 [0.74-1.72], 0.81 [0.53-1.22], and 1.03 [0.67-1.58] for 1, 2-3, and ≥4 exposures, respectively, with no exposure as the reference). Similar results were obtained for exposure to anesthesia after the age of 60 years and during 5, 10, and 20 years before the first visit. CONCLUSIONS: Exposure to general anesthesia for procedures at age ≥40 years was not associated with prevalent MCI in the elderly.

Did online publishers "get it right"? Using a naturalistic search strategy to review cognitive health promotion content on internet webpages.

BACKGROUND: One of the most common uses of the Internet is to search for health-related information. Although scientific evidence pertaining to cognitive health promotion has expanded rapidly in recent years, it is unclear how much of this information has been made available to Internet users. Thus, the purpose of our study was to assess the reliability and quality of information about cognitive health promotion encountered by typical Internet users. METHODS: To generate a list of relevant search terms employed by Internet users, we entered seed search terms in Google Trends and recorded any terms consistently used in the prior 2 years. To further approximate the behaviour of typical Internet users, we entered each term in Google and sampled the first two relevant results. This search, completed in October 2014, resulted in a sample of 86 webpages, 48 of which had content related to cognitive health promotion. An interdisciplinary team rated the information reliability and quality of these webpages using a standardized measure. RESULTS: We found that information reliability and quality were moderate, on average. Just one retrieved page mentioned best practice, national recommendations, or consensus guidelines by name. Commercial content (i.e., product promotion, advertising content, or non-commercial) was associated with differences in reliability and quality, with product promoter webpages having the lowest mean reliability and quality ratings. CONCLUSIONS: As efforts to communicate the association between lifestyle and cognitive health continue to expand, we offer these results as a baseline assessment of the reliability and quality of cognitive health promotion on the Internet.

Enantioselective Heck-Matsuda Arylations through Chiral Anion Phase-Transfer of Aryl Diazonium Salts.

A mild, asymmetric Heck-Matsuda reaction of five-, six- and seven-membered ring alkenes and aryl diazonium salts is presented. High yields and enantioselectivities were achieved using Pd0 and chiral anion co-catalysts, the latter functioning as a chiral anion phase-transfer (CAPT) reagent. For certain substrate classes, the chiral anion catalysts were modulated to minimize the formation of undesired by-products. More specifically, BINAM-derived phosphoric acid catalysts were shown to prevent alkene isomerization in cyclopentene and cycloheptene starting materials. DFT(B3LYP-D3) computations revealed that increased product selectivity resulted from a chiral anion dependent lowering of the activation barrier for the desired pathway.

Push-Pull Stabilization of Parent Monochlorosilylenes.

While reaction of carbene-stabilized disilicon L:Si═Si:L (L: = C{N(2,6-(i)Pr2C6H3)CH}2) (8) with HCl·NC5H5 results in carbene-stabilized Si2Cl2 (2) and substituted 1H-imidazole (9), combination of the corresponding Fe(CO)4-modified disilicon carbene complex L:Si═Si[Fe(CO)4]:L (6) with pyridine hydrochloride gives a species containing two push-pull-stabilized parent monochlorosilylenes that are bridged by an Fe(CO)3 unit (7). The nature of 7 was further elucidated by spectroscopic, crystallographic, and computational methods. Spectroscopic data suggest that 7 exists as two diastereoisomers.

RESPOND: a patient-centred programme to prevent secondary falls in older people presenting to the emergency department with a fall-protocol for a mixed methods programme evaluation.

BACKGROUND: Programme evaluations conducted alongside randomised controlled trials (RCTs) have potential to enhance understanding of trial outcomes. This paper describes a multi-level programme evaluation to be conducted alongside an RCT of a falls prevention programme (RESPOND). OBJECTIVES: (1) To conduct a process evaluation in order to identify the degree of implementation fidelity and associated barriers and facilitators. (2) To evaluate the primary intended impact of the programme: participation in fall prevention strategies and the factors influencing participation. (3) To identify the factors influencing RESPOND RCT outcomes: falls, fall injuries and emergency department (ED) re-presentations. METHODS/DESIGN: 528 community-dwelling adults aged 60-90 years presenting to two EDs with a fall will be recruited and randomly assigned to the intervention or standard care group. All RESPOND participants and RESPOND clinicians will be included in the evaluation. A mixed methods design will be used and a programme logic model will frame the evaluation. Data will be sourced from interviews, focus groups, questionnaires, clinician case notes, recruitment records, participant-completed calendars, hospital administrative datasets and audio-recordings of intervention contacts. Quantitative data will be analysed via descriptive and inferential statistics and qualitative data will be interpreted using thematic analysis. DISCUSSION: The RESPOND programme evaluation will provide information about contextual and influencing factors related to the RESPOND RCT outcomes. The results will assist researchers, clinicians and policy makers regarding decisions about future falls prevention interventions. Insights gained may be applicable to a range of chronic conditions where similar preventive intervention approaches are indicated. TRIAL REGISTRATION NUMBER: This programme evaluation is linked to the RESPOND RCT which is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000336684).

Serological responses to Cryptosporidium antigens in inhabitants of Hungary using conventionally filtered surface water and riverbank filtered drinking water.

In this study the putative protective seroprevalence (PPS) of IgG antibodies to the 27-kDa and 15/17-kDa Cryptosporidium antigens in sera of healthy participants who were and were not exposed to Cryptosporidium oocysts via surface water-derived drinking water was compared. The participants completed a questionnaire regarding risk factors that have been shown to be associated with infection. The PPS was significantly greater (49-61%) in settlements where the drinking water originated from surface water, than in the control city where riverbank filtration was used (21% and 23%). Logistic regression analysis on the risk factors showed an association between bathing/swimming in outdoor pools and antibody responses to the 15/17-kDa antigen complex. Hence the elevated responses were most likely due to the use of contaminated water. Results indicate that waterborne Cryptosporidium infections occur more frequently than reported but may derive from multiple sources.

RESPOND--A patient-centred programme to prevent secondary falls in older people presenting to the emergency department with a fall: protocol for a multicentre randomised controlled trial.

INTRODUCTION: Participation in falls prevention activities by older people following presentation to the emergency department (ED) with a fall is suboptimal. This randomised controlled trial (RCT) will test the RESPOND programme, an intervention designed to improve older persons' participation in falls prevention activities through delivery of patient-centred education and behaviour change strategies. DESIGN AND SETTING: A RCT at two tertiary referral EDs in Melbourne and Perth, Australia. PARTICIPANTS: 528 community-dwelling people aged 60-90 years presenting to the ED with a fall and discharged home will be recruited. People who require an interpreter or hands-on assistance to walk; live in residential aged care or >50 km from the trial hospital; have terminal illness, cognitive impairment, documented aggressive behaviour or a history of psychosis; are receiving palliative care or are unable to use a telephone will be excluded. METHODS: Participants will be randomly allocated to the RESPOND intervention or standard care control group. RESPOND incorporates (1) a home-based risk factor assessment; (2) education, coaching, goal setting and follow-up telephone support for management of one or more of four risk factors with evidence of effective interventions and (3) healthcare provider communication and community linkage delivered over 6 months. Primary outcomes are falls and fall injuries per person-year. DISCUSSION: RESPOND builds on prior falls prevention learnings and aims to help individuals make guided decisions about how they will manage their falls risk. Patient-centred models have been successfully trialled in chronic and cardiovascular disease; however, evidence to support this approach in falls prevention is limited. TRIAL REGISTRATION NUMBER: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000336684).

Transition-Metal-Mediated Cleavage of a Si=Si Double Bond.

Reaction of carbene-stabilized disilicon (1) with Fe(CO)5 gives the 1:1 adduct L:Si=Si[Fe(CO)4 ]:L (L:=C{N(2,6-Pr(i) 2 C6 H3 )CH}2 ) (2) at room temperature. At raised temperature, however, 2 may react with another equivalent of Fe(CO)5 to give L:Si[µ-Fe2 (CO)6 ](µ-CO)Si:L (3) through insertion of both CO and Fe2 (CO)6 into the Si2 core, which represents the first experimental realization of transition metal-carbonyl-mediated cleavage of a Si=Si double bond. The structures and bonding of both 2 and 3 have been investigated by spectroscopic, crystallographic, and computational methods.

Biophysical constraints on the evolution of tissue structure and function.

Phylogenetic analyses based on models of molecular sequence evolution have driven to industrial scale the generation, cataloguing and modelling of nucleic acid and polypeptide structure. The recent application of these techniques to study the evolution of protein interaction networks extends this analytical rigour to the study of nucleic acid and protein function. Can we further extend phylogenetic analysis of protein networks to the study of tissue structure and function? If the study of tissue phylogeny is to join up with mainstream efforts in the molecular evolution domain, the continuum field description of tissue biophysics must be linked to discrete descriptions of molecular biochemistry. In support of this goal we discuss tissue units, and biophysical constraints to molecular function associated with these units, to present a rationale with which to model tissue evolution. Our rationale combines a multiscale hierarchy of functional tissue units (FTUs) with the corresponding application of physical laws to describe molecular interaction networks and flow processes over continuum fields within these units. Non-dimensional numbers, derived from the equations governing biophysical processes in FTUs, are proposed as metrics for comparative studies across individuals, species or evolutionary time. We also outline the challenges inherent to the systematic cataloguing and phylogenetic analysis of tissue features relevant to the maintenance and regulation of molecular interaction networks. These features are key to understanding the core biophysical constraints on tissue evolution.

Characterization of multi-drug resistant Mycobacterium tuberculosis from immigrants residing in the USA using Ion Torrent full-gene sequencing.

SUMMARY: Drug-resistant Mycobacterium tuberculosis bacterium (MTB) is spreading worldwide. Three drug-resistant isolates were detected in Burmese, Hmong, and Indian immigrants currently residing in Milwaukee, Wisconsin, USA. Ion Torrent full-gene sequencing and complete genetic analysis was performed within 5 days and compared to results from traditional drug sensitivity testing (DST). Genetic characterization of seven, full-length resistance-associated genes revealed two MDR and one highly resistant strain with important drug-resistant mutations that were confirmed by traditional DST. The rapid turnaround from sample-to-sequence underscores the public health value of Ion Torrent full-gene sequencing of MDR/XDR genes from epidemiologically significant clinical isolates.

Chiral anion phase transfer of aryldiazonium cations: an enantioselective synthesis of C3-diazenated pyrroloindolines.

Herein is reported the first asymmetric utilization of aryldiazonium cations as a source of electrophilic nitrogen. This is achieved through a chiral anion phase-transfer pyrroloindolinization reaction that forms C3-diazenated pyrroloindolines from simple tryptamines and aryldiazonium tetrafluoroborates. The title compounds are obtained in up to 99% yield and 96% ee. The air- and water-tolerant reaction allows electronic and steric diversity of the aryldiazonium electrophile and the tryptamine core.

Cortical and subcortical functional connectivity and cognitive impairment in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease with cognitive as well as motor impairments. While much is known about the brain networks leading to motor impairments in PD, less is known about the brain networks contributing to cognitive impairments. Here, we leveraged resting-state functional magnetic resonance imaging (rs-fMRI) data from the Parkinson's Progression Marker Initiative (PPMI) to examine network dysfunction in PD patients with cognitive impairment. We focus on canonical cortical networks linked to cognition, including the salience network (SAL), frontoparietal network (FPN), and default mode network (DMN), as well as a subcortical basal ganglia network (BGN). We used the Montreal Cognitive Assessment (MoCA) as a continuous index of coarse cognitive function in PD. In 82 PD patients, we found that lower MoCA scores were linked with lower intra-network connectivity of the FPN. We also found that lower MoCA scores were linked with lower inter-network connectivity between the SAL and the BGN, the SAL and the DMN, as well as the FPN and the DMN. These data elucidate the relationship of cortical and subcortical functional connectivity with cognitive impairments in PD.

Synthetic and practical reconstructions of SST and seawater pH using the novel multiproxy SMITE method.

Geochemical proxies of sea surface temperature (SST) and seawater pH (pHsw) in scleractinian coral skeletons are valuable tools for reconstructing tropical climate variability. However, most coral skeletal SST and pHsw proxies are univariate methods that are limited in their capacity to circumvent non-climate-related variability. Here we present a novel multivariate method for reconstructing SST and pHsw from the geochemistry of coral skeletons. Our Scleractinian Multivariate Isotope and Trace Element (SMITE) method optimizes reconstruction skill by leveraging the covariance across an array of coral elemental and isotopic data with SST and pHsw. First, using a synthetic proxy experiment, we find that SMITE SST reconstruction statistics (correlation, accuracy, and precision) are insensitive to noise and variable calibration period lengths relative to Sr/Ca. While SMITE pHsw reconstruction statistics remain relative to δ11B throughout the same synthetic experiment, the magnitude of the long-term trend in pHsw is progressively lost under conditions of moderate-to-high analytical uncertainty. Next, we apply the SMITE method to an array of seven coral-based geochemical variables (B/Ca, δ11B, Li/Ca, Mg/Ca, Sr/Ca, U/Ca & Li/Mg) measured from two Bermudan Porites astreoides corals. Despite a <3.5 year calibration period, SMITE SST and pHsw estimates exhibit significantly better accuracy, precision, and correlation with their respective climate targets than the best single- and dual-proxy estimators. Furthermore, SMITE model parameters are highly reproducible between the two coral cores, indicating great potential for fossil applications (when preservation is high). The results shown here indicate that the SMITE method can outperform the most common coral-based SST and pHsw reconstructions methods to date, particularly in datasets with a large variety of geochemical variables. We therefore provide a list of recommendations and procedures for users to begin implementing the SMITE method as well as an open-source software package to facilitate dissemination of the SMITE method.

Discovery of an Azabicyclo[2.1.1]hexane Piperazinium Salt and Its Application in Medicinal Chemistry via a Rearrangement.

Herein we report the discovery of an azabicyclo[2.1.1]hexane piperazinium methanesulfonate salt from an unexpected rearrangement reaction in the preparation of ligand-directed degraders (LDDs). This bench-stable compound was found to be a versatile electrophile in a ring-opening reaction with various types of nucleophiles. Its utility as a versatile medicinal chemistry building block is further demonstrated in the synthesis of an LDD compound targeting degradation of the androgen receptor.

Optimized bimetallic ratios for durable membrane catalyst-film reactors in treating nitrate-polluted water.

Nitrate contamination of surface and ground water is a significant global challenge. Most current treatment technologies separate nitrate from water, resulting in concentrated wastestreams that need to be managed. Membrane Catalyst-film Reactors (MCfR), which utilize in-situ produced nanocatalysts attached to hydrogen-gas-permeable hollow-fiber membranes, offer a promising alternative for denitrification without generating a concentrated wastestream. In hydrogen-based MCfRs, bimetallic nano-scale catalysts reduce nitrate to nitrite and then further to di-nitrogen or ammonium. This study first investigated how different molar ratios of indium-to-palladium (In:Pd) catalytic films influenced denitrification rates in batch-mode MCfRs. We evaluated eleven In-Pd bimetallic catalyst films, with In:Pd molar ratios from 0.0029 to 0.28. Nitrate-removal exhibited a volcano-shaped dependence on In content, with the highest nitrate removal (0.19 mgNO3--N-min-1 L-1) occurring at 0.045 mol In/mol Pd. Using MCfRs with the optimal In:Pd loading, we treated nitrate-spiked tap water in continuous-flow for >60 days. Nitrate removal and reduction occurred in three stages: substantial denitrification in the first stage, a decline in denitrification efficiency in the second stage, and stabilized denitrification in the third stage. Factors contributing to the slowdown of denitrification were: loss of Pd and In catalysts from the membrane surface and elevated pH due to hydroxide ion production. Sustained nitrate removal will require that these factors be mitigated.

Longitudinal surveillance of bacteraemia in haematology and oncology patients at a UK cancer centre and the impact of ciprofloxacin use on antimicrobial resistance.

OBJECTIVES: To assess and compare the current trends in bacteraemia and antimicrobial resistance and analyse the impact of ciprofloxacin prescribing on Gram-negative bacterial resistance in haematology and oncology patients. METHODS: Information on bacteraemia episodes, causative pathogens, antimicrobial resistance and consumption was compared between haematology and oncology patients at a UK cancer centre in a 14 year longitudinal surveillance study. RESULTS: Haematology patients had a 3-fold higher incidence of bacteraemia compared with oncology patients (10.9/1000 versus 3.6/1000 admissions, respectively). Coagulase-negative staphylococci were the most common Gram-positive cause of bacteraemia for both cancer groups, whereas the overall rate of methicillin-resistant Staphylococcus aureus bacteraemia was low (0.16/1000 admissions). Escherichia coli was the most common Gram-negative cause of bacteraemia for both groups, but with a higher incidence in haematology patients (0.92/1000 admissions) compared with oncology patients (0.5/1000 admissions). Pseudomonas spp. formed the second most common Gram-negative infection in haematology patients, with a 4-fold higher bacteraemia incidence compared with oncology patients (0.76 versus 0.16/1000 admissions). Ciprofloxacin resistance of Gram-negative isolates was 22% in haematology and 5% in oncology patients. The rate of ciprofloxacin use measured showed high ciprofloxacin consumption in haematology patients compared with oncology patients (3.6 versus 1.5 defined daily doses/10 admissions, respectively), suggesting that ciprofloxacin may drive resistance. CONCLUSIONS: Our longitudinal surveillance highlights the continued importance of Gram-negative bacteraemia, in particular that due to Pseudomonas, in the cancer population and raises concerns regarding increasing ciprofloxacin use and resistance.