The prevalences of Salmonella Genomic Island 1 variants in human and animal Salmonella Typhimurium DT104 are distinguishable using a Bayesian approach

Throughout the 1990s, there was an epidemic of multidrug resistant Salmonella Typhimurium DT104 in both animals and humans in Scotland. The use of antimicrobials in agriculture is often cited as a major source of antimicrobial resistance in pathogenic bacteria of humans, suggesting that DT104 in animals and humans should demonstrate similar prevalences of resistance determinants. Until very recently, only the application of molecular methods would allow such a comparison and our understanding has been hindered by the fact that surveillance data are primarily phenotypic in nature. Here, using large scale surveillance datasets and a novel Bayesian approach, we infer and compare the prevalence of Salmonella Genomic Island 1 (SGI1), SGI1 variants, and resistance determinants independent of SGI1 in animal and human DT104 isolates from such phenotypic data. We demonstrate differences in the prevalences of SGI1, SGI1-B, SGI1-C, absence of SGI1, and tetracycline resistance determinants independent of SGI1 between these human and animal populations, a finding that challenges established tenets that DT104 in domestic animals and humans are from the same well-mixed microbial population

Treatment in the STAMPEDE era for castrate resistant prostate cancer in the UK: ongoing challenges and underappreciated clinical problems.

This study aimed to explore the opinions of healthcare professionals regarding the management of men with advanced prostate cancer with particular emphasis on treatment timing and sequencing; treatment adverse-effects and exercise a supportive therapy. Semi-structured interviews with a purposively selected group of healthcare professionals involved in prostate cancer care within the NHS, conducted over the phone or face to face. A total of 37 healthcare professionals participated in the interviews including urologists, clinical oncologists, medical oncologists, clinical nurse specialists, general practitioners, physiotherapists, exercise specialists, service managers, clinical commissioners and primary care physicians. The availability of newer treatments for advanced prostate cancer as well as results from the STAMPEDE and CHAARTED trials has resulted in new challenges for patients and HCPs. This includes the impact of an increased workload on oncologists, a potential lack of clinical continuity between urology and oncology and uncertainties regarding optimal selection, timing and sequencing of chemotherapy and second-line treatment. Fitness for treatment in advanced prostate cancer populations remains a significant barrier to accessing therapies for patients with a poor performance status. Among this, muscle wastage can significantly affect performance status and consequentially compromise cancer therapy. Exercise was regarded as a potential therapy to mitigate the adverse-effects of treatment including the prevention or reduction in muscle wastage. There is a lack of data guiding clinicians in this post STAMPEDE and CHAARTED era, work is needed to reassess and optimize the prostate cancer care pathway as it evolves. Exercise should be explored as a therapeutic option to mitigate the effects of long term ADT. Further study from a wider cohort of both prostate cancer care specialists and patients will aid in establishing a highly functioning pathway with optimal individualised care. Sustained exercise TrAining for Men wIth prostate caNcer on Androgen deprivation: the STAMINA programme (RP-DG-1213-10,010). REC Reference: 15/SW/0260 IRAS Project ID: 178340 Hospital ID: STH 18391 approved on 24/08/2015

Increased utilization of total joint arthroplasty after Medicaid expansion

BACKGROUND: The expansion of state Medicaid programs under the U.S. Affordable Care Act has led to a dramatic increase in the number of Americans with health insurance coverage. Prior analyses of a limited number of states have suggested that greater utilization of total hip arthroplasty (THA) and total knee arthroplasty (TKA) should be expected after Medicaid expansion. The purpose of our study was to examine whether increased utilization of THA and TKA occurred across a broader range of states after Medicaid expansion. METHODS: We analyzed administrative data from the Healthcare Cost and Utilization Project from 9 states (Arkansas, Arizona, Colorado, Iowa, Massachusetts, Maryland, Nevada, New York, and Vermont) that expanded Medicaid in 2014 and 2 states that did not expand Medicaid (Florida and Missouri). We included patients who were 18 to 64 years of age and had a primary THA or TKA from 2012 to 2015 with Medicaid as the primary payer. Other payers (including dual-eligible Medicaid and Medicare beneficiaries) were excluded. We performed multivariable regression modeling with the number of Medicaid-insured THAs or TKAs as the dependent variable and the interaction between the state Medicaid expansion status and year as the main policy independent variable, with adjustment for community characteristics. RESULTS: Among all 11 states, there were 39,452 total joint arthroplasties (42% THA and 58% TKA) funded by Medicaid from 2012 to 2015. After adjusting for community characteristics, within expansion states, compared with 2013, THA and TKA increased 15% in 2014 (p \u3c 0.0001) and 23% in 2015 (p \u3c 0.0001) within expansion states. Within non-expansion states, compared with 2013, there were significant utilization decreases of 18% in 2014 (p \u3c 0.0001) and 11% in 2015 (p = 0.0002). CONCLUSIONS: Medicaid expansion was associated with significant increases in Medicaid-funded THA and TKA utilization in 9 states. As additional states consider expanding Medicaid programs and as alternative health reforms that increase insurance eligibility are debated, surgeons, administrators, and policymakers should prepare for a surge in the utilization of THA and TKA

Rational design of a (S)-selective-transaminase for asymmetric synthesis of (1S)-1-(1,1′-biphenyl-2-yl)ethanamine

Amine transaminases offer an environmentally sustainable synthesis route for the production of pure chiral amines. However, their catalytic efficiency toward bulky ketone substrates is greatly limited by steric hindrance and therefore presents a great challenge for industrial synthetic applications. We hereby report an example of rational transaminase enzyme design to help alleviate these challenges. Starting from the Vibrio fluvialis amine transaminase that has no detectable catalytic activity toward the bulky aromatic ketone 2-acetylbiphenyl, we employed a rational design strategy combining in silico and in vitro studies to engineer the transaminase enzyme with a minimal number of mutations, achieving an high catalytic activity and high enantioselectivity. We found that, by introducing two mutations W57G/R415A, detectable enzyme activity was achieved. The rationally designed variant, W57F/R88H/V153S/K163F/I259M/R415A/V422A, showed an improvement in reaction rate by more than 1716-fold toward the bulky ketone under study, producing the corresponding enantiomeric pure (S)-amine (enantiomeric excess (ee) value of >99%)

A microflow electrolysis cell for laboratory synthesis on the multigram scale

A large microflow electrolysis cell for laboratory synthesis on a multigram scale is described. It is based on two circular electrodes with a diameter of 149 mm and a spiral electrolyte flow channel 2000 mm long, 5 mm wide, and 0.5 mm interelectrode gap. Using the methoxylation of N-formylpyrrolidine as a model reaction, it is demonstrated that the cell approaches 100% conversion in a single pass, and it is possible to achieve a reaction selectivity >95% and a product formation rate of >20 g h–1

Clinical Severity of Clostridium difficile PCR Ribotype 027: A Case-Case Study

BACKGROUND: Clostridium difficile is a leading infectious cause of health care associated diarrhoea. Several industrialised countries have reported increased C. difficile infections and outbreaks, which have been attributed to the emergent PCR ribotype 027 strain. METHODS AND FINDINGS: We conducted a case-case study to compare severity of C. difficile disease for patients with 027 versus non-027 ribotypes. We retrospectively collected clinical information about 123/136 patients with C. difficile infections admitted to hospitals in the East of England region in 2006 and from whom stool isolates were cultured and ribotyped as part of an earlier national survey. We defined severe C. difficile disease as having one or more of shock, paralytic ileus, pseudo membranous colitis or toxic megacolon. Patient median age was 83 years old (range 3 to 98, interquartile range 75 to 89), 86% were prescribed antibiotics in the eight weeks before illness onset, 41% had ribotype 027 and 30-day all cause mortality during hospital admission was 21%. Severe disease occurred in 24% (95%CI 13% to 37%) and 17% (95%CI 9% to 27%) of patients with PCR ribotype 027 and non-027 ribotypes respectively. In a multivariable model, ribotype 027 was not associated with severe disease after adjusting for sex, discharge from hospital prior to 60 days of current admission, gastroenteritis on admission, number of initiator antibiotics for C. difficile disease, and hospital where the patient was admitted. CONCLUSIONS: Our study found no evidence to support previous assertions that ribotype 027 is more virulent than other PCR ribotypes. This finding raises questions about the contribution of this strain to the recent increase in C. difficile disease throughout North America and Europe

Genomic analysis on broiler-associated Clostridium perfringens strains and exploratory caecal microbiome investigation reveals key factors linked to poultry necrotic enteritis.

BACKGROUND: Clostridium perfringens is a key pathogen in poultry-associated necrotic enteritis (NE). To date there are limited Whole Genome Sequencing based studies describing broiler-associated C. perfringens in healthy and diseased birds. Moreover, changes in the caecal microbiome during NE is currently not well characterised. Thus, the aim of this present study was to investigate C. perfringens virulence factors linked to health and diseased chickens, including identifying putative caecal microbiota signatures associated with NE. RESULTS: We analysed 88 broiler chicken C. perfringens genomes (representing 66 publicly available genomes and 22 newly sequenced genomes) using different phylogenomics approaches and identified a potential hypervirulent and globally-distributed clone spanning 20-year time-frame (1993-2013). These isolates harbored a greater number of virulence genes (including toxin and collagen adhesin genes) when compared to other isolates. Further genomic analysis indicated exclusive and overabundant presence of important NE-linked toxin genes including netB and tpeL in NE-associated broiler isolates. Secondary virulence genes including pfoA, cpb2, and collagen adhesin genes cna, cnaA and cnaD were also enriched in the NE-linked C. perfringens genomes. Moreover, an environmental isolate obtained from farm animal feeds was found to encode netB, suggesting potential reservoirs of NetB-positive C. perfringens strains (toxinotype G). We also analysed caecal samples from a small sub-set of 11 diseased and healthy broilers for exploratory microbiome investigation using 16S rRNA amplicon sequencing, which indicated a significant and positive correlation in genus Clostridium within the wider microbiota of those broilers diagnosed with NE, alongside reductions in beneficial microbiota members. CONCLUSIONS: These data indicate a positive association of virulence genes including netB, pfoA, cpb2, tpeL and cna variants linked to NE-linked isolates. Potential global dissemination of specific hypervirulent lineage, coupled with distinctive microbiome profiles, highlights the need for further investigations, which will require a large worldwide sample collection from healthy and NE-associated birds

Effect of metabolosome encapsulation peptides on enzyme activity, co-aggregation, incorporation and bacterial microcompartment formation

Metabolosomes, catabolic bacterial microcompartments, are proteinaceous organelles that are associated with the breakdown of metabolites such as propanediol and ethanolamine. They are composed of an outer multi-component protein shell that encases a specific metabolic pathway. Protein cargo found within BMCs is directed by the presence of an encapsulation peptide that appears to trigger aggregation prior to the formation of the outer shell. We investigated the effect of three distinct encapsulation peptides on foreign cargo in a recombinant BMC system. Our data demonstrate that these peptides cause variation with respect to enzyme activity and protein aggregation. We observed that the level of protein aggregation generally correlates with the size of metabolosomes, while in the absence of cargo BMCs self-assemble into smaller compartments. The results agree with a flexible model for BMC formation based around the ability of the BMC shell to associate with an aggregate formed due to the interaction of encapsulation peptides

Latitudinal variation in ecological opportunity and intraspecific competition indicates differences in niche variability and diet specialization of Arctic marine predators

Individual specialization (IS), where individuals within populations irrespective of age, sex, and body size are either specialized or generalized in terms of resource use, has implications on ecological niches and food web structure. Niche size and degree of IS of near‐top trophic‐level marine predators have been little studied in polar regions or with latitude. We quantified the large‐scale latitudinal variation of population‐ and individual‐level niche size and IS in ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) using stable carbon and nitrogen isotope analysis on 379 paired ringed seal liver and muscle samples and 124 paired beluga skin and muscle samples from eight locations ranging from the low to high Arctic. We characterized both within‐ and between‐individual variation in predator niche size at each location as well as accounting for spatial differences in the isotopic ranges of potential prey. Total isotopic niche width (TINW) for populations of ringed seals and beluga decreased with increasing latitude. Higher TINW values were associated with greater ecological opportunity (i.e., prey diversity) in the prey fish community which mainly consists of Capelin (Mallotus villosus) and Sand lance (Ammodytes sp.) at lower latitudes and Arctic cod (Boreogadus saida) at high latitudes. In beluga, their dietary consistency between tissues also known as the within‐individual component (WIC) increased in a near 1:1 ratio with TINW (slope = 0.84), suggesting dietary generalization, whereas the slope (0.18) of WIC relative to TINW in ringed seals indicated a high degree of individual specialization in ringed seal populations with higher TINWs. Our findings highlight the differences in TINW and level of IS for ringed seals and beluga relative to latitude as a likely response to large‐scale spatial variation in ecological opportunity, suggesting species‐specific variation in dietary plasticity to spatial differences in prey resources and environmental conditions in a rapidly changing ecosystem

Latitudinal variation in ecological opportunity and intraspecific competition indicates differences in niche variability and diet specialization of Arctic marine predators

Individual specialization (IS), where individuals within populations irrespective of age, sex, and body size are either specialized or generalized in terms of resource use, has implications on ecological niches and food web structure. Niche size and degree of IS of near‐top trophic‐level marine predators have been little studied in polar regions or with latitude. We quantified the large‐scale latitudinal variation of population‐ and individual‐level niche size and IS in ringed seals (Pusa hispida) and beluga whales (Delphinapterus leucas) using stable carbon and nitrogen isotope analysis on 379 paired ringed seal liver and muscle samples and 124 paired beluga skin and muscle samples from eight locations ranging from the low to high Arctic. We characterized both within‐ and between‐individual variation in predator niche size at each location as well as accounting for spatial differences in the isotopic ranges of potential prey. Total isotopic niche width (TINW) for populations of ringed seals and beluga decreased with increasing latitude. Higher TINW values were associated with greater ecological opportunity (i.e., prey diversity) in the prey fish community which mainly consists of Capelin (Mallotus villosus) and Sand lance (Ammodytes sp.) at lower latitudes and Arctic cod (Boreogadus saida) at high latitudes. In beluga, their dietary consistency between tissues also known as the within‐individual component (WIC) increased in a near 1:1 ratio with TINW (slope = 0.84), suggesting dietary generalization, whereas the slope (0.18) of WIC relative to TINW in ringed seals indicated a high degree of individual specialization in ringed seal populations with higher TINWs. Our findings highlight the differences in TINW and level of IS for ringed seals and beluga relative to latitude as a likely response to large‐scale spatial variation in ecological opportunity, suggesting species‐specific variation in dietary plasticity to spatial differences in prey resources and environmental conditions in a rapidly changing ecosystem