The genomes of three strains of Listeria monocytogenes that have been associated with food-borne illness in the USA were subjected to whole genome comparative analysis. A total of 51, 97 and 69 ...strain-specific genes were identified in L.monocytogenes strains F2365 (serotype 4b, cheese isolate), F6854 (serotype 1/2a, frankfurter isolate) and H7858 (serotype 4b, meat isolate), respectively. Eighty-three genes were restricted to serotype 1/2a and 51 to serotype 4b strains. These strain- and serotype-specific genes probably contribute to observed differences in pathogenicity, and the ability of the organisms to survive and grow in their respective environmental niches. The serotype 1/2a-specific genes include an operon that encodes the rhamnose biosynthetic pathway that is associated with teichoic acid biosynthesis, as well as operons for five glycosyl transferases and an adenine-specific DNA methyltransferase. A total of 8603 and 105 050 high quality single nucleotide polymorphisms (SNPs) were found on the draft genome sequences of strain H7858 and strain F6854, respectively, when compared with strain F2365. Whole genome comparative analyses revealed that the L.monocytogenes genomes are essentially syntenic, with the majority of genomic differences consisting of phage insertions, transposable elements and SNPs.
A whole-genome sequence analysis of
Listeria monocytogenes strain F2365 revealed 15 potential members of the Crp/Fnr family of transcriptional regulatory proteins. Each gene and the flanking regions ...were cloned, subjected to in vitro transpositional mutagenesis, and recombined into strain F2365. Mutant strains, produced for 14 of the family members, were compared to strain F2365 for differences in carbon utilization, resistance to oxidative stress, and growth under reduced oxygen conditions that would signal an Fnr- or Crp-like function for these proteins. There were no differences among strain F2365 and the 14 mutant strains in the utilization of the carbon sources readily utilized by
L. monocytogenes. Although strain KO2 had a reduced growth rate compared to strain F2365 and the other mutant strains at 30° but not at 37
°C, there were no differences in growth rates among strain F2365 and the mutant strains when incubated at either 30 or 37
°C under reduced oxygen conditions. However, when compared for differences in response to oxidative stress, mutants KO2 and KO5 showed reduced oxidative stress tolerance compared to the wild-type strain F2365. These results suggest that certain members of the putative Crp/Fnr family in
L. monocytogenes may function in response to oxidative stress similar to the Fnr-like protein (Flp) of other Gram-positive bacteria.
Summary
The majority of people with psoriasis have localized disease, where topical therapy forms the cornerstone of treatment. We set out to summarize evidence on the relative efficacy, safety and ...tolerability of different topical treatments used in plaque psoriasis. We undertook a systematic review and meta‐analyses of randomized trial data of U.K.‐licensed topical therapies. The primary outcome was clear or nearly clear status stratified for (i) trunk and limbs; and (ii) scalp. Network meta‐analyses allowed ranking of treatment efficacy. In total, 48 studies were available for trunk and limb psoriasis, and 17 for scalp psoriasis (22 028 patients in total); the majority included people with at least moderate severity psoriasis. Strategies containing potent corticosteroids (alone or in combination with a vitamin D analogue) or very potent corticosteroids dominated the treatment hierarchy at both sites (trunk and limbs, scalp); coal tar and retinoids were no better than placebo. No significant differences in achievement of clear or nearly clear status were observed between twice‐ and once‐daily application of the same intervention or between any of the following: combined vitamin D analogue and potent corticosteroid (applied separately or in a single product), very potent corticosteroids, or potent corticosteroids (applied twice daily). Investigator and patient assessment of response differed significantly for some interventions (response rates to very potent corticosteroids: 78% and 39%, respectively). No significant differences were noted for tolerability or steroid atrophy, but data were limited. In conclusion, corticosteroids are highly effective in psoriasis when used continuously for up to 8 weeks and intermittently for up to 52 weeks. Coal tar and retinoids are of limited benefit. There is a lack of long‐term efficacy and safety data available on topical interventions used for psoriasis.
What's already known about this topic?
Topical treatments are widely available and prescribed for plaque‐type psoriasis.
What does this study add?
Explicit rank order of efficacy, showing that treatment strategies containing potent or very potent corticosteroids are the most effective.
Investigator and patient evaluation of efficacy may differ.
Twice‐daily application of the same intervention offers no important benefit over once‐daily application for most treatments.
GcvA binds to three sites in the gcvTHP control region, from base -34 to -69 (site 1), from base -214 to -241 (site 2) and from base -242 to -271 (site 3). Previous results suggested that sites 3 and ...2 are required for both GcvA-dependent activation and repression of a gcvT::lacZ fusion. However, the results were less clear as to the role of site 1. To determine the role of site 1 in regulation, single and multiple base changes were made in site 1 and tested for their ability to alter GcvA-mediated activation and GcvA/GcvR-mediated repression. Several of the mutants were also tested for effects on GcvA binding to site 1 and the ability of GcvA to bend DNA at site 1. The results are consistent with site 1 playing primarily a role in negative regulation of the gcvTHP operon.
Listeria monocytogenes strain H7762, a frankfurter isolate, was tested to determine whether it was able to survive at 4°C in frankfurter pack fluid (exudate) and to determine whether food exposure ...affects its acid sensitivity. Cultures were sampled and tested for acid sensitivity by challenge with simulated gastric fluid (SGF). SGF challenges performed immediately after inoculation revealed that between 20 and 26% of the cells survived the full 30 min of SGF challenge regardless of whether the cells were inoculated into brain heart infusion broth (BHI) or exudate. After 2 days of incubation, cells exposed to both exudate and BHI had significantly decreased SGF resistance; however, the cells exposed to exudate were significantly more SGF resistant than cells exposed to BHI (after 15 min of SGF treatment, 33% of the exudate-exposed cells survived and 12% of the BHI-exposed cells survived). L. monocytogenes exposed to exudate had greater SGF resistance at all challenge times compared with BHI-exposed cells from day 2 through day 4. From days 8 to 15, exudate-exposed cells continued to have greater SGF resistance than BHI-exposed cells up to 10 min of SGF challenge but were as sensitive as the BHI-exposed cells at 20 to 30 min of challenge. By day 25, cells exposed to exudate were significantly more sensitive to SGF challenge than BHI-exposed cells. The survivor data generated from SGF challenges were modeled by a nonlinear regression analysis to calculate the underlying distribution of SGF resistance found in the challenged populations. These analyses indicated that L. monocytogenes exposed to exudate at 4°C had a broader distribution of resistance to SGF compared with cells exposed to BHI at 4°C. In addition, the mean time of death during SGF treatment was greater after exposure to exudate, indicating that cells exposed to exudate were more resistant to killing by SGF. These data suggest that exposure to frankfurter exudate might render L. monocytogenes more able to survive the stomach environment during the initial stages of infection.
Major orthopedic surgery, such as elective total hip replacement (eTHR) and elective total knee replacement (eTKR), are associated with a higher risk of venous thromboembolism (VTE) than other ...surgical procedures. Little is known, however, about the cost-effectiveness of VTE prophylaxis strategies in people undergoing these procedures.
The aim of this work was to assess the cost-effectiveness of these strategies from the English National Health Service perspective to inform NICE guideline (NG89) recommendations.
Cost-utility analysis, using decision modeling, was undertaken to compare 15 VTE prophylaxis strategies for eTHR and 12 for eTKR, in addition to "no prophylaxis" strategy. The analysis complied with the NICE Reference Case. Structure and assumptions were agreed with the guideline committee. Incremental net monetary benefit (INMB) was calculated, vs. the model comparator (LMWH+ antiembolism stockings), at a threshold of £20,000/quality-adjusted life-year (QALY) gained. The model was run probabilistically. Deterministic sensitivity analyses (SAs) were undertaken to assess the robustness of the results.
The most cost-effective strategies were LMWH for 10 days followed by aspirin for 28 days (INMB = £530 95% CI: -£784 to £1,103, probability of being most cost-effective = 72%) for eTHR, and foot pump (INMB = £353 95% CI: -£101 to £665; probability of being most cost-effective = 18%) for eTKR. There was considerable uncertainty regarding the cost-effectiveness ranking in the eTKR analysis. The results were robust to change in all SAs.
For eTHR, LMWH (standard dose) for 10 days followed by aspirin for 28 days is the most cost-effective VTE prophylaxis strategy. For eTKR, the results are highly uncertain but foot pump appeared to be the most cost-effective strategy, followed closely by aspirin (low dose). Future research should focus on assessing cost-effectiveness of VTE prophylaxis in the eTKR population.
Summary
Background
Topical therapies are a mainstay of psoriasis treatment, but they vary substantially in terms of cost.
Objectives
To determine the cost‐effectiveness and optimal treatment sequence ...for psoriasis of the trunk, limbs and scalp.
Methods
Probabilities of response from a network meta‐analysis were used to determine the short‐term efficacy of topical therapies. Longer‐term outcomes, including relapse, were informed by published evidence and clinical opinion. Benefits of treatment were measured as quality‐adjusted life years (QALYs). Direct costs included topical agents, primary and secondary care visits and second‐line therapies for treatment failures.
Results
For the trunk and limbs, initial treatment with a two‐compound formulation (TCF) product containing vitamin D and potent corticosteroid provided the most QALYs, followed by separate morning and evening application of vitamin D and potent corticosteroid two‐compound application, TCA (am/pm), and then twice‐daily potent corticosteroids. The use of twice‐daily potent corticosteroids was the most cost‐effective first‐line strategy (incremental cost‐effectiveness ratio £20 000 per QALY), followed by TCA (am/pm) (£22 658 per QALY) and TCF product (£179 439 per QALY). For scalp psoriasis, initial treatment with very potent corticosteroids generated the most QALYs, followed by TCF product and then potent corticosteroids. Very potent corticosteroids were the most cost‐effective treatment but, if too aggressive, potent corticosteroids were optimal followed by TCF product (£219 846 per QALY). The cost‐effectiveness of second‐ and third‐line topical agents varied with the assumptions made.
Conclusions
Potent corticosteroids, used alone or in combination with vitamin D, are the most cost‐effective treatment for patients with psoriasis of the trunk and limbs. Potent or very potent corticosteroids are the most cost‐effective treatment for patients with scalp psoriasis.
What's already known about this topic?
Topical therapies are the foundation of psoriasis treatment.
Combining agents in a single product or through concurrent application improves response. Frequency of application and potency also affect treatment efficacy.
Acquisition costs of topical agents vary substantially, and their relative value for money is uncertain.
What does this study add?
This study provides the most complete economic evaluation of topical therapies licensed for the treatment of psoriasis of the trunk, limbs and scalp.
See also the Commentary by Parkins and Burden
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