Platensimycin Activity against Mycobacterial β-Ketoacyl-ACP Synthases

Background - There is an urgent need for the discovery and development of new drugs against Mycobacterium tuberculosis, the causative agent of tuberculosis, especially due to the recent emergence of multi-drug and extensively-drug resistant strains. Herein, we have examined the susceptibility of mycobacteria to the natural product platensimycin. Methods and Findings - We have demonstrated that platensimycin has bacteriostatic activity against the fast growing Mycobacterium smegmatis (MIC = 14 µg/ml) and against Mycobacterium tuberculosis (MIC = 12 µg/ml). Growth in the presence of paltensimycin specifically inhibited the biosynthesis of mycolic acids suggesting that the antibiotic targeted the components of the mycolate biosynthesis complex. Given the inhibitory activity of platensimycin against β-ketoacyl-ACP synthases from Staphylococcus aureus, M. tuberculosis KasA, KasB or FabH were overexpressed in M. smegmatis to establish whether these mycobacterial KAS enzymes were targets of platensimycin. In M. smegmatis overexpression of kasA or kasB increased the MIC of the strains from 14 µg/ml, to 30 and 124 µg/ml respectively. However, overexpression of fabH on did not affect the MIC. Additionally, consistent with the overexpression data, in vitro assays using purified proteins demonstrated that platensimycin inhibited Mt-KasA and Mt-KasB, but not Mt-FabH. Significance - Our results have shown that platensimycin is active against mycobacterial KasA and KasB and is thus an exciting lead compound against M. tuberculosis and the development of new synthetic analogues

Predictors of pain relief following spinal cord stimulation in chronic back and leg pain and failed back surgery syndrome: a systematic review and meta-regression analysis

We sought to assess the extent to which pain relief in chronic back and leg pain (CBLP) following spinal cord stimulation (SCS) is influenced by patient‐related factors, including pain location, and technology factors. A number of electronic databases were searched with citation searching of included papers and recent systematic reviews. All study designs were included. The primary outcome was pain relief following SCS, we also sought pain score (pre‐ and post‐SCS). Multiple predictive factors were examined: location of pain, history of back surgery, initial level of pain, litigation/worker's compensation, age, gender, duration of pain, duration of follow‐up, publication year, continent of data collection, study design, quality score, method of SCS lead implant, and type of SCS lead. Between‐study association in predictive factors and pain relief were assessed by meta‐regression. Seventy‐four studies (N = 3,025 patients with CBLP) met the inclusion criteria; 63 reported data to allow inclusion in a quantitative analysis. Evidence of substantial statistical heterogeneity (P < 0.0001) in level of pain relief following SCS was noted. The mean level of pain relief across studies was 58% (95% CI: 53% to 64%, random effects) at an average follow‐up of 24 months. Multivariable meta‐regression analysis showed no predictive patient or technology factors. SCS was effective in reducing pain irrespective of the location of CBLP. This review supports SCS as an effective pain relieving treatment for CBLP with predominant leg pain with or without a prior history of back surgery. Randomized controlled trials need to confirm the effectiveness and cost‐effectiveness of SCS in the CLBP population with predominant low back pain

What should an index of school segregation measure?

The article aims to make a methodological contribution to the education segregation literature, providing a critique of previous measures of segregation used in the literature, as well as suggesting an alternative approach to measuring segregation. Specifically, the paper examines Gorard, Fitz and Taylor's finding that social segregation between schools, as measured by free school meals (FSM) entitlement, fell significantly in the years following the 1988 Education Reform Act. Using Annual Schools Census data from 1989 to 2004, the paper challenges the magnitude of their findings, suggesting that the method used by Gorard et al. seriously overstates the size of the fall in segregation. We make the case for a segregation curve approach to measuring segregation, where comparisons of the level of segregation are possible regardless of the percentage FSM eligibility. Using this approach, we develop a new method for describing both the level and the location of school segregation

Did the COVID-19 pandemic impact the dietary intake of individuals living with and beyond breast, prostate, and colorectal cancer and who were most likely to experience change?

Purpose: The present work investigated dietary changes amongst individuals living with and beyond cancer (LWBC) from before to during the pandemic. To identify those at greatest risk of unhealthy changes, it was further examined whether patterns varied by sociodemographic, health-related, and COVID-19-related characteristics. // Methods: This longitudinal cohort study analysed data from 716 individuals LWBC participating in the Advancing Survivorship Cancer Outcomes Trial (ASCOT). Using data provided before and during the pandemic, changes in fruit and vegetable, snack, and alcohol intake were tested using mixed-effect regression models. // Results: Fruit and vegetable (95%CI: − 0.30; − 0.04) and alcohol consumption (95%CI: − 1.25; − 0.31) decreased, whilst snacking increased (95%CI: 0.19; 0.53). Women and individuals with limited social contact were more likely to reduce fruit and vegetable intake during the pandemic. Women and individuals with poorer sleep quality, limited social contact, and shielding requirements and without higher education were more likely to increase snacking during the pandemic. Individuals with poorer sleep quality, poorer mental health, and regular social contact were more likely to decrease alcohol consumption during the pandemic. // Conclusions: Findings suggest decreased intake for fruit, vegetable, and alcohol consumption and increased snack intake in response to the pandemic amongst individuals LWBC. These changes appear to differ across various characteristics, suggesting the pandemic has not equally impacted everyone in this population. Findings highlight the need for targeted post-COVID strategies to support individuals LWBC most adversely affected by the pandemic, including women and socially isolated individuals. This encourages resources to be prioritised amongst these groups to prevent further negative impact of the pandemic. Whilst the findings are statistically significant, practically they appear less important. This is necessary to acknowledge when considering interventions and next steps

Getting antimalarials on target: impact of national roll-out of malaria rapid diagnostic tests on health facility treatment in three regions of Tanzania.

OBJECTIVES: Parasitological confirmation of malaria prior to treatment is recommended for patients of all ages, with malaria rapid diagnostic tests (mRDTs) an important tool to target artemisinin-based combination therapies (ACTs) to patients with malaria. To evaluate the impact on case management practices of routine government implementation of mRDTs, we conducted large-scale health facility surveys in three regions of Tanzania before and after mRDT roll-out. METHODS: Febrile patients at randomly selected health facilities were interviewed about care received at the facility, and blood samples were collected for reference blood smears. Health facility staff were interviewed about their qualifications and availability of malaria diagnostics and drugs. RESULTS: The percentage of febrile patients tested for malaria at the facility increased from 15.8% in 2010 to 54.9% in 2012. ACTs were obtained by 65.8% of patients positive by reference blood smear in 2010 and by 50.2% in 2012 (P = 0.0675); no antimalarial was obtained by 57.8% of malaria-negative patients in 2010 and by 82.3% in 2012 (P < 0.0001). Overall, ACT use decreased (39.9-21.3%, P < 0.0001) and antibiotic use increased (31.2-48.5%, P < 0.0001). CONCLUSION: Roll-out of mRDTs in Tanzania dramatically improved diagnostic testing for malaria and reduced overuse of ACTs for patients without parasitemia. However, post-roll-out almost 50% of febrile patients did not receive a diagnostic test, and almost 50% of patients testing positive did not receive ACTs. Stock-outs of ACTs and mRDTs were important problems. Further investigation is needed to determine reasons for not providing ACTs to patients with malaria and potential for inappropriate antibiotic use

Combined Superbase Ionic Liquid Approach to Separate CO2 from Flue Gas

[Image: see text] Superbase ionic liquids (ILs) with a trihexyltetradecylphosphonium cation and a benzimidazolide ([P(66614)][Benzim]) or tetrazolide ([P(66614)][Tetz]) anion were investigated in a dual-IL system allowing the selective capture and separation of CO(2) and SO(2), respectively, under realistic gas concentrations. The results show that [P(66614)][Tetz] is capable of efficiently capturing SO(2) in preference to CO(2) and thus, in a stepwise separation process, protects [P(66614)][Benzim] from the negative effects of the highly acidic contaminant. This results in [P(66614)][Benzim] maintaining >53% of its original CO(2) uptake capacity after 30 absorption/desorption cycles in comparison to the 89% decrease observed after 11 cycles when [P(66614)][Tetz] was not present. Characterization of the ILs post exposure revealed that small amounts of SO(2) were irreversibly absorbed to the [Benzim](−) anion responsible for the decrease in CO(2) capacity. While optimization of this dual-IL system is required, this feasibility study demonstrates that [P(66614)][Tetz] is a suitable sorbent for reversibly capturing SO(2) and significantly extending the lifetime of [P(66614)][Benzim] for CO(2) uptake

Short tandem repeat sequences in the Mycoplasma genitalium genome and their use in a multilocus genotyping system

<p>Abstract</p> <p>Background</p> <p>Several methods have been reported for strain typing of <it>Mycoplasma genitalium</it>. The value of these methods has never been comparatively assessed. The aims of this study were: 1) to identify new potential genetic markers based on an analysis of short tandem repeat (STR) sequences in the published <it>M. genitalium </it>genome sequence; 2) to apply previously and newly identified markers to a panel of clinical strains in order to determine the optimal combination for an efficient multi-locus genotyping system; 3) to further confirm sexual transmission of <it>M. genitalium </it>using the newly developed system.</p> <p>Results</p> <p>We performed a comprehensive analysis of STRs in the genome of the <it>M. genitalium </it>type strain G37 and identified 18 loci containing STRs. In addition to one previously studied locus, MG309, we chose two others, MG307 and MG338, for further study. Based on an analysis of 74 unrelated patient specimens from New Orleans and Scandinavia, the discriminatory indices (DIs) for these three markers were 0.9153, 0.7381 and 0.8730, respectively. Two other previously described markers, including single nucleotide polymorphisms (SNPs) in the rRNA genes (rRNA-SNPs) and SNPs in the MG191 gene (MG191-SNPs) were found to have DIs of 0.5820 and 0.9392, respectively. A combination of MG309-STRs and MG191-SNPs yielded almost perfect discrimination (DI = 0.9894). An additional finding was that the rRNA-SNPs distribution pattern differed significantly between Scandinavia and New Orleans. Finally we applied multi-locus typing to further confirm sexual transmission using specimens from 74 unrelated patients and 31 concurrently infected couples. Analysis of multi-locus genotype profiles using the five variable loci described above revealed 27 of the couples had concordant genotype profiles compared to only four examples of concordance among the 74 unrelated randomly selected patients.</p> <p>Conclusion</p> <p>We propose that a combination of the MG309-STRs and MG191-SNPs is efficient for general epidemiological studies and addition of MG307-STRs and MG338-STRs is potentially useful for sexual network studies of <it>M. genitalium </it>infection. The multi-locus typing analysis of 74 unrelated <it>M. genitalium</it>-infected individuals and 31 infected couples adds to the evidence that <it>M. genitalium </it>is sexually transmitted.</p

Reversible Reaction of CO2 with Superbasic Ionic Liquid [P66614][benzim] Studied with in Situ Photoelectron Spectroscopy

Ionic liquids (ILs) are of significant interest as CO2 capture agents, and one subgroup of ILs that has shown particular promise is that of superbasic ILs. They can absorb large quantities of CO2 in the dry state, but some will have a diminished CO2 capacity when prewetted. In the work presented here, the superbasic IL trihexyl-tetradecylphosphonium benzimidazolide, or [P66614][benzim], was exposed to 3 mbar of CO2, 2 mbar of H2O vapor, and a CO2 + H2O gas mixture and was investigated using near-ambient pressure X-ray photoelectron spectroscopy. The results show that the IL reacts with CO2 to form carbamate and that the reaction is reversible through reduction of the surrounding gas pressure. Regardless of whether the IL was exposed to CO2 or H2O vapor first, the presence of H2O under these experimental conditions does not significantly hinder the IL’s ability to absorb and react with CO2. Furthermore, the IL appears to preferentially react with CO2 over H2O vapor

The addition of CO2 to four superbase ionic liquids: a DFT study

The addition of carbon dioxide to four superbase ionic liquids, [P3333][Benzim], [P3333][124Triz], [P3333][123Triz] and [P3333][Bentriz] was studied using a molecular DFT approach involving anions alone and individual ion pairs. Intermolecular bonding within the individual ion pairs is characterised by a number of weak hydrogen bonds, with the superbase anion geometrically arranged so as to maximize interactions between the heterocyclic N atoms and the cation. The pairing energies show no correlation to the observed CO2 adsorption capacity. Addition of CO2 to the anion alone clearly resulted in the formation of a covalently-bound carbamate function with the strength of binding correlated to experimental capacity. In the ion pair however the cation significantly alters the nature of the bonding such that the overall cohesive energy is reduced. Formation of a strong carbamate function occurs at the expense of weakening the interaction between anion and cation. In the more weakly absorbing ion pairs which contain [123Triz](-) and [Bentriz](-), the carbamate-functionalised systems are very close in energy to adducts in which CO2 is more weakly bound, suggesting an equilibrium between the chemi- and physisorbed CO2