Evaluating the Viability of Successive Ring-Expansions Based on Amino Acid and Hydroxyacid Side-Chain Insertion

The outcome of ring expansion reactions based on amino/hydroxyacid side chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previous work on Successive Ring Expansion (SuRE) methods, details efforts to better define the scope and limitations of these reactions on lactam and β-ketoester ring systems with respect to ring size and additional functionality. The synthetic results provide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using a Density Functional Theory (DFT) approach. Calculating the relative Gibbs free energies of the three isomeric species that are formed reversibly during ring expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational results are expected to support the design of new lactam- and β-ketoester-based ring expansion reactions

The feasibility and results of a population-based approach to evaluating prostate-specific antigen screening for prostate cancer in men with a raised familial risk

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age ⩽65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45–69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were ⩾4 ng ml−1 and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied

CHIME/FRB Detection of Eight New Repeating Fast Radio Burst Sources

We report on the discovery of eight repeating fast radio burst (FRB) sources found using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope. These sources span a dispersion measure (DM) range of 103.5 to 1281 pc cm$^{-3}$. They display varying degrees of activity: six sources were detected twice, another three times, and one ten times. These eight repeating FRBs likely represent the bright and/or high-rate end of a distribution of infrequently repeating sources. For all sources, we determine sky coordinates with uncertainties of $\sim$10$^\prime$. FRB 180916.J0158+65 has a burst-averaged DM = $349.2 \pm 0.3$ pc cm$^{-3}$ and a low DM excess over the modelled Galactic maximum (as low as $\sim$20 pc cm$^{-3}$); this source also has a Faraday rotation measure (RM) of $-114.6 \pm 0.6$ rad m$^{-2}$, much lower than the RM measured for FRB 121102. FRB 181030.J1054+73 has the lowest DM for a repeater, $103.5 \pm 0.3$ pc cm$^{-3}$, with a DM excess of $\sim$ 70 pc cm$^{-3}$. Both sources are interesting targets for multi-wavelength follow-up due to their apparent proximity. The DM distribution of our repeater sample is statistically indistinguishable from that of the first 12 CHIME/FRB sources that have not repeated. We find, with 4$\sigma$ significance, that repeater bursts are generally wider than those of CHIME/FRB bursts that have not repeated, suggesting different emission mechanisms. Our repeater events show complex morphologies that are reminiscent of the first two discovered repeating FRBs. The repetitive behavior of these sources will enable interferometric localizations and subsequent host galaxy identifications.Comment: 40 pages, 11 figures; accepted by ApJL on 28 September 2019; added analysis of correlation between width and max. flux densit

Periodic activity from a fast radio burst source

Fast radio bursts (FRBs) are bright, millisecond-duration radio transients originating from extragalactic distances. Their origin is unknown. Some FRB sources emit repeat bursts, ruling out cataclysmic origins for those events. Despite searches for periodicity in repeat burst arrival times on time scales from milliseconds to many days, these bursts have hitherto been observed to appear sporadically, and though clustered, without a regular pattern. Here we report the detection of a $16.35\pm0.15$ day periodicity (or possibly a higher-frequency alias of that periodicity) from a repeating FRB 180916.J0158+65 detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project (CHIME/FRB). In 38 bursts recorded from September 16th, 2018 through February 4th, 2020, we find that all bursts arrive in a 5-day phase window, and 50% of the bursts arrive in a 0.6-day phase window. Our results suggest a mechanism for periodic modulation either of the burst emission itself, or through external amplification or absorption, and disfavour models invoking purely sporadic processes

Rheumatoid arthritis and the role of oral bacteria

Rheumatoid arthritis (RA) and periodontal disease (PD) have shown similar physiopathologic mechanisms such as chronic inflammation with adjacent bone resorption in an immunogenetically susceptible host; however, PD has a well-recognized bacterial etiology while the cause of RA is unclear. Some reports have indicated that an infectious agent in a susceptible host could be one possible trigger factor for RA, and it has been suggested that oral microorganisms, specialty periodontal bacteria could be the infectious agent (mainly Porphyromonas gingivalis). It has been reported that PD is more frequent and more severe in patients with RA, suggesting a positive association between both diseases. There have been reports regarding the detection of antibodies against periodontal bacteria while other studies have identified periodontal bacterial DNA in serum and synovial fluid of RA patients and have explored the possible pathways of transport of periodontal bacterial DNA. In conclusion, there is no question that RA and PD have pathologic features in common and there is strong evidence of an association between both diseases, but further studies, including experimental models, are needed to demonstrate the arthritogenicity of oral microorganisms

Right drug, right patient, right time: aspiration or future promise for biologics in rheumatoid arthritis?

Individualising biologic disease-modifying anti-rheumatic drugs (bDMARDs) to maximise outcomes and deliver safe and cost-effective care is a key goal in the management of rheumatoid arthritis (RA). Investigation to identify predictive tools of bDMARD response is a highly active and prolific area of research. In addition to clinical phenotyping, cellular and molecular characterisation of synovial tissue and blood in patients with RA, using different technologies, can facilitate predictive testing. This narrative review will summarise the literature for the available bDMARD classes and focus on where progress has been made. We will also look ahead and consider the increasing use of ‘omics’ technologies, the potential they hold as well as the challenges, and what is needed in the future to fully realise our ambition of personalised bDMARD treatment