An analysis of the relationships between peer support and diabetes outcomes in adolescents with type 1 diabetes

This study explores the relationships between the various subtypes of global and diabetes-specific peer support and health outcomes in adolescents with type 1 diabetes. Global peer support significantly predicted self-care and glycated haemoglobin, although no associations were identified for diabetes-specific support overall, nor its factors. When comparing participants with above or below average glycaemic control, significantly greater diabetes-specific support was reported in those with poorer control. It is suggested that this may be related to feelings of nagging, in which diabetes-specific support is perceived as harassment

Riverbed sediments buffer phosphorus concentrations downstream of sewage treatment works across the River Wensum catchment, UK

Purpose: Wastewater effluent discharged into rivers from sewage treatment works (STWs) represents one of the most important point sources of soluble reactive phosphorus (SRP) pollution and is a major driver of freshwater eutrophication. In this study, we assess the ability of riverbed sediments to act as a self-regulating buffering system to reduce SRP dissolved in the water column downstream of STW outflows. Materials and methods: River water and riverbed sediment samples were collected from 10 tributary outlets across the River Wensum catchment, Norfolk, UK, at monthly intervals between July and October 2016, such that 40 sediment and 40 water samples were collected in total. Of these locations, five were located downstream of STWs and five were on tributaries without STWs. Dissolved SRP concentrations were analysed and the Equilibrium Phosphorus Concentration (EPC0) of each sediment sample was measured to determine whether riverbed sediments were acting as net sources or sinks of SRP. Results and discussion: The mean SRP concentration downstream of STWs (382 µg P L-1) was double that of sites without a STW (185 µg P L-1), whilst the mean EPC0 for effluent impacted sites (105 µg P L-1) was 70% higher than that recorded at unaffected sites (62 µg P L-1). Regardless of STW influence, riverbed sediments across all 10 sites almost always acted as net sinks for SRP from the overlying water column. This was particularly true at sites downstream of STWs which displayed enhanced potential to buffer the river against increases in SRP released in sewage effluent. Conclusions: Despite EPC0 values revealing riverbed sediments were consistently acting as sinks for SRP, elevated SRP concentrations downstream of STWs clearly demonstrate the sediments have insufficient SRP sorption capacity to completely buffer the river against effluent discharge. Consequently, SRP concentrations across the catchment continue to exceed recommended standards for good chemical status, thus emphasising the need for enhanced mitigation efforts at STWs to minimise riverine phosphorus loading

Diel turbidity cycles in a headwater stream: evidence of nocturnal bioturbation?

Purpose: A small number of recent studies have linked daily cycles in stream turbidity to nocturnal bioturbation by aquatic fauna, principally crayfish, and demonstrated this process can significantly impact upon water quality under baseflow conditions. Adding to this limited body of research, we use high-resolution water quality monitoring data to investigate evidence of diel turbidity cycles in a lowland, headwater stream with a known signal crayfish (Pacifastacus leniusculus) population and explore a range of potential causal mechanisms. Materials and methods: Automatic bankside monitoring stations measured turbidity and other water quality parameters at 30-min resolution at three locations on the River Blackwater, Norfolk, UK during 2013. Specifically, we focused on two 20-day periods of baseflow conditions during January and April 2013 which displayed turbidity trends typical of winter and spring seasons, respectively. The turbidity time-series, which were smoothed with 6.5 hour Savitzky-Golay filters to highlight diel trends, were correlated against temperature, stage, dissolved oxygen and pH to assess the importance of abiotic influences on turbidity. Turbidity was also calibrated against suspended particulate matter (SPM) over a wide range of values via linear regression. Results and discussion: Pronounced diel turbidity cycles were found at two of the three sites under baseflow conditions during April. Spring night-time turbidity values consistently peaked between 21:00 and 04:00 with values increasing by ~10 nephelometric turbidity units (NTU) compared with the lowest recorded daytime values which occurred between 10:00 and 14:00. This translated into statistically significant increases in median midnight SPM concentration of up to 76% compared with midday, with night-time (18:00 – 05:30) SPM loads also up to 30% higher than that recorded during the daytime (06:00 – 17:30). Relating turbidity to other water quality parameters exhibiting diel cycles revealed there to be neither any correlation that might indicate a causal link, nor any obvious mechanistic connections to explain the temporal turbidity trends. Diel turbidity cycles were less prominent at all sites during the winter. Conclusions: Considering the seasonality and timing of elevated turbidity, visual observations of crayfish activity, and an absence of mechanistic connections with other water quality parameters, the results presented here are consistent with the hypothesis that nocturnal bioturbation is responsible for generating diel turbidity cycles under baseflow conditions in headwater streams. However, further research in a variety of fluvial environments is required to better assess the spatial extent, importance and causal mechanisms of this phenomenon

PhotoAffinity bits : a photoaffinity-based fragment screening platform for efficient identification of protein ligands

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space, however, it remains challenging to develop techniques that are both sufficiently high-throughput and sensitive. We present a fragment screening platform, termed PhABits (PhotoAffinity Bits), which utilises a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. We envision that the PhABits will be widely applicable to novel protein targets, identifying starting points in the development of therapeutic

Efficient ligand discovery using sulfur(VI) fluoride reactive fragments

Sulfur(VI) fluorides (SFs) have emerged as valuable electrophiles for the design of "beyond-cysteine" covalent inhibitors and offer potential for expansion of the liganded proteome. Since SFs target a broad range of nucleophilic amino acids, they deliver an approach for the covalent modification of proteins without requirement for a proximal cysteine residue. Further to this, libraries of reactive fragments present an innovative approach for the discovery of ligands and tools for proteins of interest by leveraging a breadth of mass spectrometry analytical approaches. Herein, we report a screening approach that exploits the unique properties of SFs for this purpose. Libraries of SF-containing reactive fragments were synthesized, and a direct-to-biology workflow was taken to efficiently identify hit compounds for CAII and BCL6. The most promising hits were further characterized to establish the site(s) of covalent modification, modification kinetics, and target engagement in cells. Crystallography was used to gain a detailed molecular understanding of how these reactive fragments bind to their target. It is anticipated that this screening protocol can be used for the accelerated discovery of "beyond-cysteine" covalent inhibitors

Case-mix & patients' reports of outcome in Independent Sector Treatment Centres: Comparison with NHS providers

BACKGROUND: There has been considerable concern expressed about the outcomes achieved in Independent Sector Treatment Centres (ISTCs) introduced in England since 2003. Our aim was to compare the case-mix and patients' reported outcomes of surgery in ISTCs and in NHS providers. METHODS: Prospective cohort study of 769 patients treated in six ISTCs and 1895 treated in 20 NHS providers (acute hospitals and treatment centres) in England during 2006-07. Participants underwent one of three day surgery procedures (inguinal hernia repair, varicose vein surgery, cataract extraction) or hip or knee replacement. Change in patient-reported health status and health related quality of life (measured using a disease-specific and a generic (EQ-5D) instrument) was assessed either 3-months (day surgery) or 6-months (hip/knee) after surgery. In addition patient-reported post-operative complications and an overall assessment of success of surgery were collected. Outcome measures were adjusted (using multivariable regression) for patient characteristics (disease severity, duration of symptoms, age, sex, socioeconomic status, general health, previous similar surgery, comorbidity). RESULTS: Post-operative response rates varied by procedure (73%-88%) and were similar for those treated in ISTCs and NHS facilities. Patients treated in ISTCs were healthier, were less likely to have any comorbidity and, for those undergoing cataract surgery or joint replacement, their primary condition was less severe. Those undergoing hernia repair or joint replacement were less likely to have had similar surgery before. When adjustment was made for pre-operative characteristics, patients undergoing cataract surgery or hip replacement in ISTCs achieved a slightly greater improvement in functional status and quality of life than those treated in NHS facilities, while the opposite was true of patients undergoing hernia repair. No significant differences were found for the two other procedures. Patients treated in ISTCs were less likely to report post-operative problems than those treated in NHS facilities for cataract surgery (Adjusted Odds Ratio 0.35; 95% CI 0.17-0.70), hernia repair (0.42; 0.28-0.63) and knee replacement (0.44; 0.28-0.69). Most patients described the result of their operation as excellent, very good or good, regardless of where they were treated. CONCLUSION: The case-mix of patients treated in ISTCs differs from that in NHS providers, in line with the intention of the contracts. Caution is needed in interpreting the observation that patients treated in ISTCs reported slightly better outcomes as very few ISTCs participated, case-mix adjustment might have been insufficient, and patients' reports might have been biased as they were more likely to be satisfied with the way they were treated

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial

BACKGROUND: Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. METHODS: In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. RESULTS: Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. CONCLUSIONS: Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics

Light interception principally drives the understory response to boxelder invasion in riparian forests

Since several decades, American boxelder (Acer negundo) is replacing white willow (Salix alba) riparian forests along southern European rivers. This study aims to evaluate the consequences of boxelder invasion on understory community in riparian areas. We determined the understory species richness, composition and biomass in boxelder and white willow stands located in three riparian forests, representative of three rivers with distinct hydrological regimes. We investigated correlation of these variables to soil moisture and particle size, main soil nutrient stocks, potential nitrification and denitrification, tree canopy cover and photosynthetic active radiation (PAR) at the ground level. A greenhouse experiment was then conducted to identify the causal factors responsible for changes in the understory. The effect of soil type, PAR level and water level on the growth and the biomass production of Urtica dioica were examined. A lower plant species richness and biomass, and a modification of community composition were observed for boxelder understory in all sites, regardless of their environmental characteristics. The strongest modification that follows boxelder invasion was the decline in U. dioica, the dominant species of the white willow forest understory. These differences were mainly correlated with a lower incident PAR under boxelder canopy. The greenhouse experiment identified PAR level as the main factor responsible for the changes in U. dioica stem number and biomass. Our results indicate that adult boxelder acts as an ecosystem engineer that decreases light availability. The opportunistic invasion by boxelder leads to important understory changes, which could alter riparian ecosystem functioning

Aberrant methylation of the Adenomatous Polyposis Coli (APC) gene promoter is associated with the inflammatory breast cancer phenotype

Aberrant methylation of the adenomatous polyposis coli (APC) gene promoter occurs in about 40% of breast tumours and has been correlated with reduced APC protein levels. To what extent epigenetic alterations of the APC gene may differ according to specific breast cancer phenotypes, remains to be elucidated. Our aim was to explore the role of APC methylation in the inflammatory breast cancer (IBC) phenotype. The status of APC gene promoter hypermethylation was investigated in DNA from normal breast tissues, IBC and non-IBC by both conventional and real-time quantitative methylation-specific PCR (MSP). APC methylation levels were compared with APC mRNA and protein levels. Hypermethylation of the APC gene promoter was present in 71% of IBC samples (n=21) and 43% of non-IBC samples (n=30) by conventional MSP (P=0.047). The APC gene also showed an increased frequency of high methylation levels in IBC (in 74% of cases, n=19) vs non-IBC (in 46% of cases, n=35) using a qMSP assay (P=0.048). We observed no significant association between APC methylation levels by qMSP and APC mRNA or protein expression levels. In conclusion, for the first time, we report the association of aberrant methylation of the APC gene promoter with the IBC phenotype, which might be of biological and clinical importance