CO2 reduction with protons and electrons at a boron-based reaction center.

Borohydrides are widely used reducing agents in chemical synthesis and have emerging energy applications as hydrogen storage materials and reagents for the reduction of CO2. Unfortunately, the high energy cost associated with the multistep preparation of borohydrides starting from alkali metals precludes large scale implementation of these latter uses. One potential solution to this issue is the direct synthesis of borohydrides from the protonation of reduced boron compounds. We herein report reactions of the redox series [Au(B2P2)] n (n = +1, 0, -1) (B2P2, 9,10-bis(2-(diisopropylphosphino)phenyl)-9,10-dihydroboranthrene) and their conversion into corresponding mono- and diborohydride complexes. Crucially, the monoborohydride can be accessed via protonation of [Au(B2P2)]-, a masked borane dianion equivalent accessible at relatively mild potentials (-2.05 V vs. Fc/Fc+). This species reduces CO2 to produce the corresponding formate complex. Cleavage of the formate complex can be achieved by reduction (ca. -1.7 V vs. Fc/Fc+) or by the addition of electrophiles including H+. Additionally, direct reaction of [Au(B2P2)]- with CO2 results in reductive disproportion to release CO and generate a carbonate complex. Together, these reactions constitute a synthetic cycle for CO2 reduction at a boron-based reaction center that proceeds through a B-H unit generated via protonation of a reduced borane with weak organic acids

Long-term health outcomes after exposure to repeated concussion in elite level: rugby union players

Background: There is continuing concern about effects of concussion in athletes, including risk of the neurodegenerative disease chronic traumatic encephalopathy. However, information on long-term health and wellbeing in former athletes is limited. Method: Outcome after exposure to repeated brain injury was investigated in 52 retired male Scottish international rugby players (RIRP) and 29 male controls who were similar in age and social deprivation. Assessment included history of playing rugby and traumatic brain injury, general and mental health, life stress, concussion symptoms, cognitive function, disability and markers of chronic stress (allostatic load). Results: The estimated number of concussions in RIRP averaged 14 (median=7; IQR 5-40). Performance was poorer in RIRP than controls on a test of verbal learning (p=0.022) and of fine co-ordination of the dominant hand (p=0.038) and not significantly different on other cognitive tests (p>0.05). There were no significant associations between number of concussions and performance on cognitive tests. Other than a higher incidence of cardiovascular disease in controls, no group differences were detected in general or mental health or estimates of allostatic load. In RIRP, persisting symptoms attributed to concussion were more common if reporting more than nine concussions (p=0.028), although these symptoms were not perceived to affect social or work functioning. Conclusions: Despite a high number of concussions in RIRP, differences in mental health, social or work functioning were not found late after injury. Subtle group differences were detected on two cognitive tests, the cause of which is uncertain. Prospective group comparison studies on representative cohorts are required

Laxatives Do Not Improve Symptoms of Opioid-Induced Constipation: Results of a Patient Survey

Introduction.:  Laxatives are commonly used to treat opioid-induced constipation, the commonest and most bothersome complication of opioids. However, laxatives have a nonspecific action and do not target underlying mechanisms of opioid-induced constipation; their use is associated with abdominal symptoms that negatively impact quality of life. Objective.:  To assess the effects of laxatives in patients taking opioids for chronic pain. Methods.:  One hundred ninety-eight UK patients who had taken opioid analgesics for at least one month completed a cross-sectional online or telephone survey. Questions addressed their pain condition, medication, and laxative use (including efficacy and side effects). The survey also assessed bowel function using the Bowel Function Index. Results.:  Since starting their current opioid, 134 of 184 patients (73%) had used laxatives at some point and 122 (91%) of these were currently taking them. The most common laxatives were osmotics and stimulants. Laxative side effects were reported in 75%, most commonly gas, bloating/fullness, and a sudden urge to defecate. Side effects were more common in patients less than 40 years of age. Approximately half of patients said laxatives interfered with work and social activities, and one-fifth needed an overnight hospital stay because of their pain condition and/or constipation. Laxatives did not improve the symptoms of constipation, as assessed by the Bowel Function Index. Constipation was not related to opioid strength, dose of opioid, or number of laxatives taken. Conclusions.:  Use of laxatives to treat opioid-induced constipation is often ineffective and associated with side effects. Instead of relieving the burden of opioid-induced constipation, laxative use is associated with a negative impact

Dental attendance, restoration and extractions in adults with intellectual disabilities compared with the general population: a record linkage study

Background: Oral health may be poorer in adults with intellectual disabilities (IDs) who rely on carer support and medications with increased dental risks. Methods: Record linkage study of dental outcomes, and associations with anticholinergic (e.g. antipsychotics) and sugar‐containing liquid medication, in adults with IDs compared with age–sex–neighbourhood deprivation‐matched general population controls. Results: A total of 2933/4305 (68.1%) with IDs and 7761/12 915 (60.1%) without IDs attended dental care: odds ratio (OR) = 1.42 [1.32, 1.53]; 1359 (31.6%) with IDs versus 5233 (40.5%) without IDs had restorations: OR = 0.68 [0.63, 0.73]; and 567 (13.2%) with IDs versus 2048 (15.9%) without IDs had dental extractions: OR = 0.80 [0.73, 0.89]. Group differences for attendance were greatest in younger ages, and restoration/extractions differences were greatest in older ages. Adults with IDs were more likely prescribed with anticholinergics (2493 (57.9%) vs. 6235 (48.3%): OR = 1.49 [1.39, 1.59]) and sugar‐containing liquids (1641 (38.1%) vs. 2315 (17.9%): OR = 2.89 [2.67, 3.12]). Conclusion: Carers support dental appointments, but dentists may be less likely to restore teeth, possibly extracting multiple teeth at individual appointments instead

Which patients with heart failure should receive specialist palliative care?

AIMS: We investigated which patients with heart failure (HF) should receive specialist palliative care (SPC) by first creating a definition of need for SPC in patients hospitalised with HF using patient-reported outcome measures (PROMs) and then testing this definition using the outcome of days alive and out of hospital (DAOH). We also evaluated which baseline variables predicted need for SPC and whether those with this need received SPC. METHODS AND RESULTS: PROMs assessing quality of life (QoL), symptoms, and mood were administered at baseline and every 4 months. SPC need was defined as persistently severe impairment of any PROM without improvement (or severe impairment immediately preceding death). We then tested whether need for SPC, so defined, was reflected in DAOH, a measure which combines length of stay, days of hospital re-admission, and days lost due to death. Of 272 patients recruited, 74 (27%) met the definition of SPC needs. These patients lived one third fewer DAOH than those without SPC need (and less than a quarter of QoL-adjusted DAOH). A Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score of <29 identified patients who subsequently had SPC needs (area under receiver operating characteristic curve 0.78). Twenty-four per cent of patients with SPC needs actually received SPC (n = 18). CONCLUSIONS: A quarter of patients hospitalised with HF had a need for SPC and were identified by a low KCCQ score on admission. Those with SPC need spent many fewer DAOH and their DAOH were of significantly worse quality. Very few patients with SPC needs accessed SPC services

Comparing uptake across breast, cervical and bowel screening at an individual level:a retrospective cohort study

Funding: CR-UK through its National Awareness & Early Diagnosis Initiative C9227/A17676.Background We investigated demographic and clinical predictors of lower participation in bowel screening relative to breast and cervical screening. Methods Data linkage study of routinely collected clinical data from 430,591 women registered with general practices in the Greater Glasgow & Clyde Health Board. Participation in the screening programmes was measured by attendance at breast or cervical screening or the return of a bowel screening kit. Results 72.6% of 159,993 women invited attended breast screening, 80.7% of 309,899 women invited attended cervical screening and 61.7% of 180,408 women invited completed bowel screening. Of the 68,324 women invited to participate in all three screening programmes during the study period, 52.1% participated in all three while 7.2% participated in none. Women who participated in breast (OR = 3.34 (3.21, 3.47), p < 0.001) or cervical (OR = 3.48 (3.32, 3.65), p < 0.001) were more likely to participate in bowel screening. Conclusion Participation in bowel screening was lower than breast or cervical for this population although the same demographic factors were associated with uptake, namely lower social deprivation, increasing age, low levels of comorbidity and prior non-malignant neoplasms. As women who complete breast and cervical are more likely to also complete bowel screening, interventions at these procedures to encourage bowel screening participation should be explored.Publisher PDFPeer reviewe

Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources.

Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the \u27hydrophobic motif\u27 of PKCβII (S660F and S660C) are loss-of-function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes. Sci Rep 2018 Apr 25; 8(1):6518

A qualitative exploration of menstruation-related restrictive practices in Fiji, Solomon Islands and Papua New Guinea

Attitudes and beliefs about menstruation can place restrictions on menstruating women and girls, limiting their ability to fully participate in community life, education and employment. This paper presents evidence on menstruation-related beliefs contributing to restrictive practices in Papua New Guinea (PNG), Solomon Islands (SI) and Fiji. Focus group discussions and interviews were undertaken with 307 adolescent girls, women and men in a rural and urban site in each country. Data were analysed using an inductive thematic approach. Participants described a range of attitudes and beliefs that restrict the behaviour of menstruating women and girls. Themes include the belief that menstrual blood is ‘dirty’; that when menstruating, girls and women can bring ‘bad luck’ to men; secrecy and shame associated with menstruation; and beliefs about the impact of certain behaviours on menstruation and health. Restrictive practices were more frequently reported in PNG and SI than Fiji, and more common in rural compared with urban sites. Some restrictions, such as avoidance of household chores, were perceived as desirable or driven by women themselves. However participants identified other restrictions, such as not being able to attend church or hygienically wash menstrual hygiene materials, as unwanted, in some cases impacting on participation in school, work and community life. Education initiatives guided by women and girls, implemented by local stakeholders and grounded in a sound understanding of specific contexts are needed to address discriminatory attitudes and beliefs that contribute to unwanted restrictions, and to support enabling attitudes and beliefs regarding menstruation

Disruption of the pro-oncogenic c-RAF–PDE8A complex represents a differentiated approach to treating KRAS–c-RAF dependent PDAC

Pancreatic ductal adenocarcinoma (PDAC) is considered the third leading cause of cancer mortality in the western world, offering advanced stage patients with few viable treatment options. Consequently, there remains an urgent unmet need to develop novel therapeutic strategies that can effectively inhibit pro-oncogenic molecular targets underpinning PDACs pathogenesis and progression. One such target is c-RAF, a downstream effector of RAS that is considered essential for the oncogenic growth and survival of mutant RAS-driven cancers (including KRASMT PDAC). Herein, we demonstrate how a novel cell-penetrating peptide disruptor (DRx-170) of the c-RAF–PDE8A protein–protein interaction (PPI) represents a differentiated approach to exploiting the c-RAF–cAMP/PKA signaling axes and treating KRAS–c-RAF dependent PDAC. Through disrupting the c-RAF–PDE8A protein complex, DRx-170 promotes the inactivation of c-RAF through an allosteric mechanism, dependent upon inactivating PKA phosphorylation. DRx-170 inhibits cell proliferation, adhesion and migration of a KRASMT PDAC cell line (PANC1), independent of ERK1/2 activity. Moreover, combining DRx-170 with afatinib significantly enhances PANC1 growth inhibition in both 2D and 3D cellular models. DRx-170 sensitivity appears to correlate with c-RAF dependency. This proof-of-concept study supports the development of DRx-170 as a novel and differentiated strategy for targeting c-RAF activity in KRAS–c-RAF dependent PDAC