A new class of self-assembled monolayers on gold using an alkynyl group as a linker

The geometry and energetics for adsorption of ethynylbenzene on Au(111) have been studied using Density Functional Theory. The alkynyl group, following removal of the terminal H atom, adsorbs covalently to the surface in the fcc hollow site with a bond energy of about 70 kcal.mol-1. Intermediate adsorption states are also possible via a hydrogen 1,2 shift to form a surface-bound vinylidene, or through the opening of the C-C triple bond without removing the hydrogen atom. © 2006 IEEE

When Is Higher Neuroticism Protective Against Death? Findings From UK Biobank

We examined the association between neuroticism and mortality in a sample of 321,456 people from UK Biobank and explored the influence of self-rated health on this relationship. After adjustment for age and sex, a 1- SD increment in neuroticism was associated with a 6% increase in all-cause mortality (hazard ratio = 1.06, 95% confidence interval = [1.03, 1.09]). After adjustment for other covariates, and, in particular, self-rated health, higher neuroticism was associated with an 8% reduction in all-cause mortality (hazard ratio = 0.92, 95% confidence interval = [0.89, 0.95]), as well as with reductions in mortality from cancer, cardiovascular disease, and respiratory disease, but not external causes. Further analyses revealed that higher neuroticism was associated with lower mortality only in those people with fair or poor self-rated health, and that higher scores on a facet of neuroticism related to worry and vulnerability were associated with lower mortality. Research into associations between personality facets and mortality may elucidate mechanisms underlying neuroticism's covert protection against death

Patients' attitudes to risk in lung cancer surgery: a qualitative study

Objectives Lung cancer surgery leads to long term survival for some patients but little is known about how patients decide whether to accept the associated surgical risks. The objective of this qualitative study was to explore patients’ attitudes to the risks associated with lung cancer surgery. Methods Fifteen patients with resectable lung cancer, recruited via multi-disciplinary team meetings at an English tertiary referral centre, participated in semi-structured interviews to explore their attitudes to the morbidity and mortality risks associated with lung cancer surgery. Transcripts were analysed using the framework method. Results Participants reported being ‘pleased’ to hear that they were suitable for surgery and felt that surgery was not a treatment to be turned down because they did not see any alternatives. Participants had some knowledge of perioperative risks, including mortality estimates; however, many voiced a preference not to know these risks and to let the medical team decide their treatment plan. Some found it difficult to relate the potential risks and complications of surgery to their own situation and appeared willing to accept high perioperative mortality risks. Generally, participants were willing to accept quite severe long-term postoperative breathlessness; however, it was apparent that many actually found this possibility difficult to imagine. Conclusion Patients do not necessarily wish to know details of risks associated with lung cancer surgery and may wish to defer decisions about treatment to their medical team. Investment in the doctor-patient relationship, particularly for the surgeon, is therefore important in the management of patients with lung cancer

Prenatal origin of childhood AML occurs less frequently than in childhood ALL

Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases

Impact of resonance decays on critical point signals in net-proton fluctuations

The non-monotonic beam energy dependence of the higher cumulants of net-proton fluctuations is a widely studied signature of the conjectured presence of a critical point in the QCD phase diagram. In this work we study the effect of resonance decays on critical fluctuations. We show that resonance effects reduce the signatures of critical fluctuations, but that for reasonable parameter choices critical effects in the net-proton cumulants survive. The relative role of resonance decays has a weak dependence on the order of the cumulants studied with a slightly stronger suppression of critical effects for higher-order cumulants

Early recognition of coeliac disease through community pharmacies: A proof of concept study

Setting: 15 community pharmacies in the UK Objective: Proof of concept study to test the use of community pharmacies for active case finding of patients with coeliac disease. Method: Customers accessing over-the counter and prescription medicines indicated in the treatment of possible symptoms of coeliac disease over a six month period were offered a free point of care test. All patients were given advice regarding the test results and those who tested positive were advised to make an appointment with their general practitioner. Patients and pharmacists involved in service provision were asked to complete a satisfaction survey. Pharmacists were additionally invited to undertake interviews to better understand their views on the service. Main outcome measures: Feasibility of service, acceptability to stakeholders and proportion testing positive for coeliac disease. Results: Of the 551 individuals tested, 52 (9.4%) tested positive. 277 (50.3%) were tested for accessing irritable bowel syndrome treatment, 142 (25.8%) due to presenting for diarrhoea. The proportion of patients testing positive with different symptoms or for different treatments were similar. Of 43 customers who returned the satisfaction survey, all would recommend the service to others, believing the community pharmacy to be a suitable location. Community pharmacists believed that it enabled them to improve relationships with their customers and that medical practices were receptive to the service. Conclusion: This proof of concept study has shown that community pharmacies using a point of care test can effectively recognise and refer patients for confirmatory coeliac disease testing with high levels of customer and service provider satisfaction

Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936

<p>Abstract</p> <p>Background</p> <p>Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables.</p> <p>Methods</p> <p>We used latent class analysis (LCA) to identify possible groups.</p> <p>Results</p> <p>Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness.</p> <p>Conclusions</p> <p>Despite there being some evidence of these groups, the results also support a largely one-dimensional construct of wellbeing in old age—for the domains assessed here—though with some evidence that some individuals have uneven profiles.</p

Exploratory Analysis of TP53\textit{TP53} Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

$\textbf{Background:}$ Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic $\textit{TP53}$ mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). $\textbf{Methods and Findings:}$ We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific $\textit{TP53}$ assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The $\textit{TP53}$ mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson $r$ = 0.59, $p$ 32 cm$^3$, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, $p$ = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. $\textbf{Conclusions:}$ In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment.This work was supported by Cancer Research UK Grant numbers: A15601 (JDB), A11906 (NR), A20240 (NR), A18072 (JDB). JDB was supported by the National Institute for Health Research Cambridge Biomedical Research Centre. CAP was supported in part by the Academy of Medical Sciences, the Wellcome Trust, British Heart Foundation and Arthritis Research UK

Small molecule anionophores promote transmembrane anion permeation matching CFTR activity

Anion selective ionophores, anionophores, are small molecules capable of facilitating the transmembrane transport of anions. Inspired in the structure of natural product prodigiosin, four novel anionophores 1a-d, including a 1,2,3-triazole group, were prepared. These compounds proved highly efficient anion exchangers in model phospholipid liposomes. The changes in the hydrogen bond cleft modified the anion transport selectivity exhibited by these compounds compared to prodigiosin and suppressed the characteristic high toxicity of the natural product. Their activity as anionophores in living cells was studied and chloride efflux and iodine influx from living cells mediated by these derivatives was demonstrated. These compounds were shown to permeabilize cellular membranes to halides with efficiencies close to the natural anion channel CFTR at doses that do not compromise cellular viability. Remarkably, optimal transport efficiency was measured in the presence of pH gradients mimicking those found in the airway epithelia of Cystic Fibrosis patients. These results support the viability of developing small molecule anionophores as anion channel protein surrogates with potential applications in the treatment of conditions such as Cystic Fibrosis derived from the malfunction of natural anion transport mechanisms.European Union’s Horizon 2020 research and innovation programme under grant agreement No. 667079, La Marató de TV3 Foundation (20132730), Consejería de Educación de la Junta de Castilla y León (Projects BU340U13 and BU092U16

Fluorinated tetrapodal anion transporters.

Synthetic anion transporters show potential in treating life-threatening diseases like cystic fibrosis and cancer. However, with increasingly complex transporter architectures designed to control anion binding and transport, it is important to consider solubility and deliverability during transporter design. The fluorination of synthetic anion transporters has been shown to tune the transporter lipophilicity, transport rates, and binding strength. In this work, we expand on our previously reported tetrapodal (thio)urea transporters with a series of fluorinated tetrapodal anion transporters. The effects of fluorination on tuning the lipophilicity, solubility, deliverability, and anion transport selectivity of the tetrapodal scaffold were investigated using anion-binding and transport assays. The primary mode of anion transport was H+/X- cotransport, with the most fluorinated tetrathiourea (8) displaying the highest transport activity in the 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) assay. Intriguingly, inversion of the transmembrane Cl- vs NO3 - transport selectivity compared with previously reported tripodal (thio)urea transporters was observed under a modified HPTS assay