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ObjectiveThrombotic complications and vasculopathy have been extensively associated with severe COVID-19 infection, however the mechanisms by which endotheliitis is induced remain poorly understood. Here we investigate vascular permeability in the context of SARS-CoV-2-mediated endotheliitis in patient samples and a vascular organoid model.Methods and ResultsWe report the presence of the Spike glycoprotein in pericytes associated with pericyte activation and increased endothelial permeability in post-mortem COVID-19 lung autopsies. A pronounced decrease in the expression of the adhesion molecule VE-cadherin is observed in patients with thrombotic complications. Interestingly, fibrin-rich thrombi did not contain platelets, did not colocalize with tissue factor and have heterogenous levels of Von Willebrand factor, suggesting a biomarker-guided therapy might be required to target thrombosis in severe patients. Using a 3D vascular organoid model, we observe that ACE2 is primarily expressed in pericytes adjacent to vascular networks, consistent with patient data, indicating a preferential uptake of the S glycoprotein by these cells. Exposure of vascular organoids to SARS-CoV-2 or its antigens, recombinant trimeric Spike glycoprotein and Nucleocapsid protein, reduced endothelial cell and pericyte viability as well as CD144 expression with no additive effect upon endothelial activation via IL-1β.ConclusionsOur data suggest that pericyte uptake of SARS-CoV-2 or Spike glycoprotein contributes to vasculopathy by altering endothelial permeability increasing the risk of thrombotic complications.

Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population.To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes.Clinical Practice Research Datalink.We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used.People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval -0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups.Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population.Future research should investigate the decline in prescribing of smoking cessation products; develop an optimal treatment algorithm for smoking cessation; use methods for using instruments with survival outcomes; and develop methods for comparing multivariable-adjusted and instrumental variable estimates.Not all of our code lists were validated, body mass index and Index of Multiple Deprivation had missing values, our results may suffer from residual confounding, and we had no information on treatment adherence.This trial is registered as NCT02681848.This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inSmoking is the number one avoidable cause of ill health and death. Experiments suggest that more smokers will quit after being given the drug varenicline than with any other smoking cessation treatment. However, most of the experiments used to license varenicline had a relatively short follow-up ( 1 year) and did not necessarily recruit participants who were representative of smokers seen in a general practice in the UK, who tend to be older, are sicker and more likely to have neuropsychiatric illnesses. In this study, we investigated the outcomes of 287,079 patients prescribed varenicline or nicotine replacement therapy (e.g. nicotine patches and gum). We followed each patient for up to 4 years after they received their prescriptions and matched their data to information on deaths from the Office for National Statistics and hospital admissions. We investigated how often these patients subsequently attended their general practitioner, and how often they received a diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression or anxiety in primary care. We found that patients who were prescribed varenicline were much more likely to quit smoking up to 4 years after they received treatment and subsequently attended their general practitioner less frequently. These findings were robust across the three different analysis methods we used. We also found that patients prescribed varenicline were much less likely to be ill or to die than those prescribed nicotine replacement therapy. However, these results may be because the patients who were prescribed varenicline were much healthier before they received the prescription. Therefore, these differences in health are unlikely to be caused by taking varenicline or quitting smoking. In conclusion, varenicline helped patients quit smoking, but there was little causal evidence that prescribing patients varenicline causally reduced rates of mortality or morbidity compared with prescribing nicotine replacement therapy.

Aims To investigate whether smokers prescribed varenicline had lower risks of serious ill-health during the 4 years following treatment compared with those prescribed nicotine replacement therapy (NRT). Design Observational cohort study of electronic medical records. Setting A total of 370 UK general practices sampled from the Clinical Practice Research Datalink. Participants A total of 126 718 patients aged 18 and over who were issued smoking cessation prescriptions between 1 September 2006 and 31 March 2014. Measurements Our primary outcome was all-cause mortality within 2 years of first prescription as indicated by linked Office of National Statistics data. Our secondary outcomes were cause-specific mortality, all-cause, cause-specific hospitalization, primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease (COPD), body mass index and attendance rate to primary care within 2 years of first prescription. Risk differences and 95% confidence intervals were estimated by multivariable adjusted regression and propensity score matched regression. We used instrumental variable analysis to overcome residual confounding. Findings People prescribed varenicline were healthier at baseline than those prescribed NRT in almost all characteristics, highlighting the potential for residual confounding. Our instrumental variable analysis results found that people prescribed varenicline had a similar risk of mortality at 2 years [risk difference per 100 patients treated = 0.67, 95% confidence interval (CI) = -0.11 to 1.46)] to those prescribed NRT, and there were similar rates of all-cause hospitalization, incident primary-care diagnoses of myocardial infarction and COPD. People prescribed varenicline subsequently attended primary care less frequently. Conclusions Smokers prescribed varenicline in primary care in the United Kingdom do not appear to be less likely to die, be hospitalized or experience a myocardial infarction or chronic obstructive pulmonary disease during the following 2 years compared with smokers prescribed nicotine replacement therapy, but they gain more weight and attend primary care less frequently.

Background and aimsVarenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.DesignCase–cross‐over study.SettingUK‐based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.ParticipantsAdult smokers observed during periods when exposed and not exposed to either varenicline or NRT.MeasurementsMain outcomes included suicide, self‐harm, myocardial infarction (MI), all‐cause death and cause‐specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91–180 days prior to the event) or multiple 90‐day reference periods to increase statistical power.FindingsIn the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18–1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self‐harm (OR = 1.32, 95% CI = 1.12–1.56) and suicide (OR = 3.56, 95% CI = 1.32–9.60) but a reduction in all‐cause death (OR = 0.75, 95% CI = 0.61–0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36–1.74), self‐harm (OR = 1.30, 95% CI = 1.18–1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11–2.10), COPD (OR = 1.33, 95% CI = 1.14–1.56) and all causes (OR = 1.28, 95% CI = 1.18–1.40) when using multiple reference periods.ConclusionsThere appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self‐harm and (2) varenicline and increased risk of self‐harm and suicide, as well as a negative association between varenicline and all‐cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self‐harm).

This study aimed to determine the effectiveness and safety of varenicline versus NRT for smoking cessation in people with neurodevelopmental disorders, compared to those without, at up to four years after exposure. We analysed electronic medical records from the Clinical Practice Research Datalink using three different statistical approaches: multivariable logistic regression, propensity score matching (PSM), and instrumental variable analysis. Exposure was prescription of varenicline versus NRT and the primary outcome was smoking cessation at 2-years. We included 235,314 people aged 18 and above with eligible smoking cessation prescriptions in the effectiveness analysis. Smokers with neurodevelopmental disorders were 48% less likely (95% confidence interval: 42%, 54%) to be prescribed varenicline than NRT, compared to smokers without neurodevelopmental disorders. At 2-year follow-up, smokers with neurodevelopmental disorders prescribed varenicline were 38% more likely to quit smoking (95% confidence interval: 6%, 78%). Similar results were obtained using PSM and instrumental variable analyses. There was little evidence showing that varenicline increased the likelihood of mental health related adverse events in people with neurodevelopmental disorders. Varenicline is less likely to be prescribed to people with neurodevelopmental disorders despite results suggesting it is more effective than NRT and little evidence of increased likelihood of mental health related adverse events.

ObjectivesOur primary objective was to estimate smoking prevalence and prescribing rates of varenicline and nicotine replacement therapy (NRT) in people with and without general practitioner (GP)-recorded dementia. Our secondary objective was to assess and compare quit rates of smokers with versus without GP-recorded dementia who were prescribed varenicline or NRT for smoking cessation.DesignA retrospective cohort study based on the analysis of electronic medical records within the Clinical Practice Research Datalink (2007–2015).Setting683 general practices in England.ParticipantsPeople with and without GP-recorded dementia, aged 18 years and have a code indicating that they are a current smoker.InterventionIndex prescription of varenicline or NRT (from 1 September 2006).Outcome measuresThe primary outcomes were smoking prevalence and prescribing rates of varenicline and NRT (2007–2015). The secondary outcome was smoking cessation at 2 years.ResultsAge and sex-standardised prevalence of smoking was slightly higher in people with GP-recorded dementia than in those without. There were 235 314 people aged 18 years and above prescribed NRT or varenicline. Among smokers with GP-recorded dementia (N=447), 409 were prescribed NRT and 38 varenicline. Smokers with GP-recorded dementia were 74% less likely (95% CI 64% to 82%) to be prescribed varenicline than NRT, compared with smokers without GP-recorded dementia. Compared with people without GP-recorded dementia, people with GP-recorded dementia had consistently lower prescribing rates of varenicline from 2007 to 2015. Two years after prescription, there was no clear evidence for a difference in the likelihood of smoking cessation after prescription of these medications between individuals with and without dementia (OR 1.0, 95% CI 0.8 to 1.2).ConclusionsBetween 2007 and 2015, people with GP-recorded dementia were less likely to be prescribed varenicline than those without dementia. Quit rates following prescription of either NRT or varenicline were similar in those with and without dementia.

Objective We conducted a prospective cohort study of the Clinical Practice Research Database to estimate rates of varenicline and nicotine replacement therapy (NRT) prescribing and the relative effects on smoking cessation, and mental health. Methods We used multivariable logistic regression, propensity score matched regression, and instrumental variable analysis. Exposure was varenicline or NRT prescription. Mental disorders were bipolar, depression, neurotic disorder, schizophrenia, or prescriptions of antidepressants, antipsychotics, hypnotics/anxiolytics, mood stabilizers. Outcomes were smoking cessation, and incidence of neurotic disorder, depression, prescription of antidepressants, or hypnotics/anxiolytics. Follow-ups were 3, 6, and 9 months, and at 1, 2, and 4 years. Results In all patients, NRT and varenicline prescribing declined during the study period. Seventy-eight thousand four hundred fifty-seven smokers with mental disorders aged ≥18 years were prescribed NRT (N = 59 340) or varenicline (N = 19 117) from September 1, 2006 to December 31, 2015. Compared with smokers without mental disorders, smokers with mental disorders had 31% (95% CI: 29% to 33%) lower odds of being prescribed varenicline relative to NRT, but had 19% (95% CI: 15% to 24%) greater odds of quitting at 2 years when prescribed varenicline relative to NRT. Overall, varenicline was associated with decreased or similar odds of worse mental health outcomes than NRT in patients both with and without mental disorders, although there was some variation when analyses were stratified by mental disorder subgroup. Conclusions Smoking cessation medication prescribing may be declining in primary care. Varenicline was more effective than NRT for smoking cessation in patients with mental disorders and there is not clear consistent evidence that varenicline is adversely associated with poorer mental health outcomes. Implications Patients with mental disorders were less likely to be prescribed varenicline than NRT. We triangulated results from three analytical techniques. We found that varenicline was more effective than NRT for smoking cessation in patients with mental disorders. Varenicline was generally associated with similar or decreased odds of poorer mental health outcomes (ie, improvements in mental health) when compared with NRT. We report these findings cautiously as our data are observational and are at risk of confounding.

Background: There is limited evidence about the effectiveness of varenicline and nicotine replacement therapy (NRT) for long-term smoking cessation in primary care, or whether the treatment effectiveness differs by socioeconomic position (SEP). Therefore, we estimated the long-term effectiveness of varenicline versus NRT ( > 2 years) on smoking cessation, and investigated whether effectiveness differs by SEP. Methods: This is a prospective cohort study of electronic medical records from 654 general practices in England, within the Clinical Practice Research Datalink, using three different analytical methods: multivariable logistic regression, propensity score matching and instrumental variable analyses. Exposure was prescription of varenicline versus NRT, and the primary outcome was smoking cessation at 2 years' follow-up; outcome was also assessed at 3, 6, and 9 months, and at 1 and 4 years after exposure. SEP was defined using the Index of Multiple Deprivation. Results: At 2 years, 28.8% (N=20 362/70 610) of participants prescribed varenicline and 24.3% (N=36 268/149 526) of those prescribed NRT quit; adjusted odds ratio was 1.26 [95% confidence interval (CI): 1.23 to 1.29], P < 0.0001. The association persisted for up to 4 years and was consistent across all analyses. We found little evidence that the effectiveness of varenicline differed greatly by SEP. However, patients from areas of higher deprivation were less likely to be prescribed varenicline; adjusted odds ratio was 0.91 (95% CI: 0.90 to 0.92), P < 0.0001. Conclusions: Patients prescribed varenicline were more likely to be abstinent up to 4 years after first prescription than those prescribed NRT. In combination with other evidence, the results from this study may be used to update clinical guidelines on the use of varenicline for smoking cessation.

Despite the documented risk of secondary poisoning to non-target species by anticoagulant rodenticides there is no statutory post-approval monitoring of their use in the UK. This paper presents results from two Scottish monitoring schemes for the period 2000-2010; recording rodenticide use on arable farms and the presence of residues in raptor carcasses. More than three quarters of arable farms used anticoagulant rodenticides; predominately the second generation compounds difenacoum and bromadiolone. There was widespread exposure to anticoagulant rodenticides in liver tissues of the raptor species tested and the residues encountered generally reflected agricultural use patterns. As found in other studies, Red Kites (Milvus milvus) appeared to be particularly vulnerable to rodenticide exposure, 70 % of those sampled (n = 114) contained residues and 10 % died as a result of rodenticide ingestion. More unexpectedly, sparrowhawks (Accipiter nisus), which prey almost exclusively on birds, had similar exposure rates to species which prey on rodents. Although, with the exception of kites, confirmed mortality from rodenticides was low, the widespread exposure recorded is concerning. Particularly when coupled with a lack of data about the sub-lethal effects of these compounds. This raises questions regarding whether statutory monitoring of use is needed; both to address whether there are deficiencies in compliance with approval conditions or whether the recommended risk management procedures are themselves adequate to protect non-target wildlife.

Recent increases in chronic cardiovascular diseases, such as hypertension, have put pressure on the food industry to reduce sodium levels. Dairy products, though full of vital nutrients, are perceived as being high in sodium. However, the reduction of salt in dairy products could potentially alter the microbial stability, as well as cause unfavorable changes in flavor. In order to reduce the sodium level, while maintaining acceptable flavor and microbial stability, salt replacers and alternative antimicrobial agents may need to be introduced into the food matrix. To identify potential antimicrobials for use in reduced sodium dairy products, this study evaluated the efficacy of eight commercially available antimicrobials in TSA, milk agar, and cheese agar. Antimicrobials included MicroGard 100, MicroGard 430, Nisaplin, NovaGard CB1, Protect-M, PuraQ Verdad RV75, SEA-i F75 and VMY1P. Antimicrobials were also tested in combination with six commercial sodium reduction agents (potassium chloride, Puracal PP/USP, Purasal Hi Pure P Plus, PuraQ Verdad NV10, SaltWise 0029 and SaltWise 1029) to if there were any interference with antimicrobial activity. Antimicrobials with and without sodium reduction agents were added to the agar systems, then a five-strain cocktail of Listeria monocytogenes, Salmonella or Escherichia coli O157:H7 was spread plated at three concentrations: 101, 102 and 104 CFU/plate. Samples were then incubated at 35°C and observed for growth after 24 and 48h. SEA-i F75 was the most effective antimicrobial in each of the agars tested. Additionally, no interactions were observed between SEA-i F75 and any of the sodium replacement agents. SEA-i F75 was selected for use in a final challenge study using six formulations of LMPS mozzarella cheese: regular sodium control cheese (1.7% NaCl, no antimicrobial added); low sodium control cheese (0.7% NaCl, no antimicrobial added); low sodium treated cheese (0.7% NaCl, treatment with SEA-i F75); low sodium cheese with KCl as salt replacer (0.7% NaCl, 1.0% KCl, treatment with SEA-i F75); low sodium cheese with Alta 2345 as salt replacer (0.7% NaCl, 0.25% Alta 2345, treatment with SEA-i F75); and low sodium cheese with Salona as salt replacer (0.7% NaCl, 0.95% Salona, treatment with SEA-i F75). Fifteen gram cheese pieces from each formulation were dipped in an antimicrobial solution containing 0.25% SEA-i F75 then inoculated with L. monocytogenes, Salmonella, or E. coli O157:H7 at a target inoculum concentration of 102-103 CFU/g and incubated at either 4° or 12°C. In all trials, over all formulations and temperatures tested, initial decreases in counts, followed by organism recovery were observed. Therefore, SEA-i F75 was not effective at reducing the counts of pathogenic bacteria in LMPS mozzarella cheese. Results from this study highlight the effect of the food matrix, and its components on antimicrobial efficacy. Future research…

The treatment of bentonite clay sols with the salts of amines and aminoalcohols containing not more than 6 carbon atoms gives gels of hydrophilic organic ammonium bentonites. The gels, e.g. 3 wt.-% methylammonium bentonite, ethylammonium bentonite and triethanolammonium bentonite in water, have plastic rheology and high yield values which depend on the nature of the organic substituents. Use of these organic derivatives of bentonite offers a means of gelling aqueous systems alternative to the use of the purified montmorillonite clays.

Systematic measurements have been made of the E – J characteristics of a Nb 3 Sn wire over four decades of electric field (0.1–1000 μV m −1 ) and five decades of current density (10 3 –5×10 8 A m −2 ) as a function of magnetic field, temperature and strain. They were parameterised using the power law E = αJ n . At low magnetic fields n tends to a constant saturation value, which decreases at high compressive and tensile strains and increases with increasing electric field. In the high magnetic-field range, n is independent of E -field and can be approximated by a strain and temperature scaling law of the form n ( B , T , e )= G ( T )( B c2 * ( T , e )− B ), where B c2 * ( T , e ) is an effective upper critical field.

Systematic measurements have been made of the engineering critical current density ( J e ) and N -value (where E = αJ N ) of a jellyroll Nb 3 Sn wire as a function of magnetic field and strain at 4.2 K. Strain cycling to very high tensile strains at 4.2 K was used to investigate the reversibility of the wire's properties. The J e data were fully reversible up to 0.67% strain, and can be approximately parameterised by the scaling law F p (4.2 K ,B,e)=J e B=A[B c2 ∗ (4.2 K ,e)] 0.5 b 0.5 (1−b) 2 , where A=1.28×10 10 Am −2 T 0.5 . However it is noted that the maximum pinning force density is not a single-valued function of B c2 ∗ , so that highly accurate parameterisation requires that A depends on strain. The N -values are a strong function of strain, peaking at ∼0.33% with values nearly double the equivalent zero-strain values.

Smoking is the world’s leading cause of preventable illness and death (1). Accounting for 6 million deaths annually, 600,000 of smoking-related deaths occur in non-smokers exposed to second hand smoke (2). A major risk factor for six of the eight leading causes of death worldwide, smoking affects nearly every organ of the body (3). Smokers usually underestimate their risk of smoking-related diseases (4). Awareness of health concerns are a major motivator to quit (5,6). One in every two smokers will die from their addiction, however quitting substantially reduces this risk (7,8). Making an attempt to quit smoking and then sustaining abstinence are both equally important in ultimately succeeding quitting. Smokers frequently attempt quitting several times unsuccessfully before achieving long-term abstinence (9,10). Smokers who seek support in quitting are much more likely to quit than those who try to quit alone, and the most effective aid for achieving smoking cessation is medication (e.g., nicotine replacement therapy, or varenicline) coupled with tailored behavioral support from specialist stop smoking services, like the National Health Service Stop Smoking Services (NHS SSS) in the UK (11-13).

A glucose-sensitive gel formulation containing concanavalin A and glycogen has been reported previously. Precipitation resulting from the addition of concanavalin A to glycogen has been documented, but the formation of glucose-sensitive gels based on lectin-glycogen interactions is novel and used here in our studies. An improved in-vitro self-regulating drug-delivery system, using covalently modified glucose-sensitive gels based on concanavalin A and a polysaccharide displacement mechanism, is described. The successful use of the covalently modified gels addresses a problem identified previously where significant leaching of the mitogenic lectin from the gel membranes of non-coupled gels was encountered. Concanavalin A was covalently coupled to glycogen by use of derivatives of Schiff's bases. The resulting gels, like the non-coupled gels, were shown to undergo a gel-sol transformation in response to glucose. Insulin delivery was demonstrated using this covalently modified system in conditions of repeated glucose triggering at 20°C and 37°C. The magnitude of the response was less variable than for the dextran-based gels studied previously. The performance of this system has been improved in terms of concanavalin A leaching. This could, therefore, be used as the basis of the design of a self-regulating drug-delivery device for therapeutic agents used to treat diabetes mellitus.

Molecular modeling using structure elucidation programs in conjunction with molecular simulation programs has been performed on asphaltene molecules, the heaviest fraction of crude oil, in order to obtain a chemical model allowing us to tentatively study their physicochemical properties. We have analyzed Boscan asphaltenes (Venezuela) derived from a marine source rock. The different steps of this molecular modeling are described. First, a 3-D chemical representation of Boscan asphaltene is defined from an analytical data set. Second, the results of molecular dynamic simulations indicate that only a few stable conformations are possible due to the high reticulation of the model of the asphaltene unit obtained.

Background Regulators have issued warnings about the potential adverse effects of the smoking cessation medication varenicline. However, there is little evidence of the long-term effects of varenicline when prescribed in everyday clinical practice. We aimed to investigate the association of varenicline and nicotine replacement therapy (NRT) with adverse outcomes when prescribed in primary care. Methods Using the Clinical Practice Research Datalink (CPRD), we conducted an observational cohort study of electronic medical records and linked mortality and hospital admission data of 126 718 primary care patients in the UK prescribed varenicline (41 742) and NRT (84 976). We used three approaches to overcome potential residual confounding: multivariable adjusted regression, propensity score matching, and instrumental variable regression. The exposure was first prescription of varenicline or nicotine replacement therapy. The primary outcome was all-cause mortality 2 years after first prescription. Secondary outcomes were mortality from cardiovascular and respiratory disease, all-cause hospital admission and for cardiovascular and respiratory disease, incident primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease, and frequency of primary care attendance. Findings In multivariable adjusted analysis, mortality was lower among patients prescribed varenicline than in those prescribed NRT (OR 0·78, 95% CI 0·69 to 0·87; p Interpretation There was little evidence of a substantial increase in risk of adverse outcomes in patients prescribed varenicline as part of their standard clinical care. The regulatory warnings associated with varenicline do not accurately reflect the scientific evidence and should be reconsidered by policy makers and regulators. Funding The research described in this paper was funded by the Medical Research Council (MR/N01006X/1), the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/49/94). KHT is funded by a clinical lectureship award from the NIHR. RMM is supported by Cancer Research UK (programme grant C18281/A19169) (the Integrative Cancer Epidemiology Programme). TJ is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West, University Hospitals Bristol NHS Foundation Trust. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the abstract for submission.

Corneal cryopreservation requires that endothelial cells remain viable and intercellular structure be preserved. High viability levels for cryopreserved endothelial cells have been achieved, but preserving intercellular structure, especially endothelial attachment to Descemet's membrane, has proved difficult. Cell detachment apparently is not caused by ice, suggesting osmotic or chemical mechanisms. Knowledge of the permeation kinetics of cryoprotectants (CPAs) into endothelial cells and stroma is essential for controlling osmotic and chemical activity and achieving adequate tissue permeation prior to cooling. Proton nuclear magnetic resonance (NMR) spectroscopy was used to assess the permeation of dimethyl sulfoxide (DMSO) into isolated rabbit corneas. Corneas with intact epithelia were exposed to isotonic medium or 2.0 mol/L DMSO for 60 min and subsequently transferred to 2.0 or 4.0 mol/L DMSO, respectively, at 22, 0, or -10 degrees C. DMSO concentration in the cornea was measured vs time. The Kedem-Katchalsky model was fitted to the data. Hydraulic permeability (m3/N.s) is 7.1 x 10(-13) + 216%-11% at 22 degrees C, 8.2 x 10(-13) + 235%-21% at 0 degree C, and 1.7 x 10(-14) + 19%-16% at -10 degrees C. The reflection coefficient is 1.0 + 2%-1% at 22 degrees C and 0 degree C, and 0.9 +/- 5% at -10 degrees C. Solute mobility (cm/s) is 5.9 x 10(-6) + 6%-11% at 22 degrees C, 3.1 x 10(-6) + 12%-11% at 0 degree C, and 5.0 x 10(-8) cm/s + 59%-40% at -10 degrees C.

A self regulating delivery device, responsive to glucose, has been shown to operate successfully in vitro. This comprises a gel membrane which determines the delivery rate of insulin from a reservoir. The gel consists of a synthetic polysucrose and the lectin, concanavalin A. The mechanism is one of displacement of the branched polysaccharide from the lectin receptors by incoming glucose. The gel loses its high viscosity as a result but reforms on removal of glucose, thus providing the switch controlling the drug diffusion rate. The drug does not require to be chemically modified and thus the device is adaptable to other anti-hyperglycaemic drugs. However, results here indicate that the molecular weight of the solute may be an important parameter. Others include path length, gel formulation and temperature. It had been hypothesised that the reversal might be improved by the use of a non-aqueous reservoir of insulin. However, with the use of insulin, the switching off was found to be superior to that found with other test solutes used in previous studies, irrespective of the reservoir solvent. The advantages in the use of the non-aqueous system include, however, more reproducibility in the magnitude of response and a reduced temperature sensitivity.

Paspalum-dominant pastures suffer from poor winter/spring herbage production, which can be corrected by direct-drilling cool-season-active species such as ryegrass. The growth and persistence of perennial ryegrass (Lolium perenne L.) and white clover (Trifolium repens L.) direct-drilled into a paspalum (Paspalum dilatatum Poir.)-dominant, rotationally grazed dairy pasture, and their effects on production, were studied over 5 years. Treatments were original pasture (control) and herbicide treatment with 0, 0.72, 1.44, and 2.16 kg a.i./ha of glyphosate (Roundup® herbicide, 36% glyphosate) before direct-drilling. Observations on tagged ryegrass and white clover plants found establishment plant numbers for ryegrass were 74% higher (788 plants/m2) in herbicide-treated than in untreated areas (452 plants/m2). Half of all tagged ryegrass plants disappeared in the first year after which losses were much reduced. The establishment and survival of tagged white clover plants were poor. Paspalum gradually re...

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 μM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with...

The orientation of the valine-1 side chain of gramicidin was determined by solid-state 2H NMR using valine-1-deuterated (d8) gramicidin. The peptide was incorporated into DMPC bilayers that were oriented between glass plates. When the plates were oriented with their normal perpendicular to the magnetic field, four quadrupolar splittings were observed of 106, 68, 9.7, and 2.0 kHz. These resonances were assigned to C alpha D, C beta D, and the deuterons of each of the C gamma D3 methyl groups, respectively. The average orientation of the various C-D bonds was calculated with respect to the helix axis. The angle obtained for the C alpha-D resonance was consistent with a single-stranded beta 6.3-helical model for the backbone but not with double-helical models. The angles of the side chain were then fitted to a model for the right-handed beta 6.3-helix. Rotation of the valine-1 side chain yielded a set of torsion angles that matched the angles as determined from the 2H NMR measurements. The corresponding orientation of the valine-1 side chain (chi 1 = -5 degrees) was found to be quite unusual, but it explains well the importance of a branched side chain at position 1 for channel formation and stability. A van der Waals interaction between valine-1 of one monomer and alanine-5 of the other helps to stabilize the gramicidin dimer.

Field desorption - mass spectrometry (FD-MS) was evaluated as a tool for characterisation of the complex mixtures of compounds typical of synthetic lubricants. The lubricants were initially screened using field ionisation, then tested samples were subjected to field desorption. Results are presented for various formulations for an ester, an ester-synthetic oil mixture, polyisobutylenes, PAO additives, and a fully formulated oil.

Two reservoir cores and one synthetic alumina sample have been quantitatively studied by means of proton, spin-lattice relaxation of the bulk samples, and by 2D-FT slice selected imaging. T1 and M0 images of high quality have been obtained with reasonable data acquisition and data processing times. T1 and T2 relaxation processes have been shown to be correlated, and possible causes for the differences between average image T1 values and those measures for the bulk samples are discussed. Variation of T1 within the images is discussed in terms of the contributions from pore size and surface relaxation effects.

A number of streptavidin-linked reporter molecules at the endpoint of a five-step detection protocol for viral in situ hybridization using biotinylated probes were examined. DNA-DNA and RNA-RNA model systems were used. Streptavidin linked to either peroxidase or fluorescein was found to be optimal in terms of sensitivity and resolution within individual cells. All other reporter molecules labelled similar numbers of cells with low background reaction. However, streptavidin-5 nm gold followed by silver enhancement gave very high background staining making interpretation of positive signals very difficult.

Field-desorption mass spectrometry has been used to characterize polystyrene oligomers of molecular weight up to 15 000 Da. The technique shows good agreement with molecular weight data calculated using vapour-phase osmometry and gel-permeation chromatography but in addition provides much more detailed information in terms of oligomer distribution and the nature of end groups present in the oligomers.

A novel glucose-responsive gel formulation was stabilised via covalent coupling to a carbomer resin. The gel formed between the plant lectin, concanavalin A and specific polysaccharides was stabilised to minimise leaching of gel components into the surroundings. This was required to prevent toxicity and to preserve the working mechanism of the formulation. Increased gel stability was introduced by covalently bonding amine groups present on the lysine residues of concanavalin A to carboxylic moieties on Carbopol 974P NF using carbodiimide chemistry. The introduction of dextran then produced a glucose-responsive formulation that transformed from gel to sol in the presence of free glucose. The rheological properties and in vitro component and insulin release of the carbomer-stabilised gel were evaluated. A decrease in viscosity over a chosen glucose concentration range was exhibited by the carbomer-based gel. The testing of such a formulation in in vitro diffusion experiments revealed that the leaching of concanavalin A from the covalently coupled gels was restricted significantly with respect to a non-coupled gel. Insulin delivery in response to glucose in the physiologically relevant glucose concentration range was demonstrated using the carbomer-stabilised gel at 37 degrees C. The performance of this novel self-regulating drug delivery system has been improved in terms of increased gel stability with reduced component leaching.

Administration to mice of harmaline (100 mg/kg SC) resulted in a greater than two-fold increase in cyclic GMP in the cerebellum 15 min later. This response was inhibited by pretreatment 5 min before the harmaline with pentobarbital (ED50 6.5 mg/kg), chlormethiazole (ED50 10.4 mg/kg) and dizocilpine (ED50 0.5 mg/kg). Harmaline-induced tremor was inhibited by pentobarbital (ED50 30 mg/kg) and chlormethiazole (ED50 50 mg/kg) but not dizocilpine. The data demonstrate that the harmaline-induced tremor and cerebellar cyclic GMP rise are probably not associated. They also demonstrate that chlormethiazole is able to inhibit a biochemical response (the increase in cerebellar cyclic GMP) which results from increased glutamate function.

Quinuclidines with a 3-biaryl substituent are a new class of potent, orally active squalene synthase (SQS) inhibitors. Variants around these rigid structures indicate key structural requirements for cationic SQS inhibitors. Thus the lower in vitro potency found for quinuclidines bearing 3-substituents, which did not overlay the biphenyl group of 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (2) (IC50 = 16 nM, rat microsomal SQS), implied a directional requirement for the 3-substituent. Similarly, the lower potency of the 3-terphenyl analogue 6 (IC50 = 370 nM) indicated size constraints for this substituent. In compounds with a linking group between the quinuclidine and biphenyl ring, linking groups of lower lipophilicity were less well tolerated (e.g., 17, CH2CH2, IC50 = 5 nM vs 19, NHCO, IC50 = 1.2 microM). Replacement of the distal phenyl ring of 2 with a more polar pyridine heterocycle caused a reduction in in vitro potency. In general, good in vivo activity in the rat was restricted to 3-hydroxy analogues, with the 3-[4-(pyrid-4-yl)phenyl] derivative 39 (IC50 = 161 nM) showing the best inhibition (following oral dosing) of cholesterol biosynthesis from mevalonate (ED50 = 2.7 mg/kg).