A large-scale conformational change couples membrane recruitment to cargo binding in the AP2 clathrin adaptor complex.

The AP2 adaptor complex (alpha, beta2, sigma2, and mu2 subunits) crosslinks the endocytic clathrin scaffold to PtdIns4,5P(2)-containing membranes and transmembrane protein cargo. In the "locked" cytosolic form, AP2's binding sites for the two endocytic motifs, YxxPhi on the C-terminal domain of mu2 (C-mu2) and [ED]xxxL[LI] on sigma2, are blocked by parts of beta2. Using protein crystallography, we show that AP2 undergoes a large conformational change in which C-mu2 relocates to an orthogonal face of the complex, simultaneously unblocking both cargo-binding sites; the previously unstructured mu2 linker becomes helical and binds back onto the complex. This structural rearrangement results in AP2's four PtdIns4,5P(2)- and two endocytic motif-binding sites becoming coplanar, facilitating their simultaneous interaction with PtdIns4,5P(2)/cargo-containing membranes. Using a range of biophysical techniques, we show that the endocytic cargo binding of AP2 is driven by its interaction with PtdIns4,5P(2)-containing membranes.

A phase 1 open label study to assess the human mass balance and metabolite profile of 14C-fosmanogepix, a novel Gwt-1 inhibitor in healthy male participants.

Fosmanogepix [FMGX; active form manogepix (MGX)], a novel antifungal, is currently being studied for the treatment of invasive fungal diseases caused by Candida spp., Aspergillus spp., and other rare molds. This Phase 1, single-dose study used 14C-radiolabeled FMGX to determine the disposition and metabolism of FMGX. Ten healthy male participants were enrolled equally into: oral cohort {FMGX 500 mg oral + 3.1 megabecquerel [MBq, 84.0 microcurie (µCi)] 14C} and intravenous (IV) cohort [FMGX 600 mg IV + 3.4 MBq (93.0 µCi) 14C]. At the end of the sampling period (456 h post-dose), 90.2% of radioactivity administered was recovered (46.4% from urine; 43.8% from feces) in oral cohort (82.3% within 240 h), and 82.4% was recovered (42.5% from urine; 39.9% from feces) in IV cohort (76.2% within 264 h), indicating that FMGX elimination occurs via renal and hepatic routes. Radioactivity transformation pathways (oral and IV) indicated multiple major routes of metabolism of FMGX, mainly via MGX, and included oxidation, oxidative deamination, and conjugation. All except one key human plasma metabolite was observed in toxicity species, but its proportion (<10%) in the human area under the curve plasma samples was not of toxicological concern. No deaths, serious, or severe adverse events (AE) were reported, and there were no AE-related withdrawals. The results of this study indicated extensive metabolism of FMGX, with similar key human plasma metabolites observed in the animal studies. The elimination of FMGX was equally through renal and hepatic routes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04804059.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

Small is Powerful: Demonstration of the Impact of Nanoformed Piroxicam in a Controlled Clinical Study.

PURPOSE: New solutions are needed to enable the efficient use of poorly water-soluble drugs. Therefore, we aimed to demonstrate that decreasing particle size with a solution-to-particle method known as nanoforming can improve dissolution and thus bioavailability. METHODS: Piroxicam, a poorly water-soluble non-steroidal anti-inflammatory drug (NSAID), was used as a model compound. A Quality-by-Design (QbD) approach was used to nanoform piroxicam and a design space was established. The pharmacokinetics of piroxicam nanoparticles were compared to two marketed products in a clinical trial. RESULTS: Nanoformed tablets showed a 33% increase in exposure during the first hour after dosing (AUC0-1 h) compared with an immediate release tablet and was similar to a fast absorbing tablet incorporating complexation of piroxicam with ß-cyclodextrin. CONCLUSIONS: The results show that nanoforming enabled more rapid absorption in comparison to a typical marketed tablet and indicate that nanoforming is an alternative to complex formulation such as cyclodextrins based products. The study outcomes support the potential of nanoforming for producing fast-acting dosage forms of poorly soluble drugs.

Molecular basis for the sorting of the SNARE VAMP7 into endocytic clathrin-coated vesicles by the ArfGAP Hrb.

SNAREs provide the specificity and energy for the fusion of vesicles with their target membrane, but how they are sorted into the appropriate vesicles on post-Golgi trafficking pathways is largely unknown. We demonstrate that the clathrin-mediated endocytosis of the SNARE VAMP7 is directly mediated by Hrb, a clathrin adaptor and ArfGAP. Hrb wraps 20 residues of its unstructured C-terminal tail around the folded VAMP7 longin domain, demonstrating that unstructured regions of clathrin adaptors can select cargo. Disrupting this interaction by mutation of the VAMP7 longin domain or depletion of Hrb causes VAMP7 to accumulate on the cell's surface. However, the SNARE helix of VAMP7 binds back onto its longin domain, outcompeting Hrb for binding to the same groove and suggesting that Hrb-mediated endocytosis of VAMP7 occurs only when VAMP7 is incorporated into a cis-SNARE complex. These results elucidate the mechanism of retrieval of a postfusion SNARE complex in clathrin-coated vesicles.

Including older people in health and social care research: best practice recommendations based on the INCLUDE framework.

BACKGROUND: Older people are often explicitly or implicitly excluded from research, in particular clinical trials. This means that study findings may not be applicable to them, or that older people may not be offered treatments due to an absence of evidence. AIMS: The aim of this work was to develop recommendations to guide all research relevant to older people. METHODS: A diverse stakeholder group identified barriers and solutions to including older people in research. In parallel, a rapid literature review of published papers was undertaken to identify existing papers on the inclusion of older people in research. The findings were synthesised and mapped onto a socio-ecological model. From the synthesis we identified themes that were developed into initial recommendations that were iteratively refined with the stakeholder group. RESULTS: A range of individual, interpersonal, organisational, community and policy factors impact on the inclusion of older people in research. A total of 14 recommendations were developed such as removing upper age limits and comorbidity exclusions, involving older people, advocates and health and social care professionals with expertise in ageing in designing the research, and considering flexible or alternative approaches to data collection to maximise opportunities for participation. We also developed four questions that may guide those developing, reviewing and funding research that is inclusive of older people. CONCLUSION: Our recommendations provide up to date, practical advice on ways to improve the inclusion of older people in health and care research.

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.

Pneumomediastinum in COVID-19: a phenotype of severe COVID-19 pneumonitis? The results of the United Kingdom (POETIC) survey.

BACKGROUND: There is an emerging understanding that coronavirus disease 2019 (COVID-19) is associated with increased incidence of pneumomediastinum. We aimed to determine its incidence among patients hospitalised with COVID-19 in the United Kingdom and describe factors associated with outcome. METHODS: A structured survey of pneumomediastinum and its incidence was conducted from September 2020 to February 2021. United Kingdom-wide participation was solicited via respiratory research networks. Identified patients had SARS-CoV-2 infection and radiologically proven pneumomediastinum. The primary outcomes were to determine incidence of pneumomediastinum in COVID-19 and to investigate risk factors associated with patient mortality. RESULTS: 377 cases of pneumomediastinum in COVID-19 were identified from 58 484 inpatients with COVID-19 at 53 hospitals during the study period, giving an incidence of 0.64%. Overall 120-day mortality in COVID-19 pneumomediastinum was 195/377 (51.7%). Pneumomediastinum in COVID-19 was associated with high rates of mechanical ventilation. 172/377 patients (45.6%) were mechanically ventilated at the point of diagnosis. Mechanical ventilation was the most important predictor of mortality in COVID-19 pneumomediastinum at the time of diagnosis and thereafter (p<0.001) along with increasing age (p<0.01) and diabetes mellitus (p=0.08). Switching patients from continuous positive airways pressure support to oxygen or high flow nasal oxygen after the diagnosis of pneumomediastinum was not associated with difference in mortality. CONCLUSIONS: Pneumomediastinum appears to be a marker of severe COVID-19 pneumonitis. The majority of patients in whom pneumomediastinum was identified had not been mechanically ventilated at the point of diagnosis.

Consensus report: Definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Family history recording in UK general practice: the lIFeLONG study.

BACKGROUND: In order to integrate genomic medicine into routine patient care and stratify personal risk, it is increasingly important to record family history (FH) information in general/family practice records. This is true for classic genetic disease as well as multifactorial conditions. Research suggests that FH recording is currently inadequate. OBJECTIVES: To provide an up-to-date analysis of the frequency, quality, and accuracy of FH recording in UK general/family practice. METHODS: An exploratory study, based at St Leonard's Practice, Exeter-a suburban UK general/family practice. Selected adult patients registered for over 1 year were contacted by post and asked to complete a written FH questionnaire. The reported information was compared with the patients' electronic medical record (EMR). Each EMR was assessed for its frequency (how often information was recorded), quality (the level of detail included), and accuracy (how closely the information matched the patient report) of FH recording. RESULTS: Two hundred and forty-one patients were approached, 65 (27.0%) responded and 62 (25.7%) were eligible to participate. Forty-three (69.4%) EMRs contained FH information. The most commonly recorded conditions were bowel cancer, breast cancer, diabetes, and heart disease. The mean quality score was 3.64 (out of 5). There was little negative recording. 83.2% of patient-reported FH information was inaccurately recorded or missing from the EMRs. CONCLUSION: FH information in general/family practice records should be better prepared for the genomic era. Whilst some conditions are well recorded, there is a need for more frequent, higher quality recording with greater accuracy, especially for multifactorial conditions.

Taking a family history (FH) of disease can be a quick, cost-effective way of gathering genetic information. Genetic medicine is beginning to transform healthcare, so it is important to gather FH information. General practitioners, also known as family physicians, are in the best position to gather FH information as they regularly see multiple family members. Research suggests that FH recording in general/family practice is not yet good enough. This study aimed to find the areas for improvement by measuring the frequency, quality, and accuracy of FH recording. This study looked at 62 patients' records in one UK general practice. Patients were asked to give up-to-date FH information in a questionnaire which was compared with their record. The study found that some conditions were often recorded. The most commonly recorded condition was heart disease. The conditions that are more likely to reflect the family environment, such as depression, were less frequently recorded. Recordings often included the side of the family the condition affected. Recordings rarely included the age that the relative was affected. The information was not very accurate, as most of the information from patient questionnaires was missing from the records. Research should now focus on how to improve recording.

Consensus report: definition and interpretation of remission in type 2 diabetes.

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks vs benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed 'remission' as the most appropriate descriptive term, and HbA1c <48 mmol/mol (6.5%) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission.

Integrating Patient Reported Outcome Measures (PROMs) into routine nurse-led primary care for patients with multimorbidity: a feasibility and acceptability study.

BACKGROUND: The use of Patient Reported Outcome Measures (PROMS) in clinical practice has the potential to promote patient-centred care and improve patients' quality of life. Individualized PROMs may be particularly helpful in identifying, prioritizing and monitoring health problems of patients with multimorbidity. We aimed to develop an intervention centred around PROMs feedback as part of Primary Care annual reviews for patients with multimorbidity and evaluate its feasibility and acceptability. METHODS: We developed a nurse-oriented intervention including (a) training of nurses on PROMs; (b) administration to patients with multimorbidity of individualized and standardized PROMS; and (c) feedback to both patients and nurses of PROMs scores and interpretation guidance. We then tailored the intervention to patients with two or more highly prevalent conditions (asthma, COPD, diabetes, heart failure, depression, and hip/knee osteoarthritis) and designed a non-controlled feasibility and acceptability evaluation in a convenience sample of primary care practices (5). PROMs were administered and scores fed back immediately ahead of scheduled annual reviews with nurses. Patients and nurses rated the acceptability of the intervention using with a brief survey including optional free comments. Thematic analysis of qualitative interviews with a sample of participating patients (10) and nurses (4) and of survey free comments was conducted for further in-depth evaluation of acceptability. Feasibility was estimated based on rates of participation and completion. RESULTS: Out of 68 recruited patients (mean age 70; 47% female), 68 completed the PROMs (100%), received feedback (100%) and confirmed nurse awareness of their scores (100%). Most patients (83%) "agreed"/"strongly agreed" that the PROMs feedback had been useful, a view supported by nurses in 89% of reviews. Thematic analysis of rich qualitative data on PROMS administration, feedback and role in annual reviews indicated that both patients and nurses perceived the intervention as acceptable and promising, emphasizing its comprehensiveness and patient-centredness. CONCLUSIONS: We have developed and tested an intervention focusing on routine PROM assessment of patients with multimorbidity in Primary Care. Preliminary findings support its feasibility and a high degree of acceptability from both patients and nurses. The next step is to conduct a full-scale trial for evaluating the effectiveness of the proposed intervention.

Is health research undertaken where the burden of disease is greatest? Observational study of geographical inequalities in recruitment to research in England 2013-2018.

BACKGROUND: Research is fundamental to high-quality care, but concerns have been raised about whether health research is conducted in the populations most affected by high disease prevalence. Geographical distribution of research activity is important for many reasons. Recruitment is a major barrier to research delivery, and undertaking recruitment in areas of high prevalence could be more efficient. Regional variability exists in risk factors and outcomes, so research done in healthier populations may not generalise. Much applied health research evaluates interventions, and their impact may vary by context (including geography). Finally, fairness dictates that publically funded research should be accessible to all, so that benefits of participating can be fairly distributed. We explored whether recruitment of patients to health research is aligned with disease prevalence in England. METHODS: We measured disease prevalence using the Quality and Outcomes Framework in England (total long-term conditions, mental health and diabetes). We measured research activity using data from the NIHR Clinical Research Network. We presented descriptive data on geographical variation in recruitment rates. We explored associations between the recruitment rate and disease prevalence rate. We calculated the share of patient recruitment that would need to be redistributed to align recruitment with prevalence. We assessed whether associations between recruitment rate and disease prevalence varied between conditions, and over time. RESULTS: There was significant geographical variation in recruitment rates. When areas were ranked by disease prevalence, recruitment was not aligned with prevalence, with disproportionately low recruitment in areas with higher prevalence of total long-term and mental health conditions. At the level of 15 local networks, analyses suggested that around 12% of current recruitment activity would need to be redistributed to align with disease prevalence. Overall, alignment showed little change over time, but there was variation in the trends over time in individual conditions. CONCLUSIONS: Geographical variations in recruitment do not reflect the suitability of the population for research. Indicators should be developed to assess the fit between research and need, and to allow assessment of interventions among funders, researchers and patients to encourage closer alignment between research activity and burden.

Safely reducing haemodialysis frequency during the COVID-19 pandemic.

BACKGROUND: Patients undergoing haemodialysis (HD) are at higher risk of developing worse outcomes if they contract COVID-19. In our renal service we reduced HD frequency from thrice to twice-weekly in selected patients with the primary aim of reducing COVID 19 exposure and transmission between HD patients. METHODS: Dialysis unit nephrologists identified 166 suitable patients (38.4% of our HD population) to temporarily convert to twice-weekly haemodialysis immediately prior to the peak of the COVID-19 pandemic in our area. Changes in pre-dialysis weight, systolic blood pressure (SBP) and biochemistry were recorded weekly throughout the 4-week project. Hyperkalaemic patients (serum potassium > 6.0 mmol/L) were treated with a potassium binder, sodium bicarbonate and received responsive dietary advice. RESULTS: There were 12 deaths (5 due to COVID-19) in the HD population, 6 of which were in the twice weekly HD group; no deaths were definitively associated with change of dialysis protocol. A further 19 patients were either hospitalised and/or developed COVID-19 and thus transferred back to thrice weekly dialysis as per protocol. 113 (68.1%) were still receiving twice-weekly HD by the end of the 4-week project. Indications for transfer back to thrice weekly were; fluid overload (19), persistent hyperkalaemia (4), patient request (4) and compliance (1). There were statistically significant increases in SBP and pre-dialysis potassium during the project. CONCLUSIONS: Short term conversion of a large but selected HD population to twice-weekly dialysis sessions was possible and safe. This approach could help mitigate COVID-19 transmission amongst dialysis patients in centres with similar organisational pressures.

Structural basis for the binding of tryptophan-based motifs by δ-COP.

Coatomer consists of two subcomplexes: the membrane-targeting, ADP ribosylation factor 1 (Arf1):GTP-binding ßγδζ-COP F-subcomplex, which is related to the adaptor protein (AP) clathrin adaptors, and the cargo-binding αß'ε-COP B-subcomplex. We present the structure of the C-terminal µ-homology domain of the yeast δ-COP subunit in complex with the WxW motif from its binding partner, the endoplasmic reticulum-localized Dsl1 tether. The motif binds at a site distinct from that used by the homologous AP µ subunits to bind YxxΦ cargo motifs with its two tryptophan residues sitting in compatible pockets. We also show that the Saccharomyces cerevisiae Arf GTPase-activating protein (GAP) homolog Gcs1p uses a related WxxF motif at its extreme C terminus to bind to δ-COP at the same site in the same way. Mutations designed on the basis of the structure in conjunction with isothermal titration calorimetry confirm the mode of binding and show that mammalian δ-COP binds related tryptophan-based motifs such as that from ArfGAP1 in a similar manner. We conclude that δ-COP subunits bind Wxn(1-6)[WF] motifs within unstructured regions of proteins that influence the lifecycle of COPI-coated vesicles; this conclusion is supported by the observation that, in the context of a sensitizing domain deletion in Dsl1p, mutating the tryptophan-based motif-binding site in yeast causes defects in both growth and carboxypeptidase Y trafficking/processing.

Dynamically Reconfigurable Metadevice Employing Nanostructured Phase-Change Materials.

Mastering dynamic free-space spectral control and modulation in the near-infrared (NIR) and optical regimes remains a challenging task that is hindered by the available functional materials at high frequencies. In this work, we have realized an efficient metadevice capable of spectral control by minimizing the thermal mass of a vanadium dioxide phase-change material (PCM) and placing the PCM at the feed gap of a bow-tie field antenna. The device has an experimentally measured tuning range of up to 360 nm in the NIR and a modulation depth of 33% at the resonant wavelength. The metadevice is configured for integrated and local heating, leading to faster switching and more precise spatial control compared with devices based on phase-change thin films. We envisage that the combined advantages of this device will open new opportunities for signal processing, memory, security, and holography at optical frequencies.

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines.

Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N1 ,N2 -bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials.

Synthesis and biological analysis of novel glycoside derivatives of l-AEP, as targeted antibacterial agents.

To develop targeted methods for treating bacterial infections, the feasibility of using glycoside derivatives of the antibacterial compound l-R-aminoethylphosphonic acid (l-AEP) has been investigated. These derivatives are hypothesized to be taken up by bacterial cells via carbohydrate uptake mechanisms, and then hydrolyzed in situ by bacterial borne glycosidase enzymes, to selectively afford l-AEP. Therefore the synthesis and analysis of ten glycoside derivatives of l-AEP, for selective targeting of specific bacteria, is reported. The ability of these derivatives to inhibit the growth of a panel of Gram-negative bacteria in two different media is discussed. ß-Glycosides (12a) and (12b) that contained l-AEP linked to glucose or galactose via a carbamate linkage inhibited growth of a range of organisms with the best MICs being <0.75mg/ml; for most species the inhibition was closely related to the hydrolysis of the equivalent chromogenic glycosides. This suggests that for (12a) and (12b), release of l-AEP was indeed dependent upon the presence of the respective glycosidase enzyme.

Fifty years of longitudinal continuity in general practice: a retrospective observational study.

BACKGROUND: Continuity of care has been defined as relational continuity between patient and doctor and longitudinal continuity describing the duration of the relationship. Measurement of longitudinal continuity alone is associated with outcomes including patient satisfaction, medical costs, hospital admissions and mortality. METHODS: In one UK general practice, records were searched for patients with continuous registration for 50 or more years. Characteristics of these patients were analysed for age, gender, social deprivation, partner registration and length of registration. Trends in numbers and proportions of this group over the previous 14 years were determined. A comparison group of patients, aged 50 or more, and registered in the same practice within the last 2-4 years, was identified. RESULTS: Patients registered for 50 years or more with a median registration of 56.2 years numbered 190 out of a population of 8420 (2.3%). These patients increased in number by 35.3% (1.7-2.3%) over 14 consecutive years. There were no differences between groups for GP consultation rate, number of repeat medications and hospital use, despite the significantly higher prevalence of multi-morbidity, depression and diabetes in patients with high continuity. CONCLUSIONS: This is the first report of 50-year continuity in general practice. Numbers of such patients and proportions are increasing. Longitudinal continuity is easily measured in general practice and associated with important clinical outcomes.

Classification of fibroglandular tissue distribution in the breast based on radiotherapy planning CT.

BACKGROUND: Accurate segmentation of breast tissues is required for a number of applications such as model based deformable registration in breast radiotherapy. The accuracy of breast tissue segmentation is affected by the spatial distribution (or pattern) of fibroglandular tissue (FT). The goal of this study was to develop and evaluate texture features, determined from planning computed tomography (CT) data, to classify the spatial distribution of FT in the breast. METHODS: Planning CT data of 23 patients were evaluated in this study. Texture features were derived from the radial glandular fraction (RGF), which described the distribution of FT within three breast regions (posterior, middle, and anterior). Using visual assessment, experts grouped patients according to FT spatial distribution: sparse or non-sparse. Differences in the features between the two groups were investigated using the Wilcoxon rank test. Classification performance of the features was evaluated for a range of support vector machine (SVM) classifiers. RESULTS: Experts found eight patients and 15 patients had sparse and non-sparse spatial distribution of FT, respectively. A large proportion of features (>9 of 13) from the individual breast regions had significant differences (p <0.05) between the sparse and non-sparse group. The features from middle region had most significant differences and gave the highest classification accuracy for all the SVM kernels investigated. Overall, the features from middle breast region achieved highest accuracy (91%) with the linear SVM kernel. CONCLUSION: This study found that features based on radial glandular fraction provide a means for discriminating between fibroglandular tissue distributions and could achieve a classification accuracy of 91%.