Effects of oral lycopene supplementation on vascular function in patients with cardiovascular disease and healthy volunteers: a randomised controlled trial.

AIMS: The mechanisms by which a 'Mediterranean diet' reduces cardiovascular disease (CVD) burden remain poorly understood. Lycopene is a potent antioxidant found in such diets with evidence suggesting beneficial effects. We wished to investigate the effects of lycopene on the vasculature in CVD patients and separately, in healthy volunteers (HV). METHODS AND RESULTS: We randomised 36 statin treated CVD patients and 36 healthy volunteers in a 2∶1 treatment allocation ratio to either 7 mg lycopene or placebo daily for 2 months in a double-blind trial. Forearm responses to intra-arterial infusions of acetylcholine (endothelium-dependent vasodilatation; EDV), sodium nitroprusside (endothelium-independent vasodilatation; EIDV), and NG-monomethyl-L-arginine (basal nitric oxide (NO) synthase activity) were measured using venous plethysmography. A range of vascular and biochemical secondary endpoints were also explored. EDV in CVD patients post-lycopene improved by 53% (95% CI: +9% to +93%, P = 0.03 vs. placebo) without changes to EIDV, or basal NO responses. HVs did not show changes in EDV after lycopene treatment. Blood pressure, arterial stiffness, lipids and hsCRP levels were unchanged for lycopene vs. placebo treatment groups in the CVD arm as well as the HV arm. At baseline, CVD patients had impaired EDV compared with HV (30% lower; 95% CI: -45% to -10%, P = 0.008), despite lower LDL cholesterol (1.2 mmol/L lower, 95% CI: -1.6 to -0.9 mmol/L, P<0.001). Post-therapy EDV responses for lycopene-treated CVD patients were similar to HVs at baseline (2% lower, 95% CI: -30% to +30%, P = 0.85), also suggesting lycopene improved endothelial function. CONCLUSIONS: Lycopene supplementation improves endothelial function in CVD patients on optimal secondary prevention, but not in HVs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01100385

Heterotic Compactification, An Algorithmic Approach

We approach string phenomenology from the perspective of computational algebraic geometry, by providing new and efficient techniques for proving stability and calculating particle spectra in heterotic compactifications. This is done in the context of complete intersection Calabi-Yau manifolds in a single projective space where we classify positive monad bundles. Using a combination of analytic methods and computer algebra we prove stability for all such bundles and compute the complete particle spectrum, including gauge singlets. In particular, we find that the number of anti-generations vanishes for all our bundles and that the spectrum is manifestly moduli-dependent.Comment: 36 pages, Late

Closed string tachyons, flips and conifolds

Following the analysis of tachyons and orbifold flips described in hep-th/0412337, we study nonsupersymmetric analogs of the supersymmetric conifold singularity and show using their toric geometry description that they are nonsupersymmetric orbifolds of the latter. Using linear sigma models, we see that these are unstable to localized closed string tachyon condensation and exhibit flip transitions between their two small resolutions (involving 2-cycles), in the process mediating mild dynamical topology change. Our analysis shows that the structure of these nonsupersymmetric conifolds as quotients of the supersymmetric conifold obstructs the 3-cycle deformation of such singularities, suggesting that these nonsupersymmetric conifolds decay by evolving towards their stable small resolutions.Comment: Latex, 22 pgs, 2 figs. v4: matches JHEP version, 29 pgs, 3 figures, more elaborate Introduction, various clarifications adde

An algorithmic approach to string phenomenology

We review the recent programme undertaken to construct, systematically and algorithmically, large classes of heterotic vacua, as well as the search for the MSSM therein. Specifically, we outline the monad construction of vector bundles over complete intersection Calabi–Yau threefolds, their classification, stability, equivariant cohomology and subsequent relevance to string phenomenology. It is hoped that this top–down algorithmic approach will isolate special corners in the heterotic landscape

Stability Walls in Heterotic Theories

We study the sub-structure of the heterotic Kahler moduli space due to the presence of non-Abelian internal gauge fields from the perspective of the four-dimensional effective theory. Internal gauge fields can be supersymmetric in some regions of the Kahler moduli space but break supersymmetry in others. In the context of the four-dimensional theory, we investigate what happens when the Kahler moduli are changed from the supersymmetric to the non-supersymmetric region. Our results provide a low-energy description of supersymmetry breaking by internal gauge fields as well as a physical picture for the mathematical notion of bundle stability. Specifically, we find that at the transition between the two regions an additional anomalous U(1) symmetry appears under which some of the states in the low-energy theory acquire charges. We compute the associated D-term contribution to the four-dimensional potential which contains a Kahler-moduli dependent Fayet-Iliopoulos term and contributions from the charged states. We show that this D-term correctly reproduces the expected physics. Several mathematical conclusions concerning vector bundle stability are drawn from our arguments. We also discuss possible physical applications of our results to heterotic model building and moduli stabilization.Comment: 37 pages, 4 figure

6D Effective Action of Heterotic Compactification on K3 with nontrivial Gauge Bundles

We compute the six-dimensional effective action of the heterotic string compactified on K3 for the standard embedding and for a class of backgrounds with line bundles and appropriate Yang-Mills fluxes. We compute the couplings of the charged scalars and the bundle moduli as functions of the geometrical K3 moduli from a Kaluza-Klein analysis. We derive the D-term potential and show that in the flux backgrounds U(1) vector multiplets become massive by a Stuckelberg mechanism.Comment: 41 pages, typos corrected, references adde

ChemoPROphyLaxIs with hydroxychloroquine For covId-19 infeCtious disease (PROLIFIC) to prevent covid-19 infection in frontline healthcare workers: A structured summary of a study protocol for a randomised controlled trial

Abstract: Objectives: Primary objective: To determine whether chemoprophylaxis with hydroxychloroquine versus placebo increases time to contracting coronavirus disease 2019 (COVID-19) in frontline healthcare workers. Secondary objectives: To determine whether chemoprophylaxis with daily versus weekly dosing of hydroxychloroquine increases time to contracting COVID-19 disease in frontline healthcare workers. To compare the number of COVID-19 cases between each trial arm on the basis of positive tests (as per current clinical testing methods and/or serology) To compare the percentage of COVID-19 positive individuals with current testing methods versus serologically-proven COVID-19 in each trial arm To compare COVID-19 disease severity in each trial arm To compare recovery time from COVID-19 infection in each trial arm Exploratory objectives: To determine compliance (as measured by trough pharmacokinetic hydroxychloroquine levels) on COVID-19 positive tests To determine if genetic factors determine susceptibility to COVID-19 disease or response to treatment To determine if blood group determines susceptibility to COVID-19 disease To compare serum biomarkers of COVID-19 disease in each arm Trial design: Double-blind, multi-centre, 2-arm (3:3:2 ratio) randomised placebo-controlled trial Participants: National Health Service (NHS) workers who have direct patient contact delivering care to patients with COVID-19. Participants in the trial will be recruited from a number of NHS hospitals directly caring for patients with COVID-19. Inclusion criteria: To be included in the trial the participant MUST: Have given written informed consent to participate Be aged 18 years to 70 years Not previously have been diagnosed with COVID-19 Work in a high-risk secondary or tertiary healthcare setting (hospitals accepting COVID-19 patients) with direct patient-facing care Exclusion criteria: The presence of any of the following will mean participants are ineligible: Known COVID-19 positive test at baseline (if available) Symptomatic for possible COVID-19 at baseline Known hypersensitivity reaction to hydroxychloroquine, chloroquine or 4-aminoquinolines Known retinal disease Known porphyria Known chronic kidney disease (CKD; eGFR<30ml/min) Known epilepsy Known heart failure or conduction problems Known significant liver disease (Gilbert’s syndrome is permitted) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency Currently taking any of the following contraindicated medications: Digoxin, Chloroquine, Halofantrine, Amiodarone, Moxifloxacin, Cyclosporin, Mefloquine, Praziquantel, Ciprofloxacin, Clarithromycin, Prochlorperazine, Fluconazole Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine Currently breastfeeding Unable to be followed-up during the trial Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit Not able to use or have access to a modern phone device/web-based technology Any other clinical reason which may preclude entry in the opinion of the investigator Intervention and comparator: Interventions being evaluated are: Daily hydroxychloroquine or Weekly hydroxychloroquine or Placebo The maximum treatment period is approximately 13 weeks per participant. Hydroxychloroquine-identical matched placebo tablets will ensure that all participants are taking the same number and dosing regimen of tablets across the three trial arms. There is no variation in the dose of hydroxychloroquine by weight. The dosing regimen for the three arms of the study (A, B, C) are described in further detail below. Arm A: Active Hydroxychloroquine (– daily dosing and placebo-matched hydroxychloroquine - weekly dosing). Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine:Days 1-2: Loading phase - 400mg (2 x 200mg tablets) taken twice a day for 2 days Days 3 onwards: Maintenance Phase - 200mg (1 x 200mg tablet) taken once daily, every day for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Arm B: Active Hydroxychloroquine (- weekly dosing and placebo matched hydroxychloroquine – daily dosing.) Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading Phase - 400mg (2 x 200mg tablets) taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg tablets) taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Arm C: Matched placebo Hydroxychloroquine (- daily dosing and matched placebo hydroxychloroquine - weekly dosing.) Form: Table. Route: Oral. Frequency: Matched placebo hydroxychloroquine - daily dosing: Days 1-2: Loading Phase - 2 tablets taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Matched placebo hydroxychloroquine – weekly dosing: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) A schematic of the dosing schedule can be found in the full study protocol (Additional File 1). Main outcomes: Time to diagnosis of positive COVID-19 disease (defined by record of date of symptoms onset and confirmed by laboratory test) Randomisation: Participants will be randomised to either hydroxychloroquine dosed daily with weekly placebo, HCQ dosed weekly with daily placebo, or placebo dosed daily and weekly. Randomisation will be in a 3:3:2 ratio [hydroxychloroquine-(daily), hydroxychloroquine-(weekly), placebo], using stratified block randomisation. Random block sizes will be used, and stratification will be by study site. Blinding (masking): Participants and trial investigators consenting participants, delivering trial assessments and procedures will be blinded to intervention. Numbers to be randomised (sample size): A sufficient number of participants will be enrolled so that approximately 1000 participants in total will have data suitable for the primary statistical analysis. It is anticipated that approximately 1,200 participants will need to be enrolled in total, to allow for a 20% dropout over the period of the trial. This would result in approximately 450:450:300 participants randomised to hydroxychloroquine daily, hydroxychloroquine weekly+daily matched placebo or matched-placebo daily and weekly. Trial Status: V 1.0, 7th April 2020 EU Clinical Trials Register EudraCT Number: 2020-001331-26 Date of registration: 14th April 2020 Trial registered before first participant enrolment. Trial site is Cambridge University Hospitals NHS Foundation Trust. Recruitment started on 11th May 2020. It is anticipated that the trial will run for 12 months. The recruitment end date cannot yet be accurately predicted. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)

Correction to: ChemoPROphyLaxIs with hydroxychloroquine For covId-19 infeCtious disease (PROLIFIC) to prevent covid-19 infection in frontline healthcare workers: A structured summary of a study protocol for a randomised controlled trial.

An amendment to this paper has been published and can be accessed via the original article

Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers - a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale.

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives. Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972). It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4. At baseline (Visit 2) and during all post-dose visits (Visits 3-4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-NG-monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers

Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.

Abstract: Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two-thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA