Near-zero-field nuclear magnetic resonance

We investigate nuclear magnetic resonance (NMR) in near-zero-field, where the Zeeman interaction can be treated as a perturbation to the electron mediated scalar interaction (J-coupling). This is in stark contrast to the high field case, where heteronuclear J-couplings are normally treated as a small perturbation. We show that the presence of very small magnetic fields results in splitting of the zero-field NMR lines, imparting considerable additional information to the pure zero-field spectra. Experimental results are in good agreement with first-order perturbation theory and with full numerical simulation when perturbation theory breaks down. We present simple rules for understanding the splitting patterns in near-zero-field NMR, which can be applied to molecules with non-trivial spectra.Comment: 5 pages, 5 figure

Maternal thyroid function and child educational attainment: prospective cohort study

Objective: To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. Design: Prospective cohort study. Setting: Avon Longitudinal Study of Parents and Children cohort in the UK. Participants: 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). Exposures: Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. Main outcome measures: Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. Results: No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. Conclusions: Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement

Oblate-prolate transition in odd-mass light mercury isotopes

Anomalous isotope shifts in the chain of light Hg isotopes are investigated by using the Hartree-Fock-Bogoliubov method with the Skyrme SIII, SkI3 and SLy4 forces. The sharp increase in the mean-square radius of the odd mass $^{181-185}$Hg isotopes is well explained in terms of the transition from an oblate to a prolate shape in the ground state of these isotopes. We discuss the polarization energy of time-odd mean-field terms in relation to the blocked level by the odd neutron.Comment: 25 pages including 19 postscript figures; accepted for publication in Nuclear Physics

Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)

Olaparib; Ceralasertib; Triple-negative advanced breast cancerOlaparib; Ceralasertib; Càncer de mama avançat triple negatiuOlaparib; Ceralasertib; Cáncer de mama avanzado triple negativoPurpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. Patients and Methods: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1–7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. Results: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4–25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. Conclusions: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.This research was funded by the Stand Up to Cancer Campaign for Cancer Research UK (CRUK/15/010, C30746/A19505; to S. Martin, H. Johnson, L. Moretti) with additional support from AstraZeneca, Guardant Health, Bio-Rad and Asociación Española Contra el Cáncer (AECC, INVES20095LLOP; to A. Llop-Guevara). The ICR Clinical Trials and Statistics Unit is supported by the Cancer Research UK core programme grant (C1491/A25351; to L.S. Kilburn). This study represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, London, UK. In addition, plasmaMATCH is supported by the NIHR Manchester Clinical Research Facility at the Christie Hospital, Manchester, UK, the NIHR UCLH Clinical Research Facility at University College London Hospitals NHS Foundation Trust, London, UK, the Cancer Research UK Cambridge Centre, Cambridge Biomedical Research Centre (BRC-1215–20014) and Cambridge Experimental Cancer Medicine Centre, Cambridge, UK. The RAD51 analysis was supported with grants from the Spanish Association of Cancer Research and Instituto de Salud Carlos III (ERAPERMED2019–215, CPII19/00033, and INVES20095LLOP). plasmaMATCH is supported at participating sites in England by the NIHR Clinical Research Network, in Scotland by the Chief Scientist Office, and in Wales by Health and Care Research Wales

Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study) : study protocol for a randomized controlled trial

This study is funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate.BACKGROUND: Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial. METHODS/DESIGN: TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions. DISCUSSION: This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).Publisher PDFPeer reviewe

Toward onset prevention of cognitive decline in adults with Down syndrome (the TOP-COG study): study protocol for a randomized controlled trial.

BACKGROUND: Early-onset dementia is common in Down syndrome adults, who have trisomy 21. The amyloid precursor protein gene is on chromosome 21, and so is over-expressed in Down syndrome, leading to amyloid β (Aβ) over-production, a major upstream pathway leading to Alzheimer disease (AD). Statins (microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), have pleiotropic effects including potentially increasing brain amyloid clearance, making them plausible agents to reduce AD risk. Animal models, human observational studies, and small scale trials support this rationale, however, there are no AD primary prevention trials in Down syndrome adults. In this study we study aim to inform the design of a full-scale primary prevention trial. METHODS/DESIGN: TOP-COG is a feasibility and pilot double-blind randomized controlled trial (RCT), with a nested qualitative study, conducted in the general community. About 60 Down syndrome adults, aged ≥50 will be included. The intervention is oral simvastatin 40 mg at night for 12 months, versus placebo. The primary endpoint is recruitment and retention rates. Secondary endpoints are (1) tolerability and safety; (2) detection of the most sensitive neurocognitive instruments; (3) perceptions of Down syndrome adults and caregivers on whether to participate, and assessment experiences; (4) distributions of cognitive decline, adaptive behavior, general health/quality of life, service use, caregiver strain, and sample size implications; (5) whether Aβ42/Aβ40 is a cognitive decline biomarker. We will describe percentages recruited from each source, the number of contacts to achieve this, plus recruitment rate by general population size. We will calculate summary statistics with 90% confidence limits where appropriate, for each study outcome as a whole, by treatment group and in relation to baseline age, cognitive function, cholesterol and other characteristics. Changes over time will be summarized graphically. The sample size for a definitive RCT will be estimated under alternative assumptions. DISCUSSION: This study is important, as AD is a major problem for Down syndrome adults, for whom there are currently no effective preventions or treatments. It will also delineate the most suitable assessment instruments for this population. Recruitment of intellectually disabled adults is notoriously difficult, and we shall provide valuable information on this, informing future studies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN Register ID: ISRCTN67338640 (17 November 2011).This study is funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate.This is the final published version. It first appeared at http://www.trialsjournal.com/content/15/1/202

Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial.

BACKGROUND: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid β (Aβ, coded on chromosome 21) deposition and, therefore, delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs) on this issue. Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. METHODS: TOP-COG was a feasibility/pilot, double-blind RCT of 12 months simvastatin 40 mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E (APOE) ε4 allele status, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre randomisation and at 12 months post randomisation. Blood Aβ40/Aβ42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework Approach to determine recruitment motivators/barriers, and participation experience. RESULTS: We identified 181 (78 %) of the likely eligible Down syndrome population, and recruited 21 (11.6 %), from an area with a general population size of 3,135,974. Recruitment was highly labour-intensive. Thirteen (62 %) participants completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aβ40 levels changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. CONCLUSION: A full-scale RCT is feasible. It will need 37 % UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population. TRIAL REGISTRATION: ISRCTN67338640 .This study was funded by the Chief Scientist Office, Scottish Government Health Department (reference: CZH/4/626). JS is funded by the NHS Lothian R&D Directorate. The study was supported by Down Syndrome Scotland, and we thank them, and all members of the Trial Steering Committee and Data Management and Ethics Committee.This is the final version of the article. It first appeared from BioMed Central via https://doi.org/10.1186/s13063-016-1370-

Statistical Model for a Complete Supernova Equation of State

A statistical model for the equation of state (EOS) and the composition of supernova matter is presented with focus on the liquid-gas phase transition of nuclear matter. It consists of an ensemble of nuclei and interacting nucleons in nuclear statistical equilibrium. A relativistic mean field model is applied for the nucleons. The masses of the nuclei are taken from nuclear structure calculations which are based on the same nuclear Lagrangian. For known nuclei experimental data is used directly. Excluded volume effects are implemented in a thermodynamic consistent way so that the transition to uniform nuclear matter at large densities can be described. Thus the model can be applied at all densities relevant for supernova simulations, i.e. rho=10^5 - 10^15 g/cm^3, and it is possible to calculate a complete supernova EOS table. The model allows to investigate the role of shell effects, which lead to narrow-peaked distributions around the neutron magic numbers for low temperatures. At larger temperatures the distributions become broad. The significance of the statistical treatment and the nuclear distributions for the composition is shown. We find that the contribution of light clusters is very important and is only poorly represented by alpha-particles alone. The results for the EOS are systematically compared to two commonly used models for supernova matter which are based on the single nucleus approximation. Apart from the composition, in general only small differences of the different EOSs are found. The differences are most pronounced around the (low-density) liquid-gas phase transition line where the distribution of light and intermediate clusters has an important effect. Possible extensions and improvements of the model are discussed.Comment: 33 pages, 22 page

Parity Violating Measurements of Neutron Densities

Parity violating electron nucleus scattering is a clean and powerful tool for measuring the spatial distributions of neutrons in nuclei with unprecedented accuracy. Parity violation arises from the interference of electromagnetic and weak neutral amplitudes, and the $Z^0$ of the Standard Model couples primarily to neutrons at low $Q^2$. The data can be interpreted with as much confidence as electromagnetic scattering. After briefly reviewing the present theoretical and experimental knowledge of neutron densities, we discuss possible parity violation measurements, their theoretical interpretation, and applications. The experiments are feasible at existing facilities. We show that theoretical corrections are either small or well understood, which makes the interpretation clean. The quantitative relationship to atomic parity nonconservation observables is examined, and we show that the electron scattering asymmetries can be directly applied to atomic PNC because the observables have approximately the same dependence on nuclear shape.Comment: 38 pages, 7 ps figures, very minor changes, submitted to Phys. Rev.

An Association of Cancer Physicians' strategy for improving services and outcomes for cancer patients.

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.The ACP is very grateful to all of its members who have expressed views on the development of the strategy and to the sponsors of our workshops and publications, especially Cancer Research UK and Macmillan Cancer SupportThis is the final version of the article. It was first available from Cancer Intelligence via http://dx.doi.org/10.3332/ecancer.2016.60