An internet-based intervention with brief nurse support to manage obesity in primary care (POWeR+): a pragmatic, parallel-group, randomised controlled trial

Background The obesity epidemic has major public health consequences. Expert dietetic and behavioural counselling with intensive follow-up is effective, but resource requirements severely restrict widespread implementation in primary care, where most patients are managed. We aimed to estimate the effectiveness and cost-effectiveness of an internet-based behavioural intervention (POWeR+) combined with brief practice nurse support in primary care. Methods We did this pragmatic, parallel-group, randomised controlled trial at 56 primary care practices in central and south England. Eligible adults aged 18 years or older with a BMI of 30 kg/m2 or more (or ≥28 kg/m2 with hypertension, hypercholesterolaemia, or diabetes) registered online with POWeR+—a 24 session, web-based, weight management intervention lasting 6 months. After registration, the website automatically randomly assigned patients (1:1:1), via computer-generated random numbers, to receive evidence-based dietetic advice to swap foods for similar, but healthier, choices and increase fruit and vegetable intake, in addition to 6 monthly nurse follow-up (control group); web-based intervention and face-to-face nurse support (POWeR+Face-to-face [POWeR+F]; up to seven nurse contacts over 6 months); or web-based intervention and remote nurse support (POWeR+Remote [POWeR+R]; up to five emails or brief phone calls over 6 months). Participants and investigators were masked to group allocation at the point of randomisation; masking of participants was not possible after randomisation. The primary outcome was weight loss averaged over 12 months. We did a secondary analysis of weight to measure maintenance of 5% weight loss at months 6 and 12. We modelled the cost-effectiveness of each intervention. We did analysis by intention to treat, with multiple imputation for missing data. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN21244703. Findings Between Jan 30, 2013, and March 20, 2014, 818 participants were randomly assigned to the control group (n=279), the POWeR+F group (n=269), or the POWeR+R group (n=270). Weight loss averaged over 12 months was recorded in 666 (81%) participants. The control group lost almost 3 kg over 12 months (crude mean weight: baseline 104·38 kg [SD 21·11; n=279], 6 months 101·91 kg [19·35; n=136], 12 months 101·74 kg [19·57; n=227]). The primary imputed analysis showed that compared with the control group, patients in the POWeR+F group achieved an additional weight reduction of 1·5 kg (95% CI 0·6–2·4; p=0·001) averaged over 12 months, and patients in the POWeR+R group achieved an additional 1·3 kg (0·34–2·2; p=0·007). 21% of patients in the control group had maintained a clinically important 5% weight reduction at month 12, compared with 29% of patients in the POWeR+F group (risk ratio 1·56, 0·96–2·51; p=0·070) and 32% of patients in the POWeR+R group (1·82, 1·31–2·74; p=0·004). The incremental overall cost to the health service per kg weight lost with the POWeR+ interventions versus the control strategy was £18 (95% CI −129 to 195) for POWeR+F and –£25 (−268 to 157) for POWeR+R; the probability of being cost-effective at a threshold of £100 per kg lost was 88% and 98%, respectively. No adverse events were reported. Interpretation Weight loss can be maintained in some individuals by use of novel written material with occasional brief nurse follow-up. However, more people can maintain clinically important weight reductions with a web-based behavioural program and brief remote follow-up, with no increase in health service costs. Future research should assess the extent to which clinically important weight loss can be maintained beyond 1 year

‘Instead of fetching flowers, the youths brought in flakes of snow’: exploring extreme weather history through English parish registers

Parish registers provide organized, dated and located population data and as such, are routinely among the most frequently consulted documents within the holdings of county record offices and archives. Throughout history, extreme weather has had significant impacts on the church, its congregation, and local landscape. It is for these reasons that extreme weather events have been deemed worthy of official note by authors of many registers. Although isolated entries have been used as supporting evidence for the occurrence of a number of historic extreme weather events, the information that parish registers contain relating to weather history has not been studied in its own right. Parish register narratives add new events to existing chronologies of extreme weather events and contribute to our understanding of their impacts at the local level. As public and well used documents they also function to keep the memory of particular events alive. The examples in this paper cover a wide range of weather types, places, and time periods, also enabling recording practice to be explored. Finally, as the number of digitized registers increases, we highlight the risks of weather narratives being obscured, and reflect on how the weather history contained within might be systematically captured

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report

Objective The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set. Methods Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis. Results The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach. Conclusion The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78048/1/27580_ftp.pd

COMAP Early Science: VIII. A Joint Stacking Analysis with eBOSS Quasars

We present a new upper limit on the cosmic molecular gas density at $z=2.4-3.4$ obtained using the first year of observations from the CO Mapping Array Project (COMAP). COMAP data cubes are stacked on the 3D positions of 282 quasars selected from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) catalog, yielding a 95% upper limit for flux from CO(1-0) line emission of 0.210 Jy km/s. Depending on the assumptions made, this value can be interpreted as either an average CO line luminosity $L'_\mathrm{CO}$ of eBOSS quasars of $\leq 7.30\times10^{10}$ K km pc$^2$ s$^{-1}$, or an average molecular gas density $\rho_\mathrm{H_2}$ in regions of the universe containing a quasar of $\leq 2.02\times10^8$ M$_\odot$ cMpc$^{-3}$. The $L'_\mathrm{CO}$ upper limit falls among CO line luminosities obtained from individually-targeted quasars in the COMAP redshift range, and the $\rho_\mathrm{H_2}$ value is comparable to upper limits obtained from other Line Intensity Mapping (LIM) surveys and their joint analyses. Further, we forecast the values obtainable with the COMAP/eBOSS stack after the full 5-year COMAP Pathfinder survey. We predict that a detection is probable with this method, depending on the CO properties of the quasar sample. Based on these achieved sensitivities, we believe that this technique of stacking LIM data on the positions of traditional galaxy or quasar catalogs is extremely promising, both as a technique for investigating large galaxy catalogs efficiently at high redshift and as a technique for bolstering the sensitivity of LIM experiments, even with a fraction of their total expected survey data.Comment: 15 pages, 8 figures. To be submitted to Ap

COMAP Early Science: VIII. A Joint Stacking Analysis with eBOSS Quasars

We present a new upper limit on the cosmic molecular gas density at z = 2.4 − 3.4 obtained using the first year of observations from the CO Mapping Array Project (COMAP). COMAP data cubes are stacked on the 3D positions of 243 quasars selected from the Extended Baryon Oscillation SpectroscopicSurvey (eBOSS) catalog, yielding a 95% upper limit for flux from CO(1-0) line emission of 0.129 Jykm/s. Depending on the balance of the emission between the quasar host and its environment, this value can be interpreted as an average CO line luminosity L′CO of eBOSS quasars of ≤ 1.26 × 1011 K km pc2s−1, or an average molecular gas density ρH2 in regions of the universe containing a quasar of ≤ 1.52 × 108 M⊙ cMpc−3. The L′ CO upper limit falls among CO line luminosities obtained fromindividually-targeted quasars in the COMAP redshift range, and the ρH2 value is comparable to upper limits obtained from other Line Intensity Mapping (LIM) surveys and their joint analyses. Further, we forecast the values obtainable with the COMAP/eBOSS stack after the full 5-year COMAP Pathfinder survey. We predict that a detection is probable with this method, depending on the CO properties of the quasar sample. Based on the achieved sensitivity, we believe that this technique of stacking LIM data on the positions of traditional galaxy or quasar catalogs is extremely promising, both asa technique for investigating large galaxy catalogs efficiently at high redshift and as a technique for bolstering the sensitivity of LIM experiments, even with a fraction of their total expected survey data

2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative

Objective The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct “rheumatoid arthritis.” Results In the new criteria set, classification as “definite RA” is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct “rheumatoid arthritis.”Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78045/1/27584_ftp.pd

COMAP Early Science: VII. Prospects for CO Intensity Mapping at Reionization

We introduce COMAP-EoR, the next generation of the Carbon Monoxide Mapping Array Project aimed at extending CO intensity mapping to the Epoch of Reionization. COMAP-EoR supplements the existing 30 GHz COMAP Pathfinder with two additional 30 GHz instruments and a new 16 GHz receiver. This combination of frequencies will be able to simultaneously map CO(1--0) and CO(2--1) at reionization redshifts ($z\sim5-8$) in addition to providing a significant boost to the $z\sim3$ sensitivity of the Pathfinder. We examine a set of existing models of the EoR CO signal, and find power spectra spanning several orders of magnitude, highlighting our extreme ignorance about this period of cosmic history and the value of the COMAP-EoR measurement. We carry out the most detailed forecast to date of an intensity mapping cross-correlation, and find that five out of the six models we consider yield signal to noise ratios (S/N) $\gtrsim20$ for COMAP-EoR, with the brightest reaching a S/N above 400. We show that, for these models, COMAP-EoR can make a detailed measurement of the cosmic molecular gas history from $z\sim2-8$, as well as probe the population of faint, star-forming galaxies predicted by these models to be undetectable by traditional surveys. We show that, for the single model that does not predict numerous faint emitters, a COMAP-EoR-type measurement is required to rule out their existence. We briefly explore prospects for a third-generation Expanded Reionization Array (COMAP-ERA) capable of detecting the faintest models and characterizing the brightest signals in extreme detail.Comment: Paper 7 of 7 in series. 19 pages, 10 figures, to be submitted to Ap

An Analysis of Enzyme Kinetics Data for Mitochondrial DNA Strand Termination by Nucleoside Reverse Transcription Inhibitors

Nucleoside analogs used in antiretroviral treatment have been associated with mitochondrial toxicity. The polymerase-γ hypothesis states that this toxicity stems from the analogs' inhibition of the mitochondrial DNA polymerase (polymerase-γ) leading to mitochondrial DNA (mtDNA) depletion. We have constructed a computational model of the interaction of polymerase-γ with activated nucleoside and nucleotide analog drugs, based on experimentally measured reaction rates and base excision rates, together with the mtDNA genome size, the human mtDNA sequence, and mitochondrial dNTP concentrations. The model predicts an approximately 1000-fold difference in the activated drug concentration required for a 50% probability of mtDNA strand termination between the activated di-deoxy analogs d4T, ddC, and ddI (activated to ddA) and the activated forms of the analogs 3TC, TDF, AZT, FTC, and ABC. These predictions are supported by experimental and clinical data showing significantly greater mtDNA depletion in cell culture and patient samples caused by the di-deoxy analog drugs. For zidovudine (AZT) we calculated a very low mtDNA replication termination probability, in contrast to its reported mitochondrial toxicity in vitro and clinically. Therefore AZT mitochondrial toxicity is likely due to a mechanism that does not involve strand termination of mtDNA replication

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality