MRI biomarker assessment of neuromuscular disease progression: a prospective observational cohort study

BACKGROUND: A substantial impediment to progress in trials of new therapies in neuromuscular disorders is the absence of responsive outcome measures that correlate with patient functional deficits and are sensitive to early disease processes. Irrespective of the primary molecular defect, neuromuscular disorder pathological processes include disturbance of intramuscular water distribution followed by intramuscular fat accumulation, both quantifiable by MRI. In pathologically distinct neuromuscular disorders, we aimed to determine the comparative responsiveness of MRI outcome measures over 1 year, the validity of MRI outcome measures by cross-sectional correlation against functionally relevant clinical measures, and the sensitivity of specific MRI indices to early muscle water changes before intramuscular fat accumulation beyond the healthy control range. METHODS: We did a prospective observational cohort study of patients with either Charcot-Marie-Tooth disease 1A or inclusion body myositis who were attending the inherited neuropathy or muscle clinics at the Medical Research Council (MRC) Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK. Genetic confirmation of the chromosome 17p11·2 duplication was required for Charcot-Marie-Tooth disease 1A, and classification as pathologically or clinically definite by MRC criteria was required for inclusion body myositis. Exclusion criteria were concomitant diseases and safety-related MRI contraindications. Healthy age-matched and sex-matched controls were also recruited. Assessments were done at baseline and 1 year. The MRI outcomes-fat fraction, transverse relaxation time (T2), and magnetisation transfer ratio (MTR)-were analysed during the 12-month follow-up, by measuring correlation with functionally relevant clinical measures, and for T2 and MTR, sensitivity in muscles with fat fraction less than the 95th percentile of the control group. FINDINGS: Between Jan 19, 2010, and July 7, 2011, we recruited 20 patients with Charcot-Marie-Tooth disease 1A, 20 patients with inclusion body myositis, and 29 healthy controls (allocated to one or both of the 20-participant matched-control subgroups). Whole muscle fat fraction increased significantly during the 12-month follow-up at calf level (mean absolute change 1·2%, 95% CI 0·5-1·9, p=0·002) but not thigh level (0·2%, -0·2 to 0·6, p=0·38) in patients with Charcot-Marie-Tooth disease 1A, and at calf level (2·6%, 1·3-4·0, p=0·002) and thigh level (3·3%, 1·8-4·9, p=0·0007) in patients with inclusion body myositis. Fat fraction correlated with the lower limb components of the inclusion body myositis functional rating score (ρ=-0·64, p=0·002) and the Charcot-Marie-Tooth examination score (ρ=0·63, p=0·003). Longitudinal T2 and MTR changed consistently with fat fraction but more variably. In muscles with a fat fraction lower than the control group 95th percentile, T2 was increased in patients compared with controls (regression coefficients: inclusion body myositis thigh 4·0 ms [SE 0·5], calf 3·5 ms [0·6]; Charcot-Marie-Tooth 1A thigh 1·0 ms [0·3], calf 2·0 ms [0·3]) and MTR reduced compared with controls (inclusion body myositis thigh -1·5 percentage units [pu; 0·2], calf -1·1 pu [0·2]; Charcot-Marie-Tooth 1A thigh -0·3 pu [0·1], calf -0·7 pu [0·1]). INTERPRETATION: MRI outcome measures can monitor intramuscular fat accumulation with high responsiveness, show validity by correlation with conventional functional measures, and detect muscle water changes preceding marked intramuscular fat accumulation. Confirmation of our results in further cohorts with these and other muscle-wasting disorders would suggest that MRI biomarkers might prove valuable in experimental trials. FUNDING: Medical Research Council UK

Direct determination of the air-sea CO₂ gas transfer velocity in Arctic sea-ice regions

The Arctic Ocean is an important sink for atmospheric CO₂. The impact of decreasing sea-ice extent and expanding marginal ice zones on Arctic air-sea CO₂ exchange depends on the rate of gas transfer in the presence of sea ice. Sea ice acts to limit air-sea gas exchange by reducing contact between air and water, but is also hypothesised to enhance gas transfer rates across surrounding open water surfaces through physical processes such as increased surface-ocean turbulence from ice-water shear and ice-edge form drag. Here we present the first direct determination of the CO₂ air-sea gas transfer velocity in a wide range of Arctic sea-ice conditions. We show that the gas transfer velocity increases near-linearly with decreasing sea-ice concentration. We also show that previous modeling approaches overestimate gas transfer rates in sea-ice regions

The social geography of unmarried cohabitation in the USA, 2007-2011

US studies of marriage and cohabitation have mainly highlighted the social and racial differentials as they were observed in cross-sections, and have as a result essentially focused on the "pattern of disadvantage". The evolution of such social differentials over time and space reveals that this pattern of disadvantage has clearly persisted, but that it is far from covering the whole story. Historically, there has been a major contribution to the rise of cohabitation by white college students, and later on young white adults with higher education continued to start unions via cohabitation to ever increasing degrees. Only, they seem to move into marriage to a greater extent later on in life than other population segments. Also, the religious affiliation matters greatly: Mormons and evangelical Christians have resisted the current trends. Furthermore this effect is not only operating at the individual but at the contextual level as well. Conversely, even after controls for competing socio-economic explanations, residence in areas (either counties or PUMA-areas) with a Democratic voting pattern is related to higher cohabitation probabilities. And, finally, different legal contexts at the level of States also significantly contributed to the emergence of strong spatial contrasts. Hence, there is a concurrence of several factors shaping the present differentiations, and the rise of secular and liberal attitudes, i.e. the "ethics revolution", is equally a part of the explanation

Has the 'Fast-Track' referral system affected the route of presentation and/or clinical outcomes in patients with colorectal cancer?

Background: The aim of this study is to determine whether the 'Fast-Track' referral system has changed the route by which patients present with colorectal cancer (CRC) and whether the route of presentation has any effect on clinical outcome. Methods: A retrospective cohort study of patients diagnosed with CRC under the care of two consultant colorectal surgeons between April 2006 and December 2012. The route by which patients presented was categorised as Fast-Track (FT), non-Fast-Track (non-FT) or acute. Outcome variables were operative intent, disease stage and 2- and 5-year survival. Results: A total of 558 patients were identified. One hundred ninety-seven patients (35.3%) were referred as FT, 108 (19.4%) presented acutely and 253 patients (45.3%) presented via other routes (non-FT). Over the study period, the route of presentation did not change significantly (P=0.135). There was no significant difference between FT and non-FT groups in terms of the proportion of patients undergoing potentially curative surgery (70.6 vs 74.3%, P=0.092) or with node-negative disease (48.2 vs 52.2%, P=0.796) nor was there any difference in 2-year or 5-year survival (74.1 vs 73.9%, P=0.837 and 52.3 vs 53.8%, P=0.889, respectively). Patients who presented acutely were less likely to undergo curative resection, had more advanced disease and had worse 2- and 5-year survival. Conclusions: The Fast-Track referral system has not affected the route by which patients present with CRC nor has it had any effect on clinical outcomes. Alternative strategies are required if the desired improvement in outcomes is to be achieved

Widespread forest vertebrate extinctions induced by a mega hydroelectric dam in lowland Amazonia

Mega hydropower projects in tropical forests pose a major emergent threat to terrestrial and freshwater biodiversity worldwide. Despite the unprecedented number of existing, underconstruction and planned hydroelectric dams in lowland tropical forests, long-term effects on biodiversity have yet to be evaluated. We examine how medium and large-bodied assemblages of terrestrial and arboreal vertebrates (including 35 mammal, bird and tortoise species) responded to the drastic 26-year post-isolation history of archipelagic alteration in landscape structure and habitat quality in a major hydroelectric reservoir of Central Amazonia. The Balbina Hydroelectric Dam inundated 3,129 km2 of primary forests, simultaneously isolating 3,546 land-bridge islands. We conducted intensive biodiversity surveys at 37 of those islands and three adjacent continuous forests using a combination of four survey techniques, and detected strong forest habitat area effects in explaining patterns of vertebrate extinction. Beyond clear area effects, edge-mediated surface fire disturbance was the most important additional driver of species loss, particularly in islands smaller than 10 ha. Based on species-area models, we predict that only 0.7% of all islands now harbor a species-rich vertebrate assemblage consisting of ≥80% of all species. We highlight the colossal erosion in vertebrate diversity driven by a man-made dam and show that the biodiversity impacts of mega dams in lowland tropical forest regions have been severely overlooked. The geopolitical strategy to deploy many more large hydropower infrastructure projects in regions like lowland Amazonia should be urgently reassessed, and we strongly advise that long-term biodiversity impacts should be explicitly included in pre-approval environmental impact assessments

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE(TM) study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE(TM) study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%), and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs. ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared to patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs. later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations

Shipborne eddy covariance observations of methane fluxes constrain Arctic sea emissions

We demonstrate direct eddy covariance (EC) observations of methane (CH4) fluxes between the sea and atmosphere from an icebreaker in the eastern Arctic Ocean. EC-derived CH4 emissions averaged 4.58, 1.74, and 0.14 mg m−2 day−1 in the Laptev, East Siberian, and Chukchi seas, respectively, corresponding to annual sea-wide fluxes of 0.83, 0.62, and 0.03 Tg year−1. These EC results answer concerns that previous diffusive emission estimates, which excluded bubbling, may underestimate total emissions. We assert that bubbling dominates sea-air CH4 fluxes in only small constrained areas: A ~100-m2 area of the East Siberian Sea showed sea-air CH4 fluxes exceeding 600 mg m−2 day−1; in a similarly sized area of the Laptev Sea, peak CH4 fluxes were ~170 mg m−2 day−1. Calculating additional emissions below the noise level of our EC system suggests total ESAS CH4 emissions of 3.02 Tg year−1, closely matching an earlier diffusive emission estimate of 2.9 Tg year−1

Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular Size in Aging Mice

The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant U01 CA164337)National Institutes of Health (U.S.) (Grant RO1CA108854

Sleep Hygiene and Light Exposure Can Improve Performance Following Long-Haul Air Travel.

PURPOSE:To assess the efficacy of a combined light exposure and sleep hygiene intervention to improve team-sport performance following eastward long-haul transmeridian travel. METHODS:Twenty physically trained males underwent testing at 09:00 and 17:00 hours local time on 4 consecutive days at home (baseline) and the first 4 days following 21 hours of air travel east across 8 time zones. In a randomized, matched-pairs design, participants traveled with (INT; n = 10) or without (CON; n = 10) a light exposure and sleep hygiene intervention. Performance was assessed via countermovement jump, 20-m sprint, T test, and Yo-Yo Intermittent Recovery Level 1 tests, together with perceptual measures of jet lag, fatigue, mood, and motivation. Sleep was measured using wrist activity monitors in conjunction with self-report diaries. RESULTS:Magnitude-based inference and standardized effect-size analysis indicated there was a very likely improvement in the mean change in countermovement jump peak power (effect size 1.10, ±0.55), and likely improvement in 5-m (0.54, ±0.67) and 20-m (0.74, ±0.71) sprint time in INT compared with CON across the 4 days posttravel. Sleep duration was most likely greater in INT both during travel (1.61, ±0.82) and across the 4 nights following travel (1.28, ±0.58) compared with CON. Finally, perceived mood and motivation were likely worse (0.73, ±0.88 and 0.63, ±0.87) across the 4 days posttravel in CON compared with INT. CONCLUSIONS:Combined light exposure and sleep hygiene improved speed and power but not intermittent-sprint performance up to 96 hours following long-haul transmeridian travel. The reduction of sleep disruption during and following travel is a likely contributor to improved performance