Drug-free remission is a desirable goal in rheumatoid arthritis (RA) for both patients and clinicians. The aim of this post hoc analysis was to investigate whether clinical and magnetic resonance ...imaging (MRI) variables in patients with early RA who achieved remission with methotrexate and/or abatacept at 12 months could predict disease flare following treatment withdrawal.
In the AVERT study of abatacept in early RA, patients with low disease activity at month 12 entered a 12-month period with all treatment discontinued (withdrawal, WD). This post hoc analysis assessed predictors of disease flare at WD+6months (mo) and WD+12mo of patients with Disease Activity Score in 28 joints (DAS28)-defined remission (DAS28C-reactive protein (CRP) <2.6) at withdrawal using univariate and multivariable regression models. Predictors investigated included the Health Assessment Questionnaire-Disability Index (HAQ-DI), pain, Patient Global Assessment; MRI synovitis, erosion, bone edema, and combined (synovitis + bone edema) inflammation scores.
Remission was achieved by 172 patients; 100 (58%) and 113 (66%) patients had experienced a flare at WD+6mo and WD+12mo, respectively. In univariate analyses, higher HAQ-DI and MRI synovitis, erosion, bone edema, and combined inflammation scores at WD were identified as potential predictors of flare (P ≤ 0.01). In multivariable analysis, high scores at WD for HAQ-DI and MRI erosion were confirmed as independent predictors of flare at WD+6mo and WD+12mo (P < 0.01).
In patients with early RA achieving clinical remission, patient function (HAQ-DI), and MRI measures of bone damage (erosion) predicted disease flare 6 and 12 months after treatment withdrawal. These variables may help identify patients with early RA in clinical remission as candidates for successful treatment withdrawal.
ClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010).
Research suggests that the rotational dynamics of an object underpins our perception of its weight. We examine the generalisability of that account using a more ecologically valid way of manipulating ...an object’s mass distribution (mass concentrated either at the top, bottom, centre, near the edges or evenly distributed throughout the object), shape (cube or sphere), and lifting approach (lifting directly by the hand or indirectly using a handle or string). The results were in line with our predictions. An interaction effect was found where the mass distribution and lifting approach both associated with the lowest rotational dynamics made the stimulus appear lighter compared to other combinations. These findings demonstrate rotational dynamic effects in a more run-of-the-mill experience of weight perception than what has been demonstrated before using cumbersome stimuli.
The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer’s Disease. We have identified a novel non-canonical ...function of several autophagy proteins in the conjugation of LC3 to Rab5+, clathrin+ endosomes containing β-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from β-amyloid deposition.
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•LC3-associated endocytosis (LANDO) requires Rubicon and ATG5, but not FIP200•LANDO is required for recycling of Aβ receptors including TREM2 in microglia.•LANDO confers protection against Aβ deposition and murine Alzheimer’s disease (AD)•Microglial LANDO protects against neuronal loss and memory impairment in murine AD
An LC3-associated endocytosis pathway involved in the recycling of amyloid receptors is essential for the clearance of amyloid aggregates by microglia in a model of AD
Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. ...However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.
Trace-element concentrations in olivine and coexisting garnets included in diamonds from the Akwatia Mine (Ghana, West African Craton) were measured to show that olivine can provide similar ...information about equilibration temperature, diamond paragenesis and mantle processes as garnet. Trace-element systematics can be used to distinguish harzburgitic olivines from lherzolite ones: if Ca/Al ratios of olivine are below the mantle lherzolite trend (Ca/Al < 2.2), they are derived from a harzburgitic mantle source, and syngenetic garnets are without exception subcalcic G10 garnets. For harzburgitic olivines that cannot be identified this way, Na and Ca contents can be used: olivine inclusions with < 60 µg/g Na and Na/Al < 0.7 are all harzburgitic, whereas those with > 300 µg/g Ca or > 60 µg/g Na are lherzolitic. Conventional geothermobarometry indicates that Akwatia diamonds formed and resided close to a 39 mW/m
2
conductive geotherm. A similar value can be derived from Al in olivine geothermometry, with
T
Al-ol
ranging from 1020 to 1325 °C. Ni in garnet temperatures is on average somewhat higher (
T
Ni-grt
= 1115–1335 °C) and the correlation between the two thermometers is weak, which may be not only due to the large uncertainties in the calibrations, but also due to disequilibrium between inclusions from the same diamond. Calcium in olivine should not be used as a geothermobarometer for harzburgitic olivines, and often gives unrealistic
P
–
T
estimates for lherzolitic olivine as well. Diamond-hosted olivine inclusions indicate growth in an extremely depleted (low Ti, Ca, Na, high Cr#) environment with no residual clinopyroxene. They are distinct from olivines from mantle xenoliths which show higher, more variable Ti contents and lower Cr#. Hence, most olivine inclusions in Akwatia diamonds escaped the refertilisation processes that have affected most mantle xenoliths. Lherzolitic inclusions are probably the result of refertilisation after undergoing high-degree melting first. Trivalent cations appear to behave differently in harzburgitic diamond-hosted olivine inclusions than lherzolitic inclusions and olivine from mantle xenoliths. Some divalent chromium is predicted to be present in most olivine inclusions, which may explain high concentrations up to 0.16 wt% Cr
2
O
3
observed in some diamond inclusions. Strong heterogeneity of Cr, V and Al in several inclusions may also result in apparent high Cr contents, and is probably due to late-stage processes during exhumation. However, in general, diamond-hosted olivine inclusions have lower Cr and V than expected compared to mantle xenoliths. Reduced Na activity in depleted harzburgites limits the uptake of Cr, V and Sc via Na–M
3+
exchange. In contrast, Al partitioning in harzburgites is not significantly reduced compared to lherzolites, presumably due to uptake of Al in olivine by Al–Al exchange.
Droughts can affect invertebrate communities in wetlands, which can have bottom-up effects on the condition and survival of top predators. Shorebirds, key predators at coastal wetlands, have ...experienced widespread population declines and could be negatively affected by droughts. We explored, in detail, the effects of drought on multiple aspects of shorebird stopover and migration ecology by contrasting a year with average wet/dry conditions (2016) with a year with moderate drought (2017) at a major subarctic stopover site on southbound migration. We also examined the effects of drought on shorebird body mass during stopover across 14 years (historical: 1974–1982 and present-day: 2014–2018). For the detailed comparison of two years, in the year with moderate drought we documented lower invertebrate abundance at some sites, higher prey family richness in shorebird faecal samples, lower shorebird refuelling rates, shorter stopover durations for juveniles, and, for most species, a higher probability of making a subsequent stopover in North America after departing the subarctic, compared to the year with average wet/dry conditions. In the 14-year dataset, shorebird body mass tended to be lower in drier years. We show that even short-term, moderate drought conditions can negatively affect shorebird refuelling performance at coastal wetlands, which may carry-over to affect subsequent stopover decisions. Given shorebird population declines and predicted changes in the severity and duration of droughts with climate change, researchers should prioritize a better understanding of how droughts affect shorebird refuelling performance and survival.
OBJECTIVES: To test whether accelerated sarcopenia in older persons with high interleukin (IL)‐6 serum levels plays a role in the prospective association between inflammation and disability found in ...many studies.
DESIGN: Cohort study of older women with moderate to severe disability.
PARTICIPANTS: Six hundred twenty older women from the Women's Health and Aging Study in whom information on baseline IL‐6 serum level was available.
MEASUREMENTS: Self‐report of functional status, objective measures of walking performance, and knee extensor strength were assessed at baseline and over six semiannual follow‐up visits. Potential confounders were baseline age, race, body mass index, smoking, depression, and medical conditions.
RESULTS: At baseline, women with high IL‐6 were more often disabled and had lower walking speed. After adjusting for confounders, women in the highest IL‐6 tertile (IL‐6>3.10 pg/mL) were at higher risk of developing incident mobility disability (risk ratio (RR) = 1.50, 95% confidence interval (CI) = 1.01–2.27), disability in activities of daily living (RR = 1.41, 95% CI = 1.01–1.98), and severe limitation in walking (RR = 1.61, 95% CI = 1.09–2.38) and experienced steeper declines in walking speed (P < .001) than women in the lowest IL‐6 tertile (IL‐6 ≤1.78 pg/mL). Decline in knee extensor strength was also steeper, but differences across IL‐6 tertiles were not significant. After adjusting for change over time in knee extensor strength, the association between high IL‐6 and accelerated decline of physical function was no longer statistically significant.
CONCLUSIONS: Older women with high IL‐6 serum levels have a higher risk of developing physical disability and experience a steeper decline in walking ability than those with lower levels, which are partially explained by a parallel decline in muscle strength.
Paired beef short loins from US Choice (
n
=
48) and US Select (
n
=
48) carcasses were assigned to be dry or wet aged for 14, 21, 28 or 35
d. After aging, short loins were processed to determine ...retail yields and processing times. Upon completion of cutting tests, steaks were served to consumers to assess palatability characteristics. Retail cutting tests showed that dry-aged short loins had reduced yields and increased cutting times when compared to wet-aged short loins. Consumers were unable to determine differences between dry- and wet-aged steaks and for aging periods; however, USDA quality grade had a significant impact on consumer perception of palatability attributes.
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