Evaluate efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that binds and neutralises membrane and soluble B-cell activating factor (BAFF) versus placebo plus standard of care (SoC) ...in patients with systemic lupus erythematosus (SLE).
This phase III, 52-week study randomised 1164 patients with moderate-to-severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index ≥6 at baseline). Patients received SoC plus subcutaneous injections of tabalumab or placebo, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every two weeks (120 Q2W, n=387), 120 mg every four weeks (120 Q4W, n=389) or placebo Q2W (n=388).
proportion of patients achieving SLE Responder Index 5 (SRI-5) response at week 52.
Similar proportions of patients in each group achieved SRI-5 response at week 52 (120 Q2W: 31.8%; 120 Q4W: 35.2% and placebo: 29.3%). Key secondary endpoints were not met. In a sensitivity analysis not excluding patients who decreased antimalarials or immunosuppressants, SRI-5 response was achieved with 120 Q4W (37.0% vs 29.8% placebo; p=0.021), but not 120 Q2W (34.1%; p=0.171). Significant reductions in anti-dsDNA antibodies, increases in C3 and C4, and reductions in total B cells and immunoglobulins were observed with tabalumab. No differences were observed between treatment groups in percentage of deaths (120 Q2W: 0.8%; 120 Q4W: 0.5%; placebo: 0.5%), serious adverse events (AEs) (range 11.1-14.4%) or treatment-emergent AEs (range 81.1-82.3%).
Tabalumab had biological activity-changes in anti-dsDNA, complement, B cells and immunoglobulins-consistent with BAFF pathway inhibition. Key clinical efficacy endpoints did not achieve statistical significance. Safety profiles were similar with tabalumab and placebo.
NCT01196091.
The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human ...genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of ...Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild-type mice. Two factors contributed to this defect: (i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and (ii) impaired retrograde synaptic signaling by the endocannabinoid 2-arachidonoylglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB
, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment.
Abstract
We present the results of a survey of CO(1−0) emission in 14 infrared luminous dusty star-forming galaxies (DSFGs) at 2 <
z
< 4 with the NSF’s Karl G. Jansky Very Large Array. All sources ...are detected in
12
CO(1−0), with an angular resolution of ∼1″. Seven sources show extended and complex structure. We measure CO luminosities of
(
μ
)
L
CO
(
1
−
0
)
′
=
0.4
–
2.9
×
10
11
K km s
−1
pc
2
, and molecular gas masses of
(
μ
)
M
H
2
=
1.3
–
8.6
×
10
11
M
⊙
, where (
μ
) is the magnification factor. The derived molecular gas depletion times of
t
dep
= 40–460 Myr, cover the expected range of both normal star-forming galaxies and starbursts. Compared to the higher −
J
CO transitions previously observed for the same sources, we find CO temperature brightness ratios of
r
32/10
= 0.4–1.4,
r
43/10
= 0.4–1.7, and
r
54/10
= 0.3–1.3. We find a wide range of CO spectral line energy distributions (SLEDs), in agreement with other high-
z
DSFGs, with the exception of three sources that are most comparable to Cloverleaf and APM08279+5255. Based on radiative transfer modeling of the CO SLEDs we determine densities of
n
H
2
=
0.3
−
8.5
×
10
3
cm
−3
and temperatures of
T
K
= 100–200 K. Lastly, four sources are detected in the continuum, three have radio emission consistent with their infrared-derived star formation rates, while HerBS-70E requires an additional synchrotron radiation component from an active galactic nucleus. Overall, we find that even though the sample is similarly luminous in the infrared, by tracing the CO(1−0) emission a diversity of galaxy and excitation properties are revealed, demonstrating the importance of CO(1−0) observations in combination to higher-
J
transitions.
Viscoelastic properties of articular cartilage have been characterised at physiological frequencies. However, studies investigating the interaction between cartilage and subchondral bone and the ...influence of underlying bone histomorphometry on the viscoelasticity of cartilage are lacking.
Dynamic Mechanical Analysis (DMA) has been used to quantify the dynamic viscoelasticity of bovine tibial plateau osteochondral cores, over a frequency sweep from 1 to 88 Hz. Specimens (approximately aged between 18 and 30 months) were neither osteoarthritic nor otherwise compromised. A maximum nominal stress of 1.7 MPa was induced. Viscoelastic properties of cores have been compared with that of its components (cartilage and bone) in terms of the elastic and viscous components of both structural stiffness and material modulus. Micro-computed tomography scans were used to quantify the histomorphological properties of the subchondral bone.
Opposing frequency-dependent loss stiffness, and modulus, trends were witnessed for osteochondral tissues: for cartilage it increased logarithmically (P < 0.05); for bone it decreased logarithmically (P < 0.05). The storage stiffness of osteochondral cores was logarithmically frequency-dependent (P < 0.05), however, the loss stiffness was typically frequency-independent (P > 0.05). A linear relationship between the subchondral bone plate (SBP) thickness and cartilage thickness (P < 0.001) was identified. Cartilage loss modulus was linearly correlated to bone mineral density (BMD) (P < 0.05) and bone volume (P < 0.05).
The relationship between the subchondral bone histomorphometry and cartilage viscoelasticity (namely loss modulus) and thickness, have implications for the initiation and progression of osteoarthritis (OA) through an altered ability of cartilage to dissipate energy.
Seagrass (Zostera capricorni) tissue metal concentrations in Sydney estuary are some of the highest reported for urban environments. A strong declining metal (As, Co, Cr, Cu, Mn, Pb and Zn) ...concentration gradient in fine sediment from highly modified to the near-pristine estuarine environments was matched by a concurrent and statistically significant, moderately strong, relationship with declining metal concentrations for leaf, rhizomes and root tissue types. Leaf tissue more consistently expressed metal concentration uptake from sediment. Rhizome tissue contained the highest concentrations for all metals, except Mn, while leaf concentrations were higher for Cr and Zn and roots were more elevated in Cr and Pb. Tissue Cr, Pb and Zn were close to background for reference sites for leaves. Maximum tissue enrichment over background was 25, 19, 47 and 8 times for Cr, Cu, Pb and Zn. Bio-sediment accumulation factors were generally <1 for all metals.
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•Highest urban-estuarine seagrass (Z. capricorni) tissue metal concentrations•Seagrass tissue metal concentrations correlate to sedimentary metal gradient•Maximum tissue metal enrichment was 25, 19, 48, 8 times for Cr, Cu, Pb and Zn.•Bio-sediment accumulation factors were generally <1.•Leaf tissue expressed metal concentration in sediment better than root/rhizome.
To assess if posttraumatic stress disorder (PTSD), recognized as a common mental disorder in the general population and veteran samples, has a unique impact on comorbidity, disability, and suicidal ...behavior (after adjusting for other mental disorders, especially depression).
Data came from the Canadian Community Health Survey Cycle 1.2 (n = 36,984; age > or = 15 years; response rate 77%). All respondents were asked if they had been given a diagnosis of PTSD by a healthcare professional. A select number of mental disorders were assessed by the Composite International Diagnostic Interview. Chronic physical health conditions, measures of quality of life, disability, and suicidal behavior were also assessed.
The prevalence of PTSD as diagnosed by health professionals was 1.0% (95% CI = 0.90-1.15). After adjusting for sociodemographic factors and other mental disorders, PTSD remained significantly associated with several physical health problems including cardiovascular diseases, respiratory diseases, chronic pain conditions, gastrointestinal illnesses, and cancer. After adjusting for sociodemographic factors, mental disorders, and severity of physical disorders, PTSD was associated with suicide attempts, poor quality of life, and short- and long-term disability.
PTSD was uniquely associated with several physical disorders, disability, and suicidal behavior. Increased early recognition and treatment of PTSD are warranted.
The MiniBooNE Collaboration observes unexplained electronlike events in the reconstructed neutrino energy range from 200 to 475 MeV. With 6.46x10;{20} protons on target, 544 electronlike events are ...observed in this energy range, compared to an expectation of 415.2+/-43.4 events, corresponding to an excess of 128.8+/-20.4+/-38.3 events. The shape of the excess in several kinematic variables is consistent with being due to either nu_{e} and nuover _{e} charged-current scattering or nu_{mu} neutral-current scattering with a photon in the final state. No significant excess of events is observed in the reconstructed neutrino energy range from 475 to 1250 MeV, where 408 events are observed compared to an expectation of 385.9+/-35.7 events.
•Companion animal clinical signs and problem behaviors correlate with client caregiver burden.•Frequency of such problems strongly predicted client caregiver burden.•Modifiable client risk factors ...for burden included client reaction to the animal’s problems and client sense of control.
Caregiver burden, found in many clients with a chronically or terminally ill companion animal, has been linked to poorer psychosocial function in the client and greater utilization of non-billable veterinary services. To reduce client caregiver burden, its determinants must first be identified. This study examined if companion animal clinical signs and problem behaviors predict veterinary client burden within broader client- and patient-based risk factor models. Data were collected in two phases. Phase 1 included 238 companion animal owners, including those with a sick companion animal (n=119) and matched healthy controls (n=119) recruited online. Phase 2 was comprised of 602 small animal general veterinary hospital clients (n=95 with a sick dog or cat). Participants completed cross-sectional online assessments of caregiver burden, psychosocial resources (social support, active coping, self-mastery), and an item pool of companion animal clinical signs and problem behaviors.
Several signs/behaviors correlated with burden, most prominently: weakness, appearing sad/depressed or anxious, appearing to have pain/discomfort, change in personality, frequent urination, and excessive sleeping/lethargy. Within patient-based risk factors, caregiver burden was predicted by frequency of the companion animal’s signs/behaviors (P<.01). Within client-based factors, potentially modifiable factors of client reaction to the animal’s signs/behaviors (P=.01), and client sense of control (P<.04) predicted burden. Understanding burden may enhance veterinarian-client communication, and is important due to potential downstream effects of client burden, such as higher workload for the veterinarian. Supporting the client’s sense of control may help alleviate burden when amelioration of the companion animal’s presentation is not feasible.
The US Army suicide rate has increased sharply in recent years. Identifying significant predictors of Army suicides in Army and Department of Defense (DoD) administrative records might help focus ...prevention efforts and guide intervention content. Previous studies of administrative data, although documenting significant predictors, were based on limited samples and models. A career history perspective is used here to develop more textured models.
The analysis was carried out as part of the Historical Administrative Data Study (HADS) of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). De-identified data were combined across numerous Army and DoD administrative data systems for all Regular Army soldiers on active duty in 2004-2009. Multivariate associations of sociodemographics and Army career variables with suicide were examined in subgroups defined by time in service, rank and deployment history.
Several novel results were found that could have intervention implications. The most notable of these were significantly elevated suicide rates (69.6-80.0 suicides per 100 000 person-years compared with 18.5 suicides per 100 000 person-years in the total Army) among enlisted soldiers deployed either during their first year of service or with less than expected (based on time in service) junior enlisted rank; a substantially greater rise in suicide among women than men during deployment; and a protective effect of marriage against suicide only during deployment.
A career history approach produces several actionable insights missed in less textured analyses of administrative data predictors. Expansion of analyses to a richer set of predictors might help refine understanding of intervention implications.
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