Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study ...in mild to moderate AD.
The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.
No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.
Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status.
Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.
The III–V semiconductor InGaAs is a key material for photonics because it provides optical emission and absorption in the 1.55 μm telecommunication wavelength window. However, InGaAs suffers from ...pronounced nonradiative effects associated with its surface states, which affect the performance of nanophotonic devices for optical interconnects, namely nanolasers and nanodetectors. This work reports the strong suppression of surface recombination of undoped InGaAs/InP nanostructured semiconductor pillars using a combination of ammonium sulfide, (NH4)2S, chemical treatment and silicon oxide, SiO x , coating. An 80-fold enhancement in the photoluminescence (PL) intensity of submicrometer pillars at a wavelength of 1550 nm is observed as compared with the unpassivated nanopillars. The PL decay time of ∼0.3 μm wide square nanopillars is dramatically increased from ∼100 ps to ∼25 ns after sulfur treatment and SiO x coating. The extremely long lifetimes reported here, to our knowledge the highest reported to date for undoped InGaAs nanostructures, are associated with a record-low surface recombination velocity of ∼260 cm/s. We also conclusively show that the SiO x capping layer plays an active role in the passivation. These results are crucial for the future development of high-performance nanoscale optoelectronic devices for applications in energy-efficient data optical links, single-photon sensing, and photovoltaics.
Seven of the best: A dynamic combinatorial library of polycatenated tetrahedra was prepared by complexation between a dynamic Fe4L6 tetrahedral cage, constructed from ligands containing an ...electron‐deficient naphthalenediimide core, and an electron‐rich aromatic crown ether, 1,5‐dinaphtho38crown‐10. The highest order species in the library is the tetrahedral 7catenane.
How the activity of populations of cortical neurons generates coordinated multijoint actions of the arm, wrist, and hand is poorly understood. This study combined multielectrode recording techniques ...with full arm motion capture to relate neural activity in primary motor cortex (M1) of macaques (Macaca mulatta) to arm, wrist, and hand postures during movement. We find that the firing rate of individual M1 neurons is typically modulated by the kinematics of multiple joints and that small, local ensembles of M1 neurons contain sufficient information to reconstruct 25 measured joint angles (representing an estimated 10 functionally independent degrees of freedom). Beyond showing that the spiking patterns of local M1 ensembles represent a rich set of naturalistic movements involving the entire upper limb, the results also suggest that achieving high-dimensional reach and grasp actions with neuroprosthetic devices may be possible using small intracortical arrays like those already being tested in human pilot clinical trials.
The common bed bug (Cimex lectularius L.) is a known pest and an obligate blood-feeding ectoparasite. Bed bugs can feed on warm-blooded animals including humans, bats, poultry, and rabbits, but no ...research has investigated the use of companion animals (canines and/or felines) as a blood source. This study investigates how long known host DNA could be detected in a bed bug and the prevalence of bed bugs feeding on companion animals. Laboratory-reared bed bugs were fed host blood to determine how long DNA of human, feline, canine, and rabbit blood could be detected up to 21 d postfeeding. Additionally, 228 bed bugs were collected from 12 apartments with pets (6: canine, 5: feline, and 1: canine and feline), characterized as engorged or unengorged, and then screened with host-specific primers to identify the bloodmeal. Host meals of human, rabbit, feline, and canine blood were detected up to 21 d after feeding laboratory strains. All bed bugs died after feeding on the canine blood, but DNA could be detected up to 21 d post feeding/death. Of the field-collected bed bugs analyzed, human DNA was amplified in 158 (69.3%) bed bugs, canine DNA amplified in 7 bed bugs (3.1%), and feline DNA amplified in 1 bed bug (0.4%). Results of this study suggest that bed bugs predominately feed on humans and rarely feed on companion animals when they cohabitate in low-income, high-rise apartments. Additionally, results from this study warrant future investigations into host use by bed bugs in different housing structures and socioeconomic environments.
Context: Resilience is the ability to deal with shocks and stresses, including the unknown and previously unimaginable, such as the Covid-19 crisis. Objective: This paper assesses (i) how different ...farming systems were exposed to the crisis, (ii) which resilience capacities were revealed and (iii) how resilience was enabled or constrained by the farming systems' social and institutional environment. Methods: The 11 farming systems included have been analysed since 2017. This allows a comparison of pre-Covid-19 findings and the Covid-19 crisis. Pre-Covid findings are from the SURE-Farm systematic sustainability and resilience assessment. For Covid-19 a special data collection was carried out during the early stage of lockdowns. Results and conclusions: Our case studies found limited impact of Covid-19 on the production and delivery of food and other agricultural products. This was due to either little exposure or the agile activation of robustness capacities of the farming systems in combination with an enabling institutional environment. Revealed capacities were mainly based on already existing connectedness among farmers and more broadly in value chains. Across cases, the experience of the crisis triggered reflexivity about the operation of the farming systems. Recurring topics were the need for shorter chains, more fairness towards farmers, and less dependence on migrant workers. However, actors in the farming systems and the enabling environment generally focused on the immediate issues and gave little real consideration to long-term implications and challenges. Hence, adaptive or transformative capacities were much less on display than coping capacities. The comparison with pre-Covid findings mostly showed similarities. If challenges, such as shortage of labour, already loomed before, they persisted during the crisis. Furthermore, the eminent role of resilience attributes was confirmed. In cases with high connectedness and diversity we found that these system characteristics contributed significantly to dealing with the crisis. Also the focus on coping capacities was already visible before the crisis. We are not sure yet whether the focus on short-term robustness just reflects the higher visibility and urgency of shocks compared to slow processes that undermine or threaten important system functions, or whether they betray an imbalance in resilience capacities at the expense of adaptability and transformability. Significance: Our analysis indicates that if transformations are required, e.g. to respond to concerns about transnational value chains and future pandemics from zoonosis, the transformative capacity of many farming systems needs to be actively enhanced through an enabling environment.
Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin ...receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc.
This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety.
Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment.
Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.
Aspergillus fumigatus is responsible for a disproportionate number of invasive mycosis cases relative to other common filamentous fungi. While many fungal factors critical for infection establishment ...are known, genes essential for disease persistence and progression are ill defined. We propose that fungal factors that promote navigation of the rapidly changing nutrient and structural landscape characteristic of disease progression represent untapped clinically relevant therapeutic targets. To this end, we find that A. fumigatus requires a carbon catabolite repression (CCR) mediated genetic network to support in vivo fungal fitness and disease progression. While CCR as mediated by the transcriptional repressor CreA is not required for pulmonary infection establishment, loss of CCR inhibits fungal metabolic plasticity and the ability to thrive in the dynamic infection microenvironment. Our results suggest a model whereby CCR in an environmental filamentous fungus is dispensable for initiation of pulmonary infection but essential for infection maintenance and disease progression. Conceptually, we argue these data provide a foundation for additional studies on fungal factors required to support fungal fitness and disease progression and term such genes and factors, DPFs (disease progression factors).
Aims. The HIFI instrument onboard Herschel has allowed high spectral resolution and sensitive observations of ground-state transitions of three molecular ions: the methylidyne cation CH+, its ...isotopologue 13CH+, and sulfanylium SH+. Because of their unique chemical properties, a comparative analysis of these cations provides essential clues to the link between the chemistry and dynamics of the diffuse interstellar medium. Methods. The CH+, 13CH+, and SH+ lines are observed in absorption towards the distant high-mass star-forming regions (SFRs) DR21(OH), G34.3+0.1, W31C, W33A, W49N, and W51, and towards two sources close to the Galactic centre, SgrB2(N) and SgrA*+50. All sight lines sample the diffuse interstellar matter along pathlengths of several kiloparsecs across the Galactic Plane. In order to compare the velocity structure of each species, the observed line profiles were deconvolved from the hyperfine structure of the SH+ transition and the CH+, 13CH+, and SH+ spectra were independently decomposed into Gaussian velocity components. To analyse the chemical composition of the foreground gas, all spectra were divided, in a second step, into velocity intervals over which the CH+, 13CH+, and SH+ column densities and abundances were derived. Results. SH+ is detected along all observed lines of sight, with a velocity structure close to that of CH+ and 13CH+. The linewidth distributions of the CH+, SH+, and 13CH+ Gaussian components are found to be similar. These distributions have the same mean (⟨Δυ⟩ ~ 4.2 km s-1) and standard deviation (σ(Δυ) ~ 1.5 km s-1). This mean value is also close to that of the linewidth distribution of the CH+ visible transitions detected in the solar neighbourhood. We show that the lack of absorption components narrower than 2 km s-1 is not an artefact caused by noise: the CH+, 13CH+, and SH+ line profiles are therefore statistically broader than those of most species detected in absorption in diffuse interstellar gas (e.g. HCO+, CH, or CN). The SH+/CH+ column density ratio observed in the components located away from the Galactic centre spans two orders of magnitude and correlates with the CH+ abundance. Conversely, the ratio observed in the components close to the Galactic centre varies over less than one order of magnitude with no apparent correlation with the CH+ abundance. The observed dynamical and chemical properties of SH+ and CH+ are proposed to trace the ubiquitous process of turbulent dissipation, in shocks or shears, in the diffuse ISM and the specific environment of the Galactic centre regions.
Aims. We describe the assignment of a previously unidentified interstellar absorption line to ArH+ and discuss its relevance in the context of hydride absorption in diffuse gas with a low H2 ...fraction. The confidence of the assignment to ArH+ is discussed, and the column densities are determined toward several lines of sight. The results are then discussed in the framework of chemical models, with the aim of explaining the observed column densities. Methods. We fitted the spectral lines with multiple velocity components, and determined column densities from the line-to-continuum ratio. The column densities of ArH+ were compared to those of other species, tracing interstellar medium (ISM) components with different H2 abundances. We constructed chemical models that take UV radiation and cosmic ray ionization into account. Results. Thanks to the detection of two isotopologues, 36ArH+ and 38ArH+, we are confident about the carrier assignment to ArH+. NeH+ is not detected with a limit of NeH+/ArH+ ≤ 0.1. The derived column densities agree well with the predictions of chemical models. ArH+ is a unique tracer of gas with a fractional H2 abundance of 10-4 − 10-3 and shows little correlation to H2O+, which traces gas with a fractional H2 abundance of ≈0.1. Conclusions. A careful analysis of variations in the ArH+, OH+, H2O+, and HF column densities promises to be a faithful tracer of the distribution of the H2 fractional abundance by providing unique information on a poorly known phase in the cycle of interstellar matter and on its transition from atomic diffuse gas to dense molecular gas traced by CO emission. Abundances of these species put strong observational constraints upon magnetohydrodynamical (MHD)simulations of the interstellar medium, and potentially could evolve into a tool characterizing the ISM. Paradoxically, the ArH+ molecule is a better tracer of almost purely atomic hydrogen gas than Hi itself, since Hi can also be present in gas with a significant molecular content, but ArH+ singles out gas that is >99.9% atomic.
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