Speech rate reduction is a global speech therapy approach for speech deficits in Parkinson's disease (PD) that has the potential to result in changes across multiple speech subsystems. While the ...overall goal of rate reduction is usually improvements in speech intelligibility, not all people with PD benefit from this approach. Speech rate is often targeted as a means of improving articulatory precision, though less is known about rate-induced changes in other speech subsystems that could help or hinder communication. The purpose of this study was to quantify phonatory changes associated with speech rate modification across a broad range of speech rates from very slow to very fast in talkers with and without PD. Four speaker groups participated: younger and older healthy controls, and people with PD with and without deep brain stimulation of the subthalamic nucleus (STN-DBS). Talkers read aloud standardized sentences at 7 speech rates elicited using magnitude production: habitual, three slower rates, and three faster rates. Acoustic measures of speech intensity, cepstral peak prominence, and fundamental frequency were measured as a function of speech rate and group. Overall, slower rates of speech were associated with differential effects on phonation across the four groups. While all talkers spoke at a lower pitch in slow speech, younger talkers showed increases in speech intensity and cepstral peak prominence, while talkers with PD and STN-DBS showed the reverse pattern. Talkers with PD without STN-DBS and older healthy controls behaved in between these two extremes. At faster rates, all groups uniformly demonstrated increases in cepstral peak prominence. While speech rate reductions are intended to promote positive changes in articulation to compensate for speech deficits in dysarthria, the present results highlight that undesirable changes may be invoked across other subsystems, such as at the laryngeal level. In particular, talkers with STN-DBS, who often demonstrate speech deterioration following DBS surgery, demonstrated more phonatory detriments at slowed speech rates. Findings have implications for speech rate candidacy considerations and speech motor control processes in PD.
Novel types of data at the individual level and the ability to analyse them with artificial intelligence (AI) models have the potential to make cancer screening more efficient and cost-effective. Yet ...continued development of AI models to efficiently integrate an increasing number of data sources and the validation of AI models in diverse populations, including in randomised controlled trials, will be needed. Looking ahead, health-care systems could harness a shift towards more informative screening to improve efficiency and cost-effectiveness—with improved accuracy and outcomes at the individual and population levels.
Information on chest imaging in patients with suspected COVID-19 is presented. Chest imaging is not routinely recommended to diagnose coronavirus disease 2019 (COVID-19) in patients with mild ...features. In patients with risk factors for disease progression, chest radiography, together with clinical symptoms, may inform whether to follow up in the community or to refer to secondary care.
In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major ...barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4
T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti-PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4
T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4
T cells with inducible virus evaluated using the
limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV
sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti-PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti-PD-1 with other interventions to reduce the HIV reservoir.
OBSERVING THE NEXT GALACTIC SUPERNOVA Adams, Scott M; Kochanek, C S; Beacom, John F ...
The Astrophysical journal,
12/2013, Letnik:
778, Številka:
2
Journal Article
Recenzirano
Odprti dostop
No supernova (SN) in the Milky Way has been observed since the invention of the optical telescope, instruments for other wavelengths, neutrino detectors, or gravitational wave observatories. It would ...be a tragedy to miss the opportunity to fully characterize the next one. To aid preparations for its observations, we model the distance, extinction, and magnitude probability distributions of a successful Galactic core-collapse supernova (ccSN), its shock breakout radiation, and its massive star progenitor. We find that shock breakouts from failed ccSNe of red supergiants may be more observable than those of successful SNe due to their lower radiation temperatures. Based on our modeled observability, we find a Galactic ccSN rate of 3.2 super(+7.3) sub(-2.6) per century and a Galactic SN Ia rate of 1.4 super(+1.4) sub(-0.8) per century for a total Galactic SN rate of 4.6 super(+7.4) sub(-2.7) per century is needed to account for the SNe observed over the last millennium, which implies a Galactic star formation rate of 3.6 super(+8.3) sub(-3.0) M sub(middot in circle) yr super(-1).
Conjugation of poly(ethylene glycol) (PEG) to protein drugs (PEGylation) is increasingly utilized in the biotherapeutics field because it improves significantly the drugs' circulatory half-life, ...solubility, and shelf-life. The activity of a PEGylated drug depends on the number, size, and location of the attached PEG chain(s). This study introduces a 2D separation approach, including reversed-phase ultra-performance liquid chromatography (RP-UPLC) and ion mobility mass spectrometry (IM-MS), in order to determine the structural properties of the conjugates, as demonstrated for a PEGylated insulin sample that was prepared by random amine PEGylation. The UPLC dimension allowed separation based on polarity. Electrospray ionization (ESI) of the eluates followed by in-source dissociation (ISD) truncated the PEG chains and created insulin fragments that provided site-specific information based on whether they contained a marker at the potential conjugation sites. Separation of the latter fragments by size and charge in the orthogonal IM dimension (pseudo-4D UPLC-ISD-IM-MS approach) enabled clear detection and identification of the positional isomers formed upon PEGylation. The results showed a highly heterogeneous mixture of singly and multiply conjugated isomers plus unconjugated material. PEGylation was observed on all three possible attachment sites (ε-NH2 of LysB29, A- and B-chain N-termini). Each PEGylation site was validated by analysis of the same product after disulfide bond cleavage, so that the PEGylated A- and B- chain could be individually characterized with the same pseudo-4D UPLC-ISD-IM-MS method.
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•LC-MS is coupled with ion mobility (IM) to separate bioconjugate mixtures.•Separation is achieved in two dimensions by polarity and shape/charge.•Conjugation sites are revealed by adding in-source dissociation (ISD).•The multidimensional LC-ISD-IM-MS approach is validated with PEGylated insulin.•PEGylation sites are confirmed by LC-ISD-IM-MS analysis after disulfide reduction.
Insertion of a microelectrode into the brain to record/stimulate neurons damages neural tissue and blood vessels and initiates the brain’s wound healing response. Due to the large difference between ...the stiffness of neural tissue and microelectrode, brain micromotion also leads to neural tissue damage and associated local immune response. Over time, following implantation, the brain’s response to the tissue damage can result in microelectrode failure. Reducing the microelectrode’s cross-sectional dimensions to single-digit microns or using soft materials with elastic modulus close to that of the neural tissue are effective methods to alleviate the neural tissue damage and enhance microelectrode longevity. However, the increase in electrical impedance of the microelectrode caused by reducing the microelectrode contact site’s dimensions can decrease the signal-to-noise ratio. Most importantly, the reduced dimensions also lead to a reduction in the critical buckling force, which increases the microelectrode’s propensity to buckling during insertion. After discussing brain micromotion, the main source of neural tissue damage, surface modification of the microelectrode contact site is reviewed as a key method for addressing the increase in electrical impedance issue. The review then focuses on recent approaches to aiding insertion of flexible microelectrodes into the brain, including bending stiffness modification, effective length reduction, and application of a magnetic field to pull the electrode. An understanding of the advantages and drawbacks of the developed strategies offers a guide for dealing with the buckling phenomenon during implantation.
•A review of strategies for addressing microelectrode buckling during implantation.•Discussion of brain micromotion as the main cause of chronic neural tissue damage.•An overview of surface modification-based methods to reduce electrical impedance.•Recent approaches to aiding insertion of flexible microelectrodes into the brain.
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