Summary Background Mobile (cell) phone communication has been suggested as a method to improve delivery of health services. However, data on the effects of mobile health technology on patient ...outcomes in resource-limited settings are limited. We aimed to assess whether mobile phone communication between health-care workers and patients starting antiretroviral therapy in Kenya improved drug adherence and suppression of plasma HIV-1 RNA load. Methods WelTel Kenya1 was a multisite randomised clinical trial of HIV-infected adults initiating antiretroviral therapy (ART) in three clinics in Kenya. Patients were randomised (1:1) by simple randomisation with a random number generating program to a mobile phone short message service (SMS) intervention or standard care. Patients in the intervention group received weekly SMS messages from a clinic nurse and were required to respond within 48 h. Randomisation, laboratory assays, and analyses were done by investigators masked to treatment allocation; however, study participants and clinic staff were not masked to treatment. Primary outcomes were self-reported ART adherence (>95% of prescribed doses in the past 30 days at both 6 and 12 month follow-up visits) and plasma HIV-1 viral RNA load suppression (<400 copies per mL) at 12 months. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , NCT00830622. Findings Between May, 2007, and October, 2008, we randomly assigned 538 participants to the SMS intervention (n=273) or to standard care (n=265). Adherence to ART was reported in 168 of 273 patients receiving the SMS intervention compared with 132 of 265 in the control group (relative risk RR for non-adherence 0·81, 95% CI 0·69–0·94; p=0·006). Suppressed viral loads were reported in 156 of 273 patients in the SMS group and 128 of 265 in the control group, (RR for virologic failure 0·84, 95% CI 0·71–0·99; p=0·04). The number needed to treat (NNT) to achieve greater than 95% adherence was nine (95% CI 5·0–29·5) and the NNT to achieve viral load suppression was 11 (5·8–227·3). Interpretation Patients who received SMS support had significantly improved ART adherence and rates of viral suppression compared with the control individuals. Mobile phones might be effective tools to improve patient outcome in resource-limited settings. Funding US President's Emergency Plan for AIDS Relief.
Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a ...common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMOD477G, confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMOD477G medulloblastoma.
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► Itraconazole inhibits the activity of GDC-0449-resistant SMOD477G ► Itraconazole and ATO combine to block SMOD477G pathway activity in vitro ► Itraconazole and ATO inhibit SMOWT and SMOD477G tumor growth and prolong survival ► Itraconazole and ATO retain activity in all reported drug-resistant SMO mutants
Despite a continuous increase in algal genome sequencing, structural annotations of most algal genome assemblies remain unavailable. This pervasive scarcity of genome annotation has restricted ...rigorous investigation of these genomic resources and may have precipitated misleading biological interpretations. However, the annotation process for eukaryotic algal species is often challenging as genomic resources and transcriptomic evidence are not always available. To address this challenge, we benchmark the cutting-edge gene prediction methods that can be generalized for a broad range of non-model eukaryotes. Using the most accurate methods selected based on high-quality algal genomes, we predict structural annotations for 135 unannotated algal genomes. Using previously available genomic data pooled together with new data obtained in this study, we identified the core orthologous genes and the multi-gene phylogeny of eukaryotic algae, including of previously unexplored algal species. This study not only provides a benchmark for the use of structural annotation methods on a variety of non-model eukaryotes, but also compensates for missing data in the current spectrum of algal genomic resources. These results bring us one step closer to the full potential of eukaryotic algal genomics.
Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well ...known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n = 21). Tissue-resident memory (Trm) CD8
T cells expressing CD69
CD103
increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log
cells per swab respectively (p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69
CD103
CD8
T cells in the blood decrease post-vaccination. Similar increases in nasal CD8
CD69
CD103
T cells are observed, particularly following the second dose. CD4
cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8
T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months (p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.
The antiangiogenic agent bevacizumab has been approved for the treatment of non-small cell lung cancer (NSCLC), although the survival benefit associated with this agent is marginal, and toxicities ...and cost are substantial. A recent screen for selective inhibitors of endothelial cell proliferation identified the oral antifungal drug itraconazole as a novel agent with potential antiangiogenic activity. In this article, we define and characterize the antiangiogenic and anticancer activities of itraconazole in relevant preclinical models of angiogenesis and lung cancer. Itraconazole consistently showed potent, specific, and dose-dependent inhibition of endothelial cell proliferation, migration, and tube formation in response to both VEGF- and basic fibroblast growth factor-mediated angiogenic stimulation. In vivo, using primary xenograft models of human NSCLC, oral itraconazole showed single-agent growth-inhibitory activity associated with induction of tumor hypoxia-inducible factor 1 alpha expression and marked inhibition of tumor vascularity. Itraconazole significantly enhanced the antitumor efficacy of the chemotherapeutic agent cisplatin in the same model systems. Taken together, these data suggest that itraconazole has potent and selective inhibitory activity against multiple key aspects of tumor-associated angiogenesis in vitro and in vivo, and strongly support clinical translation of its use. Based on these observations, we have initiated a randomized phase II study comparing the efficacy of standard cytotoxic therapy with or without daily oral itraconazole in patients with recurrent metastatic NSCLC.
Sound speed and elastic constants measurements in solids and liquids are commonly performed using the ultrasound pulse-echo technique. Recent advances have expanded the use of this technique at ...numerous high pressure synchrotron beamlines and offline laboratories. However, the increased experimental throughput has revealed many limitations in existing software for handling the rapid measurement and the subsequent data-reduction. We report the development of a collection of computer programs for sound speed measurements using the ultrasound pulse-echo technique, compatible with stepped multi-frequency, as well as broadband-pulse, couplant-corrected methods. The programs provide a highly interactive graphical interface, enable efficient measurement, exploration and near real-time analysis of the ultrasound data, and contain features useful for working with samples under high pressure and/or high temperature. The included analysis programs can alleviate the time required for data reduction from hours to less than a minute, allowing users to make timely and informed decisions regarding the appropriate experimental parameters.
Abstract Nitric oxide (NO) and electromagnetic fields (EMF) have been extensively studied for their roles in neurobiology, particularly in regulating cerebral functions and synaptic plasticity. This ...study investigates the impact of EMFs on NO modulation and its subsequent effects on neurodevelopment, building upon prior research examining EMF exposure's consequences on Wistar albino rats. Rats were exposed perinatally to either tap water, 1 g/L of L‐arginine (LA) or 0.5 g/L of N ‐methylarginine (NMA). Half of the rats in each group were also exposed to a 7‐Hz square‐wave EMF at three separate intensities (5, 50 and 500 nT) for 2–14 days following birth. Animals were allowed to develop, and their brains were harvested later in adulthood (mean age = 568.17 days, SD = 162.73). Histological analyses were used to elucidate structural changes in key brain regions. All brains were stained with Toluidine Blue O (TBO), enabling the visualization of neurons. Neuronal counts were then conducted in specific regions of interest (e.g. hippocampus, cortices, amygdala and hypothalamus). Histological analyses revealed significant alterations in neuronal density in specific brain regions, particularly in response to EMF exposure and pharmacological interventions. Notable findings include a main EMF exposure effect where increased neuronal counts were observed in the secondary somatosensory cortex under low EMF intensities ( p < 0.001) and sex‐specific responses in the hippocampus, where a significant increase in neuronal counts was observed in the left CA3 region in female rats exposed to EMF compared to unexposed females ( t (18) = 2.371, p = 0.029). Additionally, a significant increase in neuronal counts in the right entorhinal cortex was seen in male rats exposed to EMF compared to unexposed males ( t (18) = 2.216, p = 0.040). These findings emphasize the complex interaction among sex, EMF exposure and pharmacological agents on neuronal dynamics across brain regions, highlighting the need for further research to identify underlying mechanisms and potential implications for cognitive function and neurological health in clinical and environmental contexts.
In vivo electrochemistry is a vital tool of neuroscience that allows for the detection, identification, and quantification of neurotransmitters, their metabolites, and other important analytes. One ...important goal of in vivo electrochemistry is a better understanding of progressive neurological disorders (e.g., Parkinson’s disease). A complete understanding of such disorders can only be achieved through a combination of acute (i.e., minutes to hours) and chronic (i.e., days or longer) experimentation. Chronic studies are more challenging because they require prolonged implantation of electrodes, which elicits an immune response, leading to glial encapsulation of the electrodes and altered electrode performance (i.e., biofouling). Biofouling leads to increased electrode impedance and reference electrode polarization, both of which diminish the selectivity and sensitivity of in vivo electrochemical measurements. The increased impedance factor has been successfully mitigated previously with the use of a counter electrode, but the challenge of reference electrode polarization remains. The commonly used Ag/AgCl reference electrode lacks the long-term potential stability in vivo required for chronic measurements. In addition, the cytotoxicity of Ag/AgCl adversely affects animal experimentation and prohibits implantation in humans, hindering translational research progress. Thus, a move toward biocompatible reference electrodes with superior chronic potential stability is necessary. Two qualifying materials, iridium oxide and boron-doped diamond, are introduced and discussed in terms of their electrochemical properties, biocompatibilities, fabrication methods, and applications. In vivo electrochemistry continues to advance toward more chronic experimentation in both animal models and humans, necessitating the utilization of biocompatible reference electrodes that should provide superior potential stability and allow for unprecedented chronic signal fidelity when used with a counter electrode for impedance mitigation.
Abstract
The High-Resolution Rapid Refresh (HRRR) is a convection-allowing implementation of the Advanced Research version of the Weather Research and Forecasting (WRF-ARW) Model with hourly data ...assimilation that covers the conterminous United States and Alaska and runs in real time at the NOAA/National Centers for Environmental Prediction (NCEP). Implemented operationally at NOAA/NCEP in 2014, the HRRR features 3-km horizontal grid spacing and frequent forecasts (hourly for CONUS and 3-hourly for Alaska). HRRR initialization is designed for optimal short-range forecast skill with a particular focus on the evolution of precipitating systems. Key components of the initialization are radar-reflectivity data assimilation, hybrid ensemble-variational assimilation of conventional weather observations, and a cloud analysis to initialize stratiform cloud layers. From this initial state, HRRR forecasts are produced out to 18 h every hour, and out to 48 h every 6 h, with boundary conditions provided by the Rapid Refresh system. Between 2014 and 2020, HRRR development was focused on reducing model bias errors and improving forecast realism and accuracy. Improved representation of the planetary boundary layer, subgrid-scale clouds, and land surface contributed extensively to overall HRRR improvements. The final version of the HRRR (HRRRv4), implemented in late 2020, also features hybrid data assimilation using flow-dependent covariances from a 3-km, 36-member ensemble (“HRRRDAS”) with explicit convective storms. HRRRv4 also includes prediction of wildfire smoke plumes. The HRRR provides a baseline capability for evaluating NOAA’s next-generation Rapid Refresh Forecast System, now under development.
Significance Statement
NOAA’s operational hourly updating, convection-allowing model, the High-Resolution Rapid Refresh (HRRR), is a key tool for short-range weather forecasting and situational awareness. Improvements in assimilation of weather observations, as well as in physics parameterizations, have led to improvements in simulated radar reflectivity and quantitative precipitation forecasts since the initial implementation of HRRR in September 2014. Other targeted development has focused on improved representation of the diurnal cycle of the planetary boundary layer, resulting in improved near-surface temperature and humidity forecasts. Additional physics and data assimilation changes have led to improved treatment of the development and erosion of low-level clouds, including subgrid-scale clouds. The final version of HRRR features storm-scale ensemble data assimilation and explicit prediction of wildfire smoke plumes.
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Molecular dynamics (MD) may be used to investigate the velocity dependence of both the microscopic and apparent dynamic contact angles (θm and θapp).
We use large-scale MD to explore ...the steady displacement of a water-like liquid bridge between two molecularly-smooth solid plates under the influence of an external force F0. A coarse-grained model of water reduces the computational demand and the solid-liquid affinity is varied to adjust the equilibrium contact angle θ0. Protocols are devised to measure θm and θapp as a function of contact-line velocity Ucl.
For all θ0, θm is velocity-dependent and consistent with the molecular-kinetic theory of dynamic wetting (MKT). However, θapp diverges from θm as F0 is increased, especially at the receding meniscus. The behavior of θapp follows that predicted by Voinov: (θapp)3 = (θm)3 + 9Ca·ln(L/Lm), where Ca is the capillary number and L and Lm are suitably-chosen macroscopic and microscopic length scales. For each θ0, there is a critical velocity Ucrit and contact angle θcrit at which θapp→0 and the receding meniscus deposits a liquid film. Setting θapp=0, θm=θcrit and Ucl=Ucrit in the Voinov equation yields the value of L/Lm. The predicted values of θapp then agree well with those measured from the simulations. Since θm obeys the MKT, we have, therefore, demonstrated the utility of the combined model of dynamic wetting proposed by Petrov and Petrov.
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