Showing papers by "University of Texas at Austin published in 2021"

Engineering precision nanoparticles for drug delivery

Abstract: In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers - systemic, microenvironmental and cellular - that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1 In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals) These rare variants provide insights into mutational processes and recent human evolutionary history The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 001% The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history

EnlightenGAN: Deep Light Enhancement Without Paired Supervision

Abstract: Deep learning-based methods have achieved remarkable success in image restoration and enhancement, but are they still competitive when there is a lack of paired training data? As one such example, this paper explores the low-light image enhancement problem, where in practice it is extremely challenging to simultaneously take a low-light and a normal-light photo of the same visual scene. We propose a highly effective unsupervised generative adversarial network, dubbed EnlightenGAN , that can be trained without low/normal-light image pairs, yet proves to generalize very well on various real-world test images. Instead of supervising the learning using ground truth data, we propose to regularize the unpaired training using the information extracted from the input itself, and benchmark a series of innovations for the low-light image enhancement problem, including a global-local discriminator structure, a self-regularized perceptual loss fusion, and the attention mechanism. Through extensive experiments, our proposed approach outperforms recent methods under a variety of metrics in terms of visual quality and subjective user study. Thanks to the great flexibility brought by unpaired training, EnlightenGAN is demonstrated to be easily adaptable to enhancing real-world images from various domains. Our codes and pre-trained models are available at: https://github.com/VITA-Group/EnlightenGAN .

Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy

Abstract: The cystine/glutamate antiporter SLC7A11 (also commonly known as xCT) functions to import cystine for glutathione biosynthesis and antioxidant defense and is overexpressed in multiple human cancers. Recent studies revealed that SLC7A11 overexpression promotes tumor growth partly through suppressing ferroptosis, a form of regulated cell death induced by excessive lipid peroxidation. However, cancer cells with high expression of SLC7A11 (SLC7A11high) also have to endure the significant cost associated with SLC7A11-mediated metabolic reprogramming, leading to glucose- and glutamine-dependency in SLC7A11high cancer cells, which presents potential metabolic vulnerabilities for therapeutic targeting in SLC7A11high cancer. In this review, we summarize diverse regulatory mechanisms of SLC7A11 in cancer, discuss ferroptosis-dependent and -independent functions of SLC7A11 in promoting tumor development, explore the mechanistic basis of SLC7A11-induced nutrient dependency in cancer cells, and conceptualize therapeutic strategies to target SLC7A11 in cancer treatment. This review will provide the foundation for further understanding SLC7A11 in ferroptosis, nutrient dependency, and tumor biology and for developing novel effective cancer therapies.

Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.

Abstract: Severe acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.

State of the Art and Prospects for Halide Perovskite Nanocrystals.

Abstract: Metal-halide perovskites have rapidly emerged as one of the most promising materials of the 21st century, with many exciting properties and great potential for a broad range of applications, from photovoltaics to optoelectronics and photocatalysis. The ease with which metal-halide perovskites can be synthesized in the form of brightly luminescent colloidal nanocrystals, as well as their tunable and intriguing optical and electronic properties, has attracted researchers from different disciplines of science and technology. In the last few years, there has been a significant progress in the shape-controlled synthesis of perovskite nanocrystals and understanding of their properties and applications. In this comprehensive review, researchers having expertise in different fields (chemistry, physics, and device engineering) of metal-halide perovskite nanocrystals have joined together to provide a state of the art overview and future prospects of metal-halide perovskite nanocrystal research.

Population Properties of Compact Objects from the Second LIGO-Virgo Gravitational-Wave Transient Catalog

Abstract: We report on the population of 47 compact binary mergers detected with a false-alarm rate of 0.01 are dynamically assembled. Third, we estimate merger rates, finding RBBH = 23.9-+8.614.3 Gpc-3 yr-1 for BBHs and RBNS = 320-+240490 Gpc-3 yr-1 for binary neutron stars. We find that the BBH rate likely increases with redshift (85% credibility) but not faster than the star formation rate (86% credibility). Additionally, we examine recent exceptional events in the context of our population models, finding that the asymmetric masses of GW190412 and the high component masses of GW190521 are consistent with our models, but the low secondary mass of GW190814 makes it an outlier.

DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer.

Abstract: Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism1-4. Glutathione peroxidase 4 (GPX4)5,6 and ferroptosis suppressor protein 1 (FSP1)7,8 constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate-the substrate and product of dihydroorotate dehydrogenase (DHODH)-attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.

Extra storage capacity in transition metal oxide lithium-ion batteries revealed by in situ magnetometry.

Abstract: In lithium-ion batteries (LIBs), many promising electrodes that are based on transition metal oxides exhibit anomalously high storage capacities beyond their theoretical values. Although this phenomenon has been widely reported, the underlying physicochemical mechanism in such materials remains elusive and is still a matter of debate. In this work, we use in situ magnetometry to demonstrate the existence of strong surface capacitance on metal nanoparticles, and to show that a large number of spin-polarized electrons can be stored in the already-reduced metallic nanoparticles (that are formed during discharge at low potentials in transition metal oxide LIBs), which is consistent with a space charge mechanism. Through quantification of the surface capacitance by the variation in magnetism, we further show that this charge capacity of the surface is the dominant source of the extra capacity in the Fe3O4/Li model system, and that it also exists in CoO, NiO, FeF2 and Fe2N systems. The space charge mechanism revealed by in situ magnetometry can therefore be generalized to a broad range of transition metal compounds for which a large electron density of states is accessible, and provides pivotal guidance for creating advanced energy storage systems.

Material-structure-performance integrated laser-metal additive manufacturing.

Abstract: BACKGROUND Metallic components are the cornerstone of modern industries such as aviation, aerospace, automobile manufacturing, and energy production. The stringent requirements for high-performance metallic components impede the optimization of materials selection and manufacturing. Laser-based additive manufacturing (AM) is a key strategic technology for technological innovation and industrial sustainability. As the number of applications increases, so do the scientific and technological challenges. Because laser AM has domain-by-domain (e.g., point-by-point, line-by-line, and layer-by-layer) localized forming characteristics, the requisite for printing process and performance control encompasses more than six orders of magnitude, from the microstructure (nanometer- to micrometer-scale) to macroscale structure and performance of components (millimeter- to meter-scale). The traditional route of laser-metal AM follows a typical “series mode” from design to build, resulting in a cumbersome trial-and-error methodology that creates challenges for obtaining high-performance goals. ADVANCES We propose a holistic concept of material-structure-performance integrated additive manufacturing (MSPI-AM) to cope with the extensive challenges of AM. We define MSPI-AM as a one-step AM production of an integral metallic component by integrating multimaterial layout and innovative structures, with an aim to proactively achieve the designed high performance and multifunctionality. Driven by the performance or function to be realized, the MSPI-AM methodology enables the design of multiple materials, new structures, and corresponding printing processes in parallel and emphasizes their mutual compatibility, providing a systematic solution to the existing challenges for laser-metal AM. MSPI-AM is defined by two methodological ideas: “the right materials printed in the right positions” and “unique structures printed for unique functions.” The increasingly creative methods for engineering both micro- and macrostructures within single printed components have led to the use of AM to produce more complicated structures with multimaterials. It is now feasible to design and print multimaterial components with spatially varying microstructures and properties (e.g., nanocomposites, in situ composites, and gradient materials), further enabling the integration of functional structures with electronics within the volume of a laser-printed monolithic part. These complicated structures (e.g., integral topology optimization structures, biomimetic structures learned from nature, and multiscale hierarchical lattice or cellular structures) have led to breakthroughs in both mechanical performance and physical/chemical functionality. Proactive realization of high performance and multifunctionality requires cross-scale coordination mechanisms (i.e., from the nano/microscale to the macroscale). OUTLOOK Our MSPI-AM continues to develop into a practical methodology that contributes to the high performance and multifunctionality goals of AM. Many opportunities exist to enhance MSPI-AM. MSPI-AM relies on a more digitized material and structure development and printing, which could be accomplished by considering different paradigms for AM materials discovery with the Materials Genome Initiative, standardization of formats for digitizing materials and structures to accelerate data aggregation, and a systematic printability database to enhance autonomous decision-making of printers. MSPI-oriented AM becomes more intelligent in processes and production, with the integration of intelligent detection, sensing and monitoring, big-data statistics and analytics, machine learning, and digital twins. MSPI-AM further calls for more hybrid approaches to yield the final high-performance/multifunctional achievements, with more versatile materials selection and more comprehensive integration of virtual manufacturing and real production to navigate more complex printing. We hope that MSPI-AM can become a key strategy for the sustainable development of AM technologies. Download high-res image Open in new tab Download Powerpoint Material-structure-performance integrated additive manufacturing (MSPI-AM). Versatile designed materials and innovative structures are simultaneously printed within an integral metallic component to yield high performance and multifunctionality, integrating in parallel the core elements of material, structure, process, and performance and a large number of related coupling elements and future potential elements to enhance the multifunctionality of printed components and the maturity and sustainability of laser AM technologies.

Observation of Gravitational Waves from Two Neutron Star–Black Hole Coalescences

Abstract: We report the observation of gravitational waves from two compact binary coalescences in LIGO’s and Virgo’s third observing run with properties consistent with neutron star–black hole (NSBH) binaries. The two events are named GW200105_162426 and GW200115_042309, abbreviated as GW200105 and GW200115; the first was observed by LIGO Livingston and Virgo and the second by all three LIGO–Virgo detectors. The source of GW200105 has component masses 8.9−1.5+1.2 and 1.9−0.2+0.3M⊙ , whereas the source of GW200115 has component masses 5.7−2.1+1.8 and 1.5−0.3+0.7M⊙ (all measurements quoted at the 90% credible level). The probability that the secondary’s mass is below the maximal mass of a neutron star is 89%–96% and 87%–98%, respectively, for GW200105 and GW200115, with the ranges arising from different astrophysical assumptions. The source luminosity distances are 280−110+110 and 300−100+150Mpc , respectively. The magnitude of the primary spin of GW200105 is less than 0.23 at the 90% credible level, and its orientation is unconstrained. For GW200115, the primary spin has a negative spin projection onto the orbital angular momentum at 88% probability. We are unable to constrain the spin or tidal deformation of the secondary component for either event. We infer an NSBH merger rate density of 45−33+75Gpc−3yr−1 when assuming that GW200105 and GW200115 are representative of the NSBH population or 130−69+112Gpc−3yr−1 under the assumption of a broader distribution of component masses.

Origin of the heaviest elements: The rapid neutron-capture process

Abstract: The production of about half of the heavy elements found in nature is assigned to a specific astrophysical nucleosynthesis process: the rapid neutron capture process (r-process). Although this idea has been postulated more than six decades ago, the full understanding faces two types of uncertainties/open questions: (a) The nucleosynthesis path in the nuclear chart runs close to the neutron-drip line, where presently only limited experimental information is available, and one has to rely strongly on theoretical predictions for nuclear properties. (b) While for many years the occurrence of the r-process has been associated with supernovae, more recent studies have cast substantial doubts on this environment. Alternative scenarios include the mergers of neutron stars, neutron-star black hole mergers, but possibly also rare classes of supernovae as well as hypernovae/collapsars with polar jet ejecta and also accretion disk outflows related to the collapse of fast rotating massive stars with high magnetic fields. Stellar r-process abundance observations, have provided insights into, and constraints on the frequency of and conditions in the responsible stellar production sites. One of them, neutron star mergers, was just identified and related to the Gravitational Wave event GW170817. High resolution observations, increasingly more precise due to improved experimental atomic data, have been particularly important in defining the heavy element abundance patterns of the old halo stars, and thus determining the extent, and nature, of the earliest nucleosynthesis in our Galaxy. Combining new results and important breakthroughs in the related nuclear, atomic and astronomical fields of science, this review attempts to provide an answer to the question "How Were the Elements from Iron to Uranium Made?" (Abridged)

The impact of vaccination on COVID-19 outbreaks in the United States.

Abstract: Background Global vaccine development efforts have been accelerated in response to the devastating COVID-19 pandemic. We evaluated the impact of a 2-dose COVID-19 vaccination campaign on reducing incidence, hospitalizations, and deaths in the United States (US). Methods We developed an agent-based model of SARS-CoV-2 transmission and parameterized it with US demographics and age-specific COVID-19 outcomes. Healthcare workers and high-risk individuals were prioritized for vaccination, while children under 18 years of age were not vaccinated. We considered a vaccine efficacy of 95% against disease following 2 doses administered 21 days apart achieving 40% vaccine coverage of the overall population within 284 days. We varied vaccine efficacy against infection, and specified 10% pre-existing population immunity for the base-case scenario. The model was calibrated to an effective reproduction number of 1.2, accounting for current non-pharmaceutical interventions in the US. Results Vaccination reduced the overall attack rate to 4.6% (95% CrI: 4.3% - 5.0%) from 9.0% (95% CrI: 8.4% - 9.4%) without vaccination, over 300 days. The highest relative reduction (54-62%) was observed among individuals aged 65 and older. Vaccination markedly reduced adverse outcomes, with non-ICU hospitalizations, ICU hospitalizations, and deaths decreasing by 63.5% (95% CrI: 60.3% - 66.7%), 65.6% (95% CrI: 62.2% - 68.6%), and 69.3% (95% CrI: 65.5% - 73.1%), respectively, across the same period. Conclusions Our results indicate that vaccination can have a substantial impact on mitigating COVID-19 outbreaks, even with limited protection against infection. However, continued compliance with non-pharmaceutical interventions is essential to achieve this impact.

Data feminism: by Catherine D’Ignazio and Lauren F. Klein, Cambridge, MA, The MIT Press, 2020, pp. 328, hardcover $29.95, ISBN 9780262044004

Abstract: All data have biographies: they are collected, cleaned, and complied before they could support powerful decisions. Every junction on this trajectory matters. Yet, according to Catherine D’Ignazio a...

When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis

Abstract: Mucormycosis (MCR) has been increasingly described in patients with coronavirus disease 2019 (COVID-19) but the epidemiological factors, presentation, diagnostic certainty, and outcome of such patients are not well described. We review the published COVID-19-associated mucormycosis (CAMCR) cases (total 41) to identify risk factors, clinical features, and outcomes. CAMCR was typically seen in patients with diabetes mellitus (DM) (94%) especially the ones with poorly controlled DM (67%) and severe or critical COVID-19 (95%). Its presentation was typical of MCR seen in diabetic patients (mostly rhino-orbital and rhino-orbital-cerebral presentation). In sharp contrast to reported COVID-associated aspergillosis (CAPA) cases, nearly all CAMCR infections were proven (93%). Treating physicians should have a high suspicion for CAMCR in patients with uncontrolled diabetes mellitus and severe COVID-19 presenting with rhino-orbital or rhino-cerebral syndromes. CAMR is the convergence of two storms, one of DM and the other of COVID-19.

The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates.

Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour-1 kg-1, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.

Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis.

Abstract: Importance Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them. Objective To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information. Data Sources We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019. Study Selection Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization. Data Extraction and Synthesis We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression. Main Outcomes and Measures Patient Health Questionnaire–9 (PHQ-9) scores. Results Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, −0.8; 95% CI, −1.4 to −0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9. Conclusions and Relevance In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.

Center-based 3D Object Detection and Tracking

Abstract: Three-dimensional objects are commonly represented as 3D boxes in a point-cloud. This representation mimics the well-studied image-based 2D bounding-box detection but comes with additional challenges. Objects in a 3D world do not follow any particular orientation, and box-based detectors have difficulties enumerating all orientations or fitting an axis-aligned bounding box to rotated objects. In this paper, we instead propose to represent, detect, and track 3D objects as points. Our framework, CenterPoint, first detects centers of objects using a keypoint detector and regresses to other attributes, including 3D size, 3D orientation, and velocity. In a second stage, it refines these estimates using additional point features on the object. In CenterPoint, 3D object tracking simplifies to greedy closest-point matching. The resulting detection and tracking algorithm is simple, efficient, and effective. CenterPoint achieved state-of-the-art performance on the nuScenes benchmark for both 3D detection and tracking, with 65.5 NDS and 63.8 AMOTA for a single model. On the Waymo Open Dataset, Center-Point outperforms all previous single model methods by a large margin and ranks first among all Lidar-only submissions. The code and pretrained models are available at https://github.com/tianweiy/CenterPoint.

Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody.

Abstract: The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope that overlaps the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.

Satellite imaging reveals increased proportion of population exposed to floods

Abstract: Flooding affects more people than any other environmental hazard and hinders sustainable development1,2. Investing in flood adaptation strategies may reduce the loss of life and livelihood caused by floods3. Where and how floods occur and who is exposed are changing as a result of rapid urbanization4, flood mitigation infrastructure5 and increasing settlements in floodplains6. Previous estimates of the global flood-exposed population have been limited by a lack of observational data, relying instead on models, which have high uncertainty3,7–11. Here we use daily satellite imagery at 250-metre resolution to estimate flood extent and population exposure for 913 large flood events from 2000 to 2018. We determine a total inundation area of 2.23 million square kilometres, with 255–290 million people directly affected by floods. We estimate that the total population in locations with satellite-observed inundation grew by 58–86 million from 2000 to 2015. This represents an increase of 20 to 24 per cent in the proportion of the global population exposed to floods, ten times higher than previous estimates7. Climate change projections for 2030 indicate that the proportion of the population exposed to floods will increase further. The high spatial and temporal resolution of the satellite observations will improve our understanding of where floods are changing and how best to adapt. The global flood database generated from these observations will help to improve vulnerability assessments, the accuracy of global and local flood models, the efficacy of adaptation interventions and our understanding of the interactions between landcover change, climate and floods. Satellite imagery for the period 2000–2018 reveals that population growth was greater in flood-prone regions than elsewhere, thus exposing a greater proportion of the population to floods.

A Double Burden of Exclusion?Digital and Social Exclusion of Older Adults in Times of COVID-19.

Abstract: The COVID-19 pandemic has excluded older adults from a society based on physical social contact. Vulnerable populations like older adults also tend to be excluded from digital services because they opt not to use the internet, lack necessary devices and network connectivity, or inexperience using the technology. Older adults who are frail and are not online, many of whom are in long-term care facilities, struggle with the double burden of social and digital exclusion. This paper discusses the potential outcomes of this exclusion and provides recommendations for rectifying the situation, with a particular focus on older adults in long-term care facilities.

Ultra-high-voltage Ni-rich layered cathodes in practical Li metal batteries enabled by a sulfonamide-based electrolyte

Abstract: By increasing the charging voltage, a cell specific energy of >400 W h kg−1 is achievable with LiNi0.8Mn0.1Co0.1O2 in Li metal batteries. However, stable cycling of high-nickel cathodes at ultra-high voltages is extremely challenging. Here we report that a rationally designed sulfonamide-based electrolyte enables stable cycling of commercial LiNi0.8Co0.1Mn0.1O2 with a cut-off voltage up to 4.7 V in Li metal batteries. In contrast to commercial carbonate electrolytes, the electrolyte not only suppresses side reactions, stress-corrosion cracking, transition-metal dissolution and impedance growth on the cathode side, but also enables highly reversible Li metal stripping and plating leading to a compact morphology and low pulverization. Our lithium-metal battery delivers a specific capacity >230 mA h g−1 and an average Coulombic efficiency >99.65% over 100 cycles. Even under harsh testing conditions, the 4.7 V lithium-metal battery can retain >88% capacity for 90 cycles, advancing practical lithium-metal batteries. Charging at high voltages in principle makes batteries energy dense, but this is often achieved at the cost of the cycling stability. Here the authors design a sulfonamide-based electrolyte to enable a Li metal battery with a state-of-the-art cathode at an ultra-high voltage of 4.7 V while maintaining cyclability.

COVID-19 Vaccine Acceptance Among Health Care Workers in the United States

Abstract: Background Acceptance of the COVID-19 vaccine will play a major role in combating the pandemic. Healthcare workers (HCWs) are amongst the first group to receive vaccination, so it is important to consider their attitudes about COVID-19 vaccination to better address barriers to widespread vaccination acceptance. Methods We conducted a cross sectional study to assess the attitude of HCWs toward COVID-19 vaccination. Data was collected between October 7th and November 9th, 2020. We received 4080 responses out of which 3479 were complete responses and were included in final analysis. Results 36% of respondents were willing to take the vaccine as soon as it became available while 56% were not sure or would wait to review more data. Vaccine acceptance increased with increasing age, education, and income level. Lower acceptance was noted in females (31%), Black (10%), Latinx (30%) and Conservative/Republican (21%) HCWs, and those working in a rural setting (26%). Direct medical care providers had higher vaccine acceptance (49%). Safety (69%), effectiveness (69%) and speed of development/approval (74%) were noted as the most common concerns regarding COVID-19 vaccination in our survey. Conclusion Immediate acceptance of a COVID-19 vaccine is low, with the majority of HCWs choosing to wait to review more data before deciding on personal vaccination. Overall attitudes toward vaccination were positive but specific concerns regarding COVID-19 vaccine are prevalent. Differences in vaccine acceptance were noted between individual and group characteristics which should be addressed to avoid exacerbating health inequities.

Burden of Neurological Disorders Across the US From 1990-2017: A Global Burden of Disease Study

Abstract: IMPORTANCE Accurate and up-to-date estimates on incidence, prevalence, mortality, and disability-adjusted life-years (burden) of neurological disorders are the backbone of evidence-based health care planning and resource allocation for these disorders. It appears that no such estimates have been reported at the state level for the US. OBJECTIVE To present burden estimates of major neurological disorders in the US states by age and sex from 1990 to 2017. DESIGN, SETTING, AND PARTICIPANTS This is a systematic analysis of the Global Burden of Disease (GBD) 2017 study. Data on incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) of major neurological disorders were derived from the GBD 2017 study of the 48 contiguous US states, Alaska, and Hawaii. Fourteen major neurological disorders were analyzed: stroke, Alzheimer disease and other dementias, Parkinson disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, traumatic brain injury, spinal cord injuries, brain and other nervous system cancers, meningitis, encephalitis, and tetanus. EXPOSURES Any of the 14 listed neurological diseases. MAIN OUTCOME AND MEASURE Absolute numbers in detail by age and sex and age-standardized rates (with 95% uncertainty intervals) were calculated. RESULTS The 3 most burdensome neurological disorders in the US in terms of absolute number of DALYs were stroke (3.58 [95% uncertainty interval [UI], 3.25-3.92] million DALYs), Alzheimer disease and other dementias (2.55 [95% UI, 2.43-2.68] million DALYs), and migraine (2.40 [95% UI, 1.53-3.44] million DALYs). The burden of almost all neurological disorders (in terms of absolute number of incident, prevalent, and fatal cases, as well as DALYs) increased from 1990 to 2017, largely because of the aging of the population. Exceptions for this trend included traumatic brain injury incidence (−29.1% [95% UI, −32.4% to −25.8%]); spinal cord injury prevalence (−38.5% [95% UI, −43.1% to −34.0%]); meningitis prevalence (−44.8% [95% UI, −47.3% to −42.3%]), deaths (−64.4% [95% UI, −67.7% to −50.3%]), and DALYs (−66.9% [95% UI, −70.1% to −55.9%]); and encephalitis DALYs (−25.8% [95% UI, −30.7% to −5.8%]). The different metrics of age-standardized rates varied between the US states from a 1.2-fold difference for tension-type headache to 7.5-fold for tetanus; southeastern states and Arkansas had a relatively higher burden for stroke, while northern states had a relatively higher burden of multiple sclerosis and eastern states had higher rates of Parkinson disease, idiopathic epilepsy, migraine and tension-type headache, and meningitis, encephalitis, and tetanus. CONCLUSIONS AND RELEVANCE There is a large and increasing burden of noncommunicable neurological disorders in the US, with up to a 5-fold variation in the burden of and trends in particular neurological disorders across the US states. The information reported in this article can be used by health care professionals and policy makers at the national and state levels to advance their health care planning and resource allocation to prevent and reduce the burden of neurological disorders.

Cascading risks: Understanding the 2021 winter blackout in Texas

Abstract: The Texas freeze of February 2021 left more than 4.5 million customers (more than 10 million people) without electricity at its peak, some for several days. The freeze had cascading effects on other services reliant upon electricity including drinking water treatment and medical services. Economic losses from lost output and damage are estimated to be $130 billion in Texas alone. In the wake of the freeze, there has been major fallout among regulators and utilities as actors sought to apportion blame and utilities and generators began to settle up accounts. This piece offers a retrospective on what caused the blackouts and the knock-on effects on other services, the subsequent financial and political effects of the freeze, and the implications for Texas and the country going forward. Texas failed to sufficiently winterize its electricity and gas systems after 2011. Feedback between failures in the two systems made the situation worse. Overall, the state faced outages of 30 GW of electricity as demand reached unprecedented highs. The gap between production and demand forced the non-profit grid manager, the Electric Reliability Council of Texas (ERCOT), to cut off supply to millions of customers or face a systems collapse that by some accounts was minutes away. The 2021 freeze suggests a need to rethink the state’s regulatory approach to energy to avoid future such outcomes. Weatherization, demand response, and expanded interstate interconnections are potential solutions Texas should consider to avoid generation losses, reduce demand, and tap neighboring states’ capacity.

Adjuvanting a subunit COVID-19 vaccine to induce protective immunity.

Abstract: The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative1. Here we demonstrate the capacity of a subunit vaccine, comprising the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).