The impact of health inequity on spatial variation of COVID-19 transmission in England.

Considerable spatial heterogeneity has been observed in COVID-19 transmission across administrative areas of England throughout the pandemic. This study investigates what drives these differences. We constructed a probabilistic case count model for 306 administrative areas of England across 95 weeks, fit using a Bayesian evidence synthesis framework. We incorporate the impact of acquired immunity, of spatial exportation of cases, and 16 spatially-varying socio-economic, socio-demographic, health, and mobility variables. Model comparison assesses the relative contributions of these respective mechanisms. We find that spatially-varying and time-varying differences in week-to-week transmission were definitively associated with differences in: time spent at home, variant-of-concern proportion, and adult social care funding. However, model comparison demonstrates that the impact of these terms is negligible compared to the role of spatial exportation between administrative areas. While these results confirm the impact of some, but not all, static measures of spatially-varying inequity in England, our work corroborates the finding that observed differences in disease transmission during the pandemic were predominantly driven by underlying epidemiological factors rather than aggregated metrics of demography and health inequity between areas. Further work is required to assess how health inequity more broadly contributes to these epidemiological factors.

Bayesian workflow for time-varying transmission in stratified compartmental infectious disease transmission models.

Compartmental models that describe infectious disease transmission across subpopulations are central for assessing the impact of non-pharmaceutical interventions, behavioral changes and seasonal effects on the spread of respiratory infections. We present a Bayesian workflow for such models, including four features: (1) an adjustment for incomplete case ascertainment, (2) an adequate sampling distribution of laboratory-confirmed cases, (3) a flexible, time-varying transmission rate, and (4) a stratification by age group. Within the workflow, we benchmarked the performance of various implementations of two of these features (2 and 3). For the second feature, we used SARS-CoV-2 data from the canton of Geneva (Switzerland) and found that a quasi-Poisson distribution is the most suitable sampling distribution for describing the overdispersion in the observed laboratory-confirmed cases. For the third feature, we implemented three methods: Brownian motion, B-splines, and approximate Gaussian processes (aGP). We compared their performance in terms of the number of effective samples per second, and the error and sharpness in estimating the time-varying transmission rate over a selection of ordinary differential equation solvers and tuning parameters, using simulated seroprevalence and laboratory-confirmed case data. Even though all methods could recover the time-varying dynamics in the transmission rate accurately, we found that B-splines perform up to four and ten times faster than Brownian motion and aGPs, respectively. We validated the B-spline model with simulated age-stratified data. We applied this model to 2020 laboratory-confirmed SARS-CoV-2 cases and two seroprevalence studies from the canton of Geneva. This resulted in detailed estimates of the transmission rate over time and the case ascertainment. Our results illustrate the potential of the presented workflow including stratified transmission to estimate age-specific epidemiological parameters. The workflow is freely available in the R package HETTMO, and can be easily adapted and applied to other infectious diseases.

Experimental demonstration of a nanobeam Fano laser.

Microscopic single-mode lasers with low power consumption, large modulation bandwidth, and ultra-narrow linewidth are essential for numerous applications, such as on-chip photonic networks. A recently demonstrated microlaser using an optical Fano resonance between a discrete mode and a continuum of modes to form one of the mirrors, i.e., the so-called Fano laser, holds great promise for meeting these requirements. Here, we suggest and experimentally demonstrate what we believe is a new configuration of the Fano laser based on a nanobeam geometry. Compared to the conventional two-dimensional photonic crystal geometry, the nanobeam structure makes it easier to engineer the phase-matching condition that facilitates the realization of a bound-state-in-the-continuum (BIC). We investigate the laser threshold in two scenarios based on the new nanobeam geometry. In the first, classical case, the gain is spatially located in the part of the cavity that supports a continuum of modes. In the second case, instead, the gain is located in the region that supports a discrete mode. We find that the laser threshold for the second case can be significantly reduced compared to the conventional Fano laser. These results pave the way for the practical realization of high-performance microlasers.

Heterogeneous integration of single InAs/InP quantum dots with the SOI chip using direct bonding.

Quantum information processing with photons in small-footprint and highly integrated silicon-based photonic chips requires incorporating non-classical light sources. In this respect, self-assembled III-V semiconductor quantum dots (QDs) are an attractive solution, however, they must be combined with the silicon platform. Here, by utilizing the large-area direct bonding technique, we demonstrate the hybridization of InP and SOI chips, which allows for coupling single photons to the SOI chip interior, offering cost-effective scalability in setting up a multi-source environment for quantum photonic chips. We fabricate devices consisting of self-assembled InAs QDs embedded in the tapered InP waveguide (WG) positioned over the SOI-defined Si WG. Focusing on devices generating light in the telecom C-band compatible with the low-loss optical fiber networks, we demonstrate the light coupling between InP and SOI platforms by observing photons outcoupled at the InP-made circular Bragg grating outcoupler fabricated at the end of an 80 µm-long Si WG, and at the cleaved edge of the Si WG. Finally, for a device with suppressed multi-photon generation events exhibiting 80% single photon generation purity, we measure the photon number outcoupled at the cleaved facet of the Si WG. We estimate the directional on-chip photon coupling between the source and the Si WG to 5.1%.

Bidirectional electrostatic MEMS-tunable VCSELs.

Microelectromechanical system (MEMS) vertical cavity surface-emitting lasers (VCSELs) are the fastest coherently tunable lasers (nm/ns) due to their unique Doppler-assisted tuning mechanism. However, in standard electrostatic actuation, the response is highly nonlinear and large (>100 V) dynamic voltages are needed for MHz sweep rates. We present a bidirectional MEMS VCSEL as a solution to these challenges where static voltages can be used to enable substantially linear and amplified wavelength tuning with respect to the fast tuning (MEMS) voltage. Using an InP/SOI MEMS bonded structure, we show a tuning range of 54.5 nm (gain limited) centered around 1586 nm at an actuation frequency of 2.73 MHz.

Optimization of heterogeneously integrated InP-Si on-chip photonic components.

We demonstrate comprehensive numerical studies on a hybrid III-V/Si-based waveguide system, serving as a platform for efficient light coupling between an integrated III-V quantum dot emitter to an on-chip quantum photonic integrated circuit defined on a silicon substrate. We propose a platform consisting of a hybrid InP/Si waveguide and an InP-embedded InAs quantum dot, emitting at the telecom C-band near 1550 nm. The platform can be fabricated using existing semiconductor processing technologies. Our numerical studies reveal nearly 87% of the optical field transfer efficiency between geometrically-optimized InP/Si and Si waveguides, considering propagating field along a tapered geometry. The coupling efficiency of a directional dipole emission to the hybrid InP/Si waveguide is evaluated to ∼38%, which results in more than 33% of the total on-chip optical field transfer efficiency from the dipole to the Si waveguide. We also consider the off-chip outcoupling efficiency of the propagating photon field along the Si waveguide by examining the normal to the chip plane and in-plane outcoupling configurations. In the former case, the outcoupling amounts to ∼26% when using the circular Bragg grating outcoupler design. In the latter case, the efficiency reaches up to 8%. Finally, we conclude that the conceptual device's performance is weakly susceptible to the transferred photon wavelength, offering a broadband operation within the 1.5-1.6 µm spectral range.

RpoS-Regulated Genes and Phenotypes in the Phytopathogenic Bacterium Pectobacterium atrosepticum.

The alternative sigma factor RpoS is considered to be one of the major regulators providing stress resistance and cross-protection in bacteria. In phytopathogenic bacteria, the effects of RpoS have not been analyzed with regard to cross-protection, and genes whose expression is directly or indirectly controlled by RpoS have not been determined at the whole-transcriptome level. Our study aimed to determine RpoS-regulated genes and phenotypes in the phytopathogenic bacterium Pectobacterium atrosepticum. Knockout of the rpoS gene in P. atrosepticum affected the long-term starvation response, cross-protection, and virulence toward plants with enhanced immune status. The whole-transcriptome profiles of the wild-type P. atrosepticum strain and its ΔrpoS mutant were compared under different experimental conditions, and functional gene groups whose expression was affected by RpoS were determined. The RpoS promoter motif was inferred within the promoter regions of the genes affected by rpoS deletion, and the P. atrosepticum RpoS regulon was predicted. Based on RpoS-controlled phenotypes, transcriptome profiles, and RpoS regulon composition, the regulatory role of RpoS in P. atrosepticum is discussed.

In situoff-axis electron holography of real-time dopant diffusion in GaAs nanowires.

Off-axis electron holography was used to reveal remote doping in GaAs nanowires occurring duringin situannealing in a transmission electron microscope. Dynamic changes to the electrostatic potential caused by carbon dopant diffusion upon annealing were measured across GaAs nanowires with radial p-p+ core-shell junctions. Electrostatic potential profiles were extracted from holographic phase maps and built-in potentials (Vbi) and depletion layer widths (DLWs) were estimated as function of temperature over 300-873 K. Simulations in absence of remote doping predict a significant increase ofVbiand DLWs with temperature. In contrast, we measured experimentally a nearly constantVbiand a weak increase of DLWs. Moreover, we observed the appearance of a depression in the potential profile of the core upon annealing. We attribute these deviations from the predicted behavior to carbon diffusion from the shell to the core through the nanowire sidewalls, i.e. to remote doping, becoming significant at 673 K. The DLW in the p and p+ regions are in the 10-30 nm range.

The use of Bayesian methodology in the development and validation of a tiered assessment approach towards prediction of rat acute oral toxicity.

There exists consensus that the traditional means by which safety of chemicals is assessed-namely through reliance upon apical outcomes obtained following in vivo testing-is increasingly unfit for purpose. Whilst efforts in development of suitable alternatives continue, few have achieved levels of robustness required for regulatory acceptance. An array of "new approach methodologies" (NAM) for determining toxic effect, spanning in vitro and in silico spheres, have by now emerged. It has been suggested, intuitively, that combining data obtained from across these sources might serve to enhance overall confidence in derived judgment. This concept may be formalised in the "tiered assessment" approach, whereby evidence gathered through a sequential NAM testing strategy is exploited so to infer the properties of a compound of interest. Our intention has been to provide an illustration of how such a scheme might be developed and applied within a practical setting-adopting for this purpose the endpoint of rat acute oral lethality. Bayesian statistical inference is drawn upon to enable quantification of degree of confidence that a substance might ultimately belong to one of five LD50-associated toxicity categories. Informing this is evidence acquired both from existing in silico and in vitro resources, alongside a purposely-constructed random forest model and structural alert set. Results indicate that the combination of in silico methodologies provides moderately conservative estimations of hazard, conducive for application in safety assessment, and for which levels of certainty are defined. Accordingly, scope for potential extension of approach to further toxicological endpoints is demonstrated.

Bayesian workflow for disease transmission modeling in Stan.

This tutorial shows how to build, fit, and criticize disease transmission models in Stan, and should be useful to researchers interested in modeling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and other infectious diseases in a Bayesian framework. Bayesian modeling provides a principled way to quantify uncertainty and incorporate both data and prior knowledge into the model estimates. Stan is an expressive probabilistic programming language that abstracts the inference and allows users to focus on the modeling. As a result, Stan code is readable and easily extensible, which makes the modeler's work more transparent. Furthermore, Stan's main inference engine, Hamiltonian Monte Carlo sampling, is amiable to diagnostics, which means the user can verify whether the obtained inference is reliable. In this tutorial, we demonstrate how to formulate, fit, and diagnose a compartmental transmission model in Stan, first with a simple susceptible-infected-recovered model, then with a more elaborate transmission model used during the SARS-CoV-2 pandemic. We also cover advanced topics which can further help practitioners fit sophisticated models; notably, how to use simulations to probe the model and priors, and computational techniques to scale-up models based on ordinary differential equations.

744-nm wavelength conversion of PAM-4 signal using an AlGaAsOI nanowaveguide.

Exploring new frequency bands for optical transmission is essential to overcome the capacity crunch. The 2-µm band is becoming a research spotlight due to available broadband thulium-doped fiber amplifiers as well as low-latency, low-loss hollow-core fibers. Yet most of the 2-µm band devices designed for optical communication are still in their infancy. In this Letter, we propose wavelength conversion based on four-wave mixing in a highly nonlinear AlGaAsOI nanowaveguide to bridge the 2-µm band and the conventional bands. Due to the strong light confinement of the AlGaAsOI nanowaveguide, high-order phase match is enabled by dispersion engineering to achieve a large synergetic conversion bandwidth with high conversion efficiency. Simulation results show a possible conversion bandwidth over an octave. An AlGaAsOI nanowaveguide with 3-mm length and a nominal cross-section dimension of $ 320\;{\rm nm} \times 680\;{\rm nm} $320nm×680nm is used for the wavelength conversion of a 10 Gbit/s non-return-to-zero on-off keying signal and a 10 Gbit/s Nyquist-shaped four-level pulse-amplitude modulation signal. A conversion efficiency of $ - {28}\;{\rm dB}$-28dB is achieved using a 17.5-dBm continuous-wave pump in the C band, with 744 nm conversion from 1999.65 to 1255.35 nm.

Predicting Drug-Induced Liver Injury with Bayesian Machine Learning.

Drug induced liver injury (DILI) can require significant risk management in drug development and on occasion can cause morbidity or mortality, leading to drug attrition. Optimizing candidates preclinically can minimize hepatotoxicity risk, but it is difficult to predict due to multiple etiologies encompassing DILI, often with multifactorial and overlapping mechanisms. In addition to epidemiological risk factors, physicochemical properties, dose, disposition, lipophilicity, and hepatic metabolic function are also relevant for DILI risk. Better human-relevant, predictive models are required to improve hepatotoxicity risk assessment in drug discovery. Our hypothesis is that integrating mechanistically relevant hepatic safety assays with Bayesian machine learning will improve hepatic safety risk prediction. We present a quantitative and mechanistic risk assessment for candidate nomination using data from in vitro assays (hepatic spheroids, BSEP, mitochondrial toxicity, and bioactivation), together with physicochemical (cLogP) and exposure (Cmaxtotal) variables from a chemically diverse compound set (33 no/low-, 40 medium-, and 23 high-severity DILI compounds). The Bayesian model predicts the continuous underlying DILI severity and uses a data-driven prior distribution over the parameters to prevent overfitting. The model quantifies the probability that a compound falls into either no/low-, medium-, or high-severity categories, with a balanced accuracy of 63% on held-out samples, and a continuous prediction of DILI severity along with uncertainty in the prediction. For a binary yes/no DILI prediction, the model has a balanced accuracy of 86%, a sensitivity of 87%, a specificity of 85%, a positive predictive value of 92%, and a negative predictive value of 78%. Combining physiologically relevant assays, improved alignment with FDA recommendations, and optimal statistical integration of assay data leads to improved DILI risk prediction.

High-confinement gallium nitride-on-sapphire waveguides for integrated nonlinear photonics.

We demonstrate a highly effective nonlinearity of 7.3 W-1 m-1 in a high-confinement gallium nitride-on-sapphire waveguide by performing four-wave mixing characterization at telecom wavelengths. Benefitting from a high-index-contrast waveguide layout, we can engineer the device dispersion efficiently and achieve broadband four-wave mixing operation over more than 100 nm. The intrinsic material nonlinearity of gallium nitride is extracted. Furthermore, we fabricate microring resonators with quality factors above 100,000, which will be promising for various nonlinear applications.

Low-loss high-confinement waveguides and microring resonators in AlGaAs-on-insulator.

AlGaAs is a promising material for integrated nonlinear photonics due to its intrinsic high nonlinearity. However, the challenging fabrication of deep etched AlGaAs devices makes it difficult to realize high-performance devices such as low-loss dispersion engineered waveguides and high-quality microring resonators. Here, we report a process to make high-quality AlGaAs-on-insulator (AlGaAsOI) wafers where high confinement waveguides can be realized. Using optimized patterning processes, we fabricated AlGaAsOI waveguides with propagation losses as low as 1 dB/cm and microring resonators with quality factors up to 350,000 at telecom wavelengths. Our demonstration opens new prospects for AlGaAs devices in integrated nonlinear photonics.

Threshold Characteristics of Slow-Light Photonic Crystal Lasers.

The threshold properties of photonic crystal quantum dot lasers operating in the slow-light regime are investigated experimentally and theoretically. Measurements show that, in contrast to conventional lasers, the threshold gain attains a minimum value for a specific cavity length. The experimental results are explained by an analytical theory for the laser threshold that takes into account the effects of slow light and random disorder due to unavoidable fabrication imperfections. Longer lasers are found to operate deeper into the slow-light region, leading to a trade-off between slow-light induced reduction of the mirror loss and slow-light enhancement of disorder-induced losses.

Thermal analysis of line-defect photonic crystal lasers.

We report a systematic study of thermal effects in photonic crystal membrane lasers based on line-defect cavities. Two material platforms, InGaAsP and InP, are investigated experimentally and numerically. Lasers with quantum dot layers embedded in an InP membrane exhibit lasing at room temperature under CW optical pumping, whereas InGaAsP membranes only lase under pulsed conditions. By varying the duty cycle of the pump beam, we quantify the heating induced by optical pumping in the two material platforms and compare their thermal properties. Full 3D finite element simulations show the spatial temperature profile and are in good agreement with the experimental results concerning the thermal tolerance of the two platforms.

National, regional, and global trends in insufficient physical activity among adults from 2000 to 2022: a pooled analysis of 507 population-based surveys with 5·7 million participants.

BACKGROUND: Insufficient physical activity increases the risk of non-communicable diseases, poor physical and cognitive function, weight gain, and mental ill-health. Global prevalence of adult insufficient physical activity was last published for 2016, with limited trend data. We aimed to estimate the prevalence of insufficient physical activity for 197 countries and territories, from 2000 to 2022. METHODS: We collated physical activity reported by adults (aged ≥18 years) in population-based surveys. Insufficient physical activity was defined as not doing 150 minutes of moderate-intensity activity, 75 minutes of vigorous-intensity activity, or an equivalent combination per week. We used a Bayesian hierarchical model to compute estimates of insufficient physical activity by country or territory, year, age, and sex. We assessed whether countries or territories, regions, and the world would meet the global target of a 15% relative reduction of the prevalence of insufficient physical activity by 2030 if 2010-22 trends continue. FINDINGS: We included 507 surveys across 163 countries and territories. The global age-standardised prevalence of insufficient physical activity was 31·3% (95% uncertainty interval 28·6-34·0) in 2022, an increase from 23·4% (21·1-26·0) in 2000 and 26·4% (24·8-27·9) in 2010. Prevalence was increasing in 103 (52%) of 197 countries and territories and six (67%) of nine regions, and was declining in the remainder. Prevalence was 5 percentage points higher among female (33·8% [29·9-37·7]) than male (28·7% [25·0-32·6]) individuals. Insufficient physical activity increased in people aged 60 years and older in all regions and both sexes, but age patterns differed for those younger than 60 years. If 2010-22 trends continue, the global target of a 15% relative reduction between 2010 and 2030 will not be met (posterior probability <0·01); however, two regions, Oceania and sub-Saharan Africa, were on track with considerable uncertainty (posterior probabilities 0·70-0·74). INTERPRETATION: Concerted multi-sectoral efforts to reduce insufficient physical activity levels are needed to meet the 2030 target. Physical activity promotion should not exacerbate sex, age, or geographical inequalities. FUNDING: Ministry of Public Health, Qatar, and World Health Organization. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

On-Demand Generation of Indistinguishable Photons in the Telecom C-Band Using Quantum Dot Devices.

Semiconductor quantum dots (QDs) enable the generation of single and entangled photons, which are useful for various applications in photonic quantum technologies. Specifically for quantum communication via fiber-optical networks, operation in the telecom C-band centered around 1550 nm is ideal. The direct generation of QD-photons in this spectral range with high quantum-optical quality, however, remained challenging. Here, we demonstrate the coherent on-demand generation of indistinguishable photons in the telecom C-band from single QD devices consisting of InAs/InP QD-mesa structures heterogeneously integrated with a metallic reflector on a silicon wafer. Using pulsed two-photon resonant excitation of the biexciton-exciton radiative cascade, we observe Rabi rotations up to pulse areas of 4π and a high single-photon purity in terms of g(2)(0) = 0.005(1) and 0.015(1) for exciton and biexciton photons, respectively. Applying two independent experimental methods, based on fitting Rabi rotations in the emission intensity and performing photon cross-correlation measurements, we consistently obtain preparation fidelities at the π-pulse exceeding 80%. Finally, performing Hong-Ou-Mandel-type two-photon interference experiments, we obtain a photon-indistinguishability of the full photon wave packet of up to 35(3)%, representing a significant advancement in the photon-indistinguishability of single photons emitted directly in the telecom C-band.

High-throughput quantum photonic devices emitting indistinguishable photons in the telecom C-band.

Single indistinguishable photons at telecom C-band wavelengths are essential for quantum networks and the future quantum internet. However, high-throughput technology for single-photon generation at 1550 nm remained a missing building block to overcome present limitations in quantum communication and information technologies. Here, we demonstrate the high-throughput fabrication of quantum-photonic integrated devices operating at C-band wavelengths based on epitaxial semiconductor quantum dots. Our technique enables the deterministic integration of single pre-selected quantum emitters into microcavities based on circular Bragg gratings. Respective devices feature the triggered generation of single photons with ultra-high purity and record-high photon indistinguishability. Further improvements in yield and coherence properties will pave the way for implementing single-photon non-linear devices and advanced quantum networks at telecom wavelengths.

Assessment of COVID-19 as the Underlying Cause of Death Among Children and Young People Aged 0 to 19 Years in the US.

Importance: COVID-19 was the underlying cause of death for more than 940 000 individuals in the US, including at least 1289 children and young people (CYP) aged 0 to 19 years, with at least 821 CYP deaths occurring in the 1-year period from August 1, 2021, to July 31, 2022. Because deaths among US CYP are rare, the mortality burden of COVID-19 in CYP is best understood in the context of all other causes of CYP death. Objective: To determine whether COVID-19 is a leading (top 10) cause of death in CYP in the US. Design, Setting, and Participants: This national population-level cross-sectional epidemiological analysis for the years 2019 to 2022 used data from the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (WONDER) database on underlying cause of death in the US to identify the ranking of COVID-19 relative to other causes of death among individuals aged 0 to 19 years. COVID-19 deaths were considered in 12-month periods between April 1, 2020, and August 31, 2022, compared with deaths from leading non-COVID-19 causes in 2019, 2020, and 2021. Main Outcomes and Measures: Cause of death rankings by total number of deaths, crude rates per 100 000 population, and percentage of all causes of death, using the National Center for Health Statistics 113 Selected Causes of Death, for ages 0 to 19 and by age groupings (<1 year, 1-4 years, 5-9 years, 10-14 years, 15-19 years). Results: There were 821 COVID-19 deaths among individuals aged 0 to 19 years during the study period, resulting in a crude death rate of 1.0 per 100 000 population overall; 4.3 per 100 000 for those younger than 1 year; 0.6 per 100 000 for those aged 1 to 4 years; 0.4 per 100 000 for those aged 5 to 9 years; 0.5 per 100 000 for those aged 10 to 14 years; and 1.8 per 100 000 for those aged 15 to 19 years. COVID-19 mortality in the time period of August 1, 2021, to July 31, 2022, was among the 10 leading causes of death in CYP aged 0 to 19 years in the US, ranking eighth among all causes of deaths, fifth in disease-related causes of deaths (excluding unintentional injuries, assault, and suicide), and first in deaths caused by infectious or respiratory diseases when compared with 2019. COVID-19 deaths constituted 2% of all causes of death in this age group. Conclusions and Relevance: The findings of this study suggest that COVID-19 was a leading cause of death in CYP. It caused substantially more deaths in CYP annually than any vaccine-preventable disease historically in the recent period before vaccines became available. Various factors, including underreporting and not accounting for COVID-19's role as a contributing cause of death from other diseases, mean that these estimates may understate the true mortality burden of COVID-19. The findings of this study underscore the public health relevance of COVID-19 to CYP. In the likely future context of sustained SARS-CoV-2 circulation, appropriate pharmaceutical and nonpharmaceutical interventions (eg, vaccines, ventilation, air cleaning) will continue to play an important role in limiting transmission of the virus and mitigating severe disease in CYP.