Experimentally realized in situ backpropagation for deep learning in photonic neural networks.

Integrated photonic neural networks provide a promising platform for energy-efficient, high-throughput machine learning with extensive scientific and commercial applications. Photonic neural networks efficiently transform optically encoded inputs using Mach-Zehnder interferometer mesh networks interleaved with nonlinearities. We experimentally trained a three-layer, four-port silicon photonic neural network with programmable phase shifters and optical power monitoring to solve classification tasks using "in situ backpropagation," a photonic analog of the most popular method to train conventional neural networks. We measured backpropagated gradients for phase-shifter voltages by interfering forward- and backward-propagating light and simulated in situ backpropagation for 64-port photonic neural networks trained on MNIST image recognition given errors. All experiments performed comparably to digital simulations ([Formula: see text]94% test accuracy), and energy scaling analysis indicated a route to scalable machine learning.

Modelling lung cancer diagnostic pathways using discrete event simulation.

The United Kingdom has one of the poorest lung cancer survival rates in Europe. In this study, to help design and evaluate a single lung cancer pathway (SCP) for Wales, existing diagnostic pathways and processes have been mapped and then modelled with a discrete event simulation. The validated models have been used to provide key performance indicators and to examine different diagnostic testing strategies. Under the current diagnostic pathways, the mean time to treatment was 72 days for surgery patients, 56 days for chemotherapy patients, and 61 days for radiotherapy patients. Our research demonstrated that by ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 11 days from the current lung cancer pathway resulting in a 21% increase in patients receiving treatment within the Welsh Government set target of 62 days.

A Randomized Trial Of Letters To Encourage Prescription Monitoring Program Use And Safe Opioid Prescribing.

To facilitate safer prescribing of opioids and other drugs, nearly all states operate prescription monitoring programs (PMPs), which collect and share data on controlled substance dispensing. Policy makers have sought to raise clinicians' engagement with these programs but lack evidence on effective interventions. Working with the Minnesota Prescription Monitoring Program, we conducted a randomized trial to assess whether letters to clinicians increased program use and decreased risky coprescribing of opioids with benzodiazepines or gabapentinoids. In March 2021 we randomly assigned 12,000 coprescribers to either a control arm or one of three study arms sent differing letters. The respective letters highlighted a new mandate to check the PMP before prescribing, provided information about coprescribing risks with a list of coprescribed patients, or contained both messages combined. Letters highlighting the mandate alone or along with coprescribing information increased PMP search rates by 4.5 and 4.0 percentage points, respectively, with no significant effect on coprescribing. These letters also increased PMP account-holding rates among clinicians. Effects persisted for at least eight months. The letter with only coprescribing information had no detected effects on key outcomes. Our results support the use of simple letter interventions as evidence-based tools to increase PMP engagement and potentially facilitate better-informed prescribing.

Prescription drug monitoring program use by opioid prescribers: a cross-sectional study.

Clinician use of prescription drug monitoring programs (PDMPs) has been linked to better patient outcomes, but state requirements to use PDMPs are unevenly enforced. We assessed PDMP use in Minnesota, which requires opioid prescribers to hold accounts and, in most cases, search the PDMP before prescribing, but where enforcement authority is limited. Using 2023 PDMP data, we found that 4 in 10 opioid prescribers did not search and 2 in 10 did not hold an account. PDMP use was strongly associated with prescribing volume, but even among the top decile of opioid prescribers, 8% never searched the PDMP. Thirty-two percent of opioid fills came from clinicians who did not search the PDMP. Failures to use the PDMP may be driven by a lack of information about state requirements, beliefs that these requirements are not enforced, and the costs of accessing the PDMP relative to the benefits. These results highlight the potential for policy makers to promote safer and better-informed prescribing of opioids and other drugs by addressing the forces that have limited PDMP use so far.

Glycerate from intestinal fructose metabolism induces islet cell damage and glucose intolerance.

Dietary fructose, especially in the context of a high-fat western diet, has been linked to type 2 diabetes. Although the effect of fructose on liver metabolism has been extensively studied, a significant portion of the fructose is first metabolized in the small intestine. Here, we report that dietary fat enhances intestinal fructose metabolism, which releases glycerate into the blood. Chronic high systemic glycerate levels induce glucose intolerance by slowly damaging pancreatic islet cells and reducing islet sizes. Our findings provide a link between dietary fructose and diabetes that is modulated by dietary fat.

Patient-derived micro-organospheres enable clinical precision oncology.

Patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here, we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of micro-organospheres (MOSs) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology. A clinical study of recently diagnosed metastatic colorectal cancer (CRC) patients using an MOS-based precision oncology pipeline reliably assessed tumor drug response within 14 days, a timeline suitable for guiding treatment decisions in the clinic. Furthermore, MOSs capture original stromal cells and allow T cell penetration, providing a clinical assay for testing immuno-oncology (IO) therapies such as PD-1 blockade, bispecific antibodies, and T cell therapies on patient tumors.

A Planar Culture Model of Human Absorptive Enterocytes Reveals Metformin Increases Fatty Acid Oxidation and Export.

BACKGROUND & AIMS: Fatty acid oxidation by absorptive enterocytes has been linked to the pathophysiology of type 2 diabetes, obesity, and dyslipidemia. Caco-2 and organoids have been used to study dietary lipid-handling processes including fatty acid oxidation, but are limited in physiological relevance or preclude simultaneous apical and basal access. Here, we developed a high-throughput planar human absorptive enterocyte monolayer system for investigating lipid handling, and then evaluated the role of fatty acid oxidation in fatty acid export, using etomoxir, C75, and the antidiabetic drug metformin. METHODS: Single-cell RNA-sequencing, transcriptomics, and lineage trajectory was performed on primary human jejunum. In vivo absorptive enterocyte maturational states informed conditions used to differentiate human intestinal stem cells (ISCs) that mimic in vivo absorptive enterocyte maturation. The system was scaled for high-throughput drug screening. Fatty acid oxidation was modulated pharmacologically and BODIPY (Thermo Fisher Scientific, Waltham, MA) (B)-labeled fatty acids were used to evaluate fatty acid handling via fluorescence and thin-layer chromatography. RESULTS: Single-cell RNA-sequencing shows increasing expression of lipid-handling genes as absorptive enterocytes mature. Culture conditions promote ISC differentiation into confluent absorptive enterocyte monolayers. Fatty acid-handling gene expression mimics in vivo maturational states. The fatty acid oxidation inhibitor etomoxir decreased apical-to-basolateral export of medium-chain B-C12 and long-chain B-C16 fatty acids, whereas the CPT1 agonist C75 and the antidiabetic drug metformin increased apical-to-basolateral export. Short-chain B-C5 was unaffected by fatty acid oxidation inhibition and diffused through absorptive enterocytes. CONCLUSIONS: Primary human ISCs in culture undergo programmed maturation. Absorptive enterocyte monolayers show in vivo maturational states and lipid-handling gene expression profiles. Absorptive enterocytes create strong epithelial barriers in 96-Transwell format. Fatty acid export is proportional to fatty acid oxidation. Metformin enhances fatty acid oxidation and increases basolateral fatty acid export, supporting an intestine-specific role.

Examining the diagnostic pathway for lung cancer patients in Wales using discrete event simulation.

BACKGROUND: UK's National Health Service (NHS) has one of the poorest lung cancer survival rates in Europe. To improve patient outcomes, a single cancer pathway was introduced in the NHS. In this study, a Discrete Event Simulation was developed to understand bottlenecks during lung cancer treatment. METHODS: This study focused on the lung cancer diagnostic pathways at two Welsh hospitals. Discrete Event Simulation is a computer-based method that has been effectively used in demand and capacity planning. In this study, simulation models were developed for the current and proposed single cancer pathways. The validated models were used to provide Key Performance Indicators. Several "what-if" scenarios were considered for the current and proposed pathways. RESULTS: Under the current diagnostic pathway, the mean time to treatment for a surgery patient was 68 days at the Royal Glamorgan Hospital and 79 days at Prince Charles Hospital. For chemotherapy patients, the mean time to treatment was 52 days at the Royal Glamorgan Hospital and 57 days at Prince Charles Hospital. For radiotherapy patients, the mean time to treatment was 44 days at Royal Glamorgan Hospital and 54 days at Prince Charles Hospital. Ensuring that the patient attends their first outpatient appointment within 7 days and streamlining the diagnostic tests would have the potential to remove approximately 20 days from the current lung cancer pathway resulting in a 20-25% increase of patients receiving treatment within 62 days. Ensuring that patients begin their treatment within 21 days of diagnosis sees almost all patients comply with the 62-day target. CONCLUSIONS: Discrete Event Simulation coupled with a detailed statistical analysis provides a useful decision support tool which can be used to examine the current and proposed lung cancer pathways in terms of time spent on the pathway.

Arbitrary linear transformations for photons in the frequency synthetic dimension.

Arbitrary linear transformations are of crucial importance in a plethora of photonic applications spanning classical signal processing, communication systems, quantum information processing and machine learning. Here, we present a photonic architecture to achieve arbitrary linear transformations by harnessing the synthetic frequency dimension of photons. Our structure consists of dynamically modulated micro-ring resonators that implement tunable couplings between multiple frequency modes carried by a single waveguide. By inverse design of these short- and long-range couplings using automatic differentiation, we realize arbitrary scattering matrices in synthetic space between the input and output frequency modes with near-unity fidelity and favorable scaling. We show that the same physical structure can be reconfigured to implement a wide variety of manipulations including single-frequency conversion, nonreciprocal frequency translations, and unitary as well as non-unitary transformations. Our approach enables compact, scalable and reconfigurable integrated photonic architectures to achieve arbitrary linear transformations in both the classical and quantum domains using current state-of-the-art technology.

Cost-Effectiveness of Ivacaftor Therapy for Treatment of Cystic Fibrosis Patients With the G551D Gating Mutation.

OBJECTIVES: Cystic fibrosis (CF) is a rare genetic disease with no cure. Until recently, treatment has targeted symptoms of the disease and not the disease-causing genetic defect. Ivacaftor is included in a new class of breakthrough drugs targeting the genetic defects of CF. We sought to estimate the long-term cost-effectiveness of ivacaftor from a US payer perspective. METHODS: We developed an individual-level microsimulation model that followed a cohort of heterogeneous US CF patients over a lifetime. The primary outcome of interest was quality-adjusted life years (QALYs). We also compared unadjusted life years, count of acute pulmonary exacerbations, and count of lung transplants over a lifetime between patients treated with ivacaftor plus best supportive care and patients treated with best supportive care alone. We conducted one-way and probabilistic sensitivity analyses to test the impact of various model inputs and uncertainties. RESULTS: We found a substantial increase in QALYs, life years, and treatment costs over a lifetime for patients treated with ivacaftor plus best supportive care versus best supportive care alone. Discounted results for ivacaftor were 22.92 QALYs and $8 797 840 in total lifetime costs compared to 16.12 QALYs and $2 336 366 lifetime costs for best supportive care alone. The incremental cost-effectiveness ratios (ICERs) were $950 217 per QALY. Results from the probabilistic sensitivity analysis indicated a 0% chance that ivacaftor was cost-effective at a willingness-to-pay (WTP) threshold of $500 000 per QALY. CONCLUSIONS: Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.

PT-Symmetric Topological Edge-Gain Effect.

We demonstrate a non-Hermitian topological effect that is characterized by having complex eigenvalues only in the edge states of a topological material, despite the fact that the material is completely uniform. Such an effect can be constructed in any topological structure formed by two gapped subsystems, e.g., a quantum spin-Hall system, with a suitable non-Hermitian coupling between the spins. The resulting complex-eigenvalued edge state is robust against defects due to the topological protection. In photonics, such an effect can be used for the implementation of topological lasers, in which a uniform pumping provides gain only in the edge lasing state. Furthermore, such a topological lasing model is reciprocal and is thus compatible with standard photonic platforms.

Higher-order topological insulators in synthetic dimensions.

Conventional topological insulators support boundary states with dimension one lower than that of the bulk system that hosts them, and these states are topologically protected due to quantized bulk dipole moments. Recently, higher-order topological insulators have been proposed as a way of realizing topological states with dimensions two or more lower than that of the bulk due to the quantization of bulk quadrupole or octupole moments. However, all these proposals as well as experimental realizations have been restricted to real-space dimensions. Here, we construct photonic higher-order topological insulators (PHOTIs) in synthetic dimensions. We show the emergence of a quadrupole PHOTI supporting topologically protected corner modes in an array of modulated photonic molecules with a synthetic frequency dimension, where each photonic molecule comprises two coupled rings. By changing the phase difference of the modulation between adjacent coupled photonic molecules, we predict a dynamical topological phase transition in the PHOTI. Furthermore, we show that the concept of synthetic dimensions can be exploited to realize even higher-order multipole moments such as a fourth-order hexadecapole (16-pole) insulator supporting 0D corner modes in a 4D hypercubic synthetic lattice that cannot be realized in real-space lattices.

The future of feedback: Motivating performance improvement through future-focused feedback.

Managerial feedback discussions often fail to produce the desired performance improvements. Three studies shed light on why performance feedback fails and how it can be made more effective. In Study 1, managers described recent performance feedback experiences in their work settings. In Studies 2 and 3, pairs of managers role-played a performance review meeting. In all studies, recipients of mixed and negative feedback doubted the accuracy of the feedback and the providers' qualifications to give it. Disagreement regarding past performance was greater following the feedback discussion than before, due to feedback recipients' increased self-protective and self-enhancing attributions. Managers were motivated to improve to the extent they perceived the feedback conversation to be focused on future actions rather than on past performance. Our findings have implications for the theory and practice of performance management.

Experimental realization of arbitrary activation functions for optical neural networks.

We experimentally demonstrate an on-chip electro-optic circuit for realizing arbitrary nonlinear activation functions for optical neural networks (ONNs). The circuit operates by converting a small portion of the input optical signal into an electrical signal and modulating the intensity of the remaining optical signal. Electrical signal processing allows the activation function circuit to realize any optical-to-optical nonlinearity that does not require amplification. Such line shapes are not constrained to those of conventional optical nonlinearities. Through numerical simulations, we demonstrate that the activation function improves the performance of an ONN on the MNIST image classification task. Moreover, the activation circuit allows for the realization of nonlinearities with far lower optical signal attenuation, paving the way for much deeper ONNs.

Cost-Effectiveness of MRI-Based Identification of Presymptomatic Autism in a High-Risk Population.

Biological siblings of children with autism spectrum disorder (ASD) have increased risk of receiving an ASD diagnosis. In the U.S., most children with ASD are diagnosed after the optimal age to initiate early intervention which can reduce symptom severity and improve outcomes. Recent evidence suggests magnetic resonance imaging (MRI) in the first year of life can predict later diagnostic status in high-risk siblings. We investigated whether MRI-based screening is a cost-effective method for assigning early intervention. A hybrid decision tree/Markov model was used to evaluate two MRI-based screening strategies at 6 and 12 months of age. Primary outcomes were costs in U.S. dollars and quality-adjusted life years (QALYs). Results were reported as incremental cost-effectiveness ratios (ICERs). Costs were estimated from societal, health care, and educational perspectives. One-way and probabilistic sensitivity analyses were performed. From a societal perspective, the ICER for MRI-based screening at 6 months was $49,000 per QALY when compared to the status quo, implying that such screening is cost-effective at willingness-to-pay (WTP) thresholds of $50,000-$100,000 per QALY. From the health care and educational perspectives, the ICERs were larger at $99,000 and $76,000 per QALY, respectively. Sensitivity analysis identified that the parameters most influential in affecting cost-effectiveness were the prevalence of ASD and/or co-occurring intellectual disability. MRI specificity also has significant impacts which add to the uncertainty of the results. Future work is needed to determine the sensitivity and, in particular, the specificity of MRI with more certainty. Notably, the cost of the MRI-based screening had the least impact.

Absence of unidirectionally propagating surface plasmon-polaritons at nonreciprocal metal-dielectric interfaces.

In the presence of an external magnetic field, the surface plasmon polariton that exists at the metal-dielectric interface is believed to support a unidirectional frequency range near the surface plasmon frequency, where the surface plasmon polariton propagates along one but not the opposite direction. Recent works have pointed to some of the paradoxical consequences of such a unidirectional range, including in particular the violation of the time-bandwidth product constraint that should otherwise apply in general in static systems. Here we show that such a unidirectional frequency range is nonphysical using both a general thermodynamic argument and a detailed calculation based on a nonlocal hydrodynamic Drude model for the metal permittivity. Our calculation reveals that the surface plasmon-polariton at metal-dielectric interfaces remains bidirectional for all frequencies.

Nasal balloon autoinflation for glue ear in primary care: a qualitative interview study.

BACKGROUND: Nasal balloon autoinflation is an effective, non-surgical treatment for symptomatic children with glue ear, although uptake is variable and evidence about acceptability and feasibility is limited. AIM: To explore parent and healthcare professional views and experiences of nasal balloon autoinflation for children with glue ear in primary care. DESIGN AND SETTING: Qualitative study using semi-structured interviews with a maximum-variety sample of parents, GPs, and practice nurses. The study took place between February 2013 and September 2014. METHOD: Semi-structured face-to-face and telephone interviews were audiorecorded, transcribed verbatim, and analysed using inductive thematic analysis. RESULTS: In all, 14 parents, 31 GPs, and 19 nurses were included in the study. Parents described the nasal balloon as a natural, holistic treatment that was both acceptable and appealing to children. GPs and nurses perceived the method to be a low-cost, low-risk strategy, applicable to the primary care setting. Good instruction and demonstration ensured children mastered the technique and engaged with the treatment, but uncertainties were raised about training provision and potential impact on the GP consultation. Making nasal balloon autoinflation part of a child's daily routine enhances compliance, but difficulties can arise if children are unwell or refuse to cooperate. CONCLUSION: Nasal balloon autoinflation is an acceptable, low-cost treatment option for children with glue ear in primary care. Provision of educational materials and demonstration of the method are likely to promote uptake and compliance. Wider use of the nasal balloon has the potential to enhance early management, and may help to fill the management gap arising from forthcoming changes to care pathways.

IL22 Inhibits Epithelial Stem Cell Expansion in an Ileal Organoid Model.

Background & Aims: Crohn's disease is an inflammatory bowel disease that affects the ileum and is associated with increased cytokines. Although interleukin (IL)6, IL17, IL21, and IL22 are increased in Crohn's disease and are associated with disrupted epithelial regeneration, little is known about their effects on the intestinal stem cells (ISCs) that mediate tissue repair. We hypothesized that ILs may target ISCs and reduce ISC-driven epithelial renewal. Methods: A screen of IL6, IL17, IL21, or IL22 was performed on ileal mouse organoids. Computational modeling was used to predict microenvironment cytokine concentrations. Organoid size, survival, proliferation, and differentiation were characterized by morphometrics, quantitative reverse-transcription polymerase chain reaction, and immunostaining on whole organoids or isolated ISCs. ISC function was assayed using serial passaging to single cells followed by organoid quantification. Single-cell RNA sequencing was used to assess Il22ra1 expression patterns in ISCs and transit-amplifying (TA) progenitors. An IL22-transgenic mouse was used to confirm the impact of increased IL22 on proliferative cells in vivo. Results: High IL22 levels caused decreased ileal organoid survival, however, resistant organoids grew larger and showed increased proliferation over controls. Il22ra1 was expressed on only a subset of ISCs and TA progenitors. IL22-treated ISCs did not show appreciable differentiation defects, but ISC biomarker expression and self-renewal-associated pathway activity was reduced and accompanied by an inhibition of ISC expansion. In vivo, chronically increased IL22 levels, similar to predicted microenvironment levels, showed increases in proliferative cells in the TA zone with no increase in ISCs. Conclusions: Increased IL22 limits ISC expansion in favor of increased TA progenitor cell expansion.

Wave physics as an analog recurrent neural network.

Analog machine learning hardware platforms promise to be faster and more energy efficient than their digital counterparts. Wave physics, as found in acoustics and optics, is a natural candidate for building analog processors for time-varying signals. Here, we identify a mapping between the dynamics of wave physics and the computation in recurrent neural networks. This mapping indicates that physical wave systems can be trained to learn complex features in temporal data, using standard training techniques for neural networks. As a demonstration, we show that an inverse-designed inhomogeneous medium can perform vowel classification on raw audio signals as their waveforms scatter and propagate through it, achieving performance comparable to a standard digital implementation of a recurrent neural network. These findings pave the way for a new class of analog machine learning platforms, capable of fast and efficient processing of information in its native domain.

Quantitative Analysis of Intestinal Stem Cell Dynamics Using Microfabricated Cell Culture Arrays.

Regeneration of intestinal epithelium is fueled by a heterogeneous population of rapidly proliferating stem cells (ISCs) found in the base of the small intestine and colonic crypts. ISCs populations can be enriched by fluorescence-activated cell sorting (FACS) based on expression of combinatorial cell surface markers, and fluorescent transgenes. Conventional ISC culture is performed by embedding single ISCs or whole crypt units in a matrix and culturing in conditions that stimulate or repress key pathways to recapitulate ISC niche signaling. Cultured ISCs form organoid, which are spherical, epithelial monolayers that are self-renewing, self-patterning, and demonstrate the full complement of intestinal epithelial cell lineages. However, this conventional "bulk" approach to studying ISC biology is often semiquantitative, low throughput, and masks clonal effects and ISC phenotypic heterogeneity. Our group has recently reported the construction, long-term biocompatibility, and use of microfabricated cell raft arrays (CRA) for high-throughput analysis of single ISCs and organoids. CRAs are composed of thousands of indexed and independently retrievable microwells, which in combination with time-lapse microscopy and/or gene-expression analyses are a powerful tool for studying clonal ISC dynamics and micro-niches. In this protocol, we describe how CRAs are used as an adaptable experimental platform to study the effect of exogenous factors on clonal stem cell behavior.