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.

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.

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.

Zero-Index Bound States in the Continuum.

Metamaterials with an effective zero refractive index associated with their electromagnetic response are sought for a number of applications in communications and nonlinear optics. A promising way that this can be achieved in all-dielectric photonic crystals is through the design of a Dirac cone at zero Bloch wave vector in the photonic band structure. In the optical frequency range, the natural way to implement this design is through the use of a photonic crystal slab. In the existing implementation, however, the zero-index photonic modes also radiate strongly into the environment due to intrinsic symmetry properties. This has resulted in large losses in recent experimental realizations of this zero-index paradigm. Here, we propose a photonic crystal slab with zero-index modes which are also symmetry-protected bound states in the continuum. Our approach thus eliminates the associated radiation loss. This could enable, for the first time, large-scale integration of zero-index materials in photonic devices.

Probiotic capsules and xylitol chewing gum to manage symptoms of pharyngitis: a randomized controlled factorial trial.

BACKGROUND: Reducing the use of antibiotics for upper respiratory tract infections is needed to limit the global threat of antibiotic resistance. We estimated the effectiveness of probiotics and xylitol for the management of pharyngitis. METHODS: In this parallel-group factorial randomized controlled trial, participants in primary care (aged 3 years or older) with pharyngitis underwent randomization by nurses who provided sequential intervention packs. Pack contents for 3 kinds of material and advice were previously determined by computer-generated random numbers: no chewing gum, xylitol-based chewing gum (15% xylitol; 5 pieces daily) and sorbitol gum (5 pieces daily). Half of each group were also randomly assigned to receive either probiotic capsules (containing 24 × 109 colony-forming units of lactobacilli and bifidobacteria) or placebo. The primary outcome was mean self-reported severity of sore throat and difficulty swallowing (scale 0-6) in the first 3 days. We used multiple imputation to avoid the assumption that data were missing completely at random. RESULTS: A total of 1009 individuals consented, 934 completed the baseline assessment, and 689 provided complete data for the primary outcome. Probiotics were not effective in reducing the severity of symptoms: mean severity scores 2.75 with no probiotic and 2.78 with probiotic (adjusted difference -0.001, 95% confidence interval [CI] -0.24 to 0.24). Chewing gum was also ineffective: mean severity scores 2.73 without gum, 2.72 with sorbitol gum (adjusted difference 0.07, 95% CI -0.23 to 0.37) and 2.73 with xylitol gum (adjusted difference 0.01, 95% CI -0.29 to 0.30). None of the secondary outcomes differed significantly between groups, and no harms were reported. INTERPRETATION: Neither probiotics nor advice to chew xylitol-based chewing gum was effective for managing pharyngitis. Trial registration: ISRCTN, no. ISRCTN51472596.

An internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (PRIMIT): a primary care randomised trial.

BACKGROUND: Handwashing to prevent transmission of respiratory tract infections (RTIs) has been widely advocated, especially during the H1N1 pandemic. However, the role of handwashing is debated, and no good randomised evidence exists among adults in non-deprived settings. We aimed to assess whether an internet-delivered intervention to modify handwashing would reduce the number of RTIs among adults and their household members. METHODS: We recruited individuals sharing a household by mailed invitation through general practices in England. After consent, participants were randomised online by an automated computer-generated random number programme to receive either no access or access to a bespoke automated web-based intervention that maximised handwashing intention, monitored handwashing behaviour, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs. We enrolled participants into an additional cohort (randomised to receive intervention or no intervention) to assess whether the baseline questionnaire on handwashing would affect handwashing behaviour. Participants were not masked to intervention allocation, but statistical analysis commands were constructed masked to group. The primary outcome was number of episodes of RTIs in index participants in a modified intention-to-treat population of randomly assigned participants who completed follow-up at 16 weeks. This trial is registered with the ISRCTN registry, number ISRCTN75058295. FINDINGS: Across three winters between Jan 17, 2011, and March 31, 2013, we enrolled 20,066 participants and randomly assigned them to receive intervention (n=10,040) or no intervention (n=10,026). 16,908 (84%) participants were followed up with the 16 week questionnaire (8241 index participants in intervention group and 8667 in control group). After 16 weeks, 4242 individuals (51%) in the intervention group reported one or more episodes of RTI compared with 5135 (59%) in the control group (multivariate risk ratio 0·86, 95% CI 0·83-0·89; p<0·0001). The intervention reduced transmission of RTIs (reported within 1 week of another household member) both to and from the index person. We noted a slight increase in minor self-reported skin irritation (231 [4%] of 5429 in intervention group vs 79 [1%] of 6087 in control group) and no reported serious adverse events. INTERPRETATION: In non-pandemic years, an effective internet intervention designed to increase handwashing could have an important effect in reduction of infection transmission. In view of the heightened concern during a pandemic and the likely role of the internet in access to advice, the intervention also has potential for effective implementation during a pandemic. FUNDING: Medical Research Council.

Effectiveness of steam inhalation and nasal irrigation for chronic or recurrent sinus symptoms in primary care: a pragmatic randomized controlled trial.

BACKGROUND: Systematic reviews support nasal saline irrigation for chronic or recurrent sinus symptoms, but trials have been small and few in primary care settings. Steam inhalation has also been proposed, but supporting evidence is lacking. We investigated whether brief pragmatic interventions to encourage use of nasal irrigation or steam inhalation would be effective in relieving sinus symptoms. METHODS: We conducted a pragmatic randomized controlled trial involving adults (age 18-65 yr) from 72 primary care practices in the United Kingdom who had a history of chronic or recurrent sinusitis and reported a "moderate to severe" impact of sinus symptoms on their quality of life. Participants were recruited between Feb. 11, 2009, and June 30, 2014, and randomly assigned to 1 of 4 advice strategies: usual care, daily nasal saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions. The primary outcome measure was the Rhinosinusitis Disability Index (RSDI). Patients were followed up at 3 and 6 months. We imputed missing data using multiple imputation methods. RESULTS: Of the 961 patients who consented, 871 returned baseline questionnaires (210 usual care, 219 nasal irrigation, 232 steam inhalation and 210 combined treatment). A total of 671 (77.0%) of the 871 participants reported RSDI scores at 3 months. Patients' RSDI scores improved more with nasal irrigation than without nasal irrigation by 3 months (crude change -7.42 v. -5.23; estimated adjusted mean difference between groups -2.51, 95% confidence interval -4.65 to -0.37). By 6 months, significantly more patients maintained a 10-point clinically important improvement in the RSDI score with nasal irrigation (44.1% v. 36.6%); fewer used over-the-counter medications (59.4% v. 68.0%) or intended to consult a doctor in future episodes. Steam inhalation reduced headache but had no significant effect on other outcomes. The proportion of participants who had adverse effects was the same in both intervention groups. INTERPRETATION: Advice to use steam inhalation for chronic or recurrent sinus symptoms in primary care was not effective. A similar strategy to use nasal irrigation was less effective than prior evidence suggested, but it provided some symptomatic benefit. TRIAL REGISTRATION: ISRCTN, no. 88204146.

Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial.

BACKGROUND: Otitis media with effusion is a common problem that lacks an evidence-based nonsurgical treatment option. We assessed the clinical effectiveness of treatment with a nasal balloon device in a primary care setting. METHODS: We conducted an open, pragmatic randomized controlled trial set in 43 family practices in the United Kingdom. Children aged 4-11 years with a recent history of ear symptoms and otitis media with effusion in 1 or both ears, confirmed by tympanometry, were allocated to receive either autoinflation 3 times daily for 1-3 months plus usual care or usual care alone. Clearance of middle-ear fluid at 1 and 3 months was assessed by experts masked to allocation. RESULTS: Of 320 children enrolled, those receiving autoinflation were more likely than controls to have normal tympanograms at 1 month (47.3% [62/131] v. 35.6% [47/132]; adjusted relative risk [RR] 1.36, 95% confidence interval [CI] 0.99 to 1.88) and at 3 months (49.6% [62/125] v. 38.3% [46/120]; adjusted RR 1.37, 95% CI 1.03 to 1.83; number needed to treat = 9). Autoinflation produced greater improvements in ear-related quality of life (adjusted between-group difference in change from baseline in OMQ-14 [an ear-related measure of quality of life] score -0.42, 95% CI -0.63 to -0.22). Compliance was 89% at 1 month and 80% at 3 months. Adverse events were mild, infrequent and comparable between groups. INTERPRETATION: Autoinflation in children aged 4-11 years with otitis media with effusion is feasible in primary care and effective both in clearing effusions and improving symptoms and ear-related child and parent quality of life. TRIAL REGISTRATION: ISRCTN, No. 55208702.

ATP-dependent citrate lyase Drives Left Ventricular Dysfunction by Metabolic Remodeling of the Heart.

Background: Metabolic remodeling is a hallmark of the failing heart. Oncometabolic stress during cancer increases the activity and abundance of the ATP-dependent citrate lyase (ACL, Acly ), which promotes histone acetylation and cardiac adaptation. ACL is critical for the de novo synthesis of lipids, but how these metabolic alterations contribute to cardiac structural and functional changes remains unclear. Methods: We utilized human heart tissue samples from healthy donor hearts and patients with hypertrophic cardiomyopathy. Further, we used CRISPR/Cas9 gene editing to inactivate Acly in cardiomyocytes of MyH6-Cas9 mice. In vivo, positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to the loss of ACL. We conducted a multi-omics analysis using RNA-sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. Results: Here, we show that in mice, ACL drives metabolic adaptation in the heart to sustain contractile function, histone acetylation, and lipid modulation. Notably, we show that loss of ACL increases glucose oxidation while maintaining fatty acid oxidation. Ex vivo isotope tracing experiments revealed a reduced efflux of glucose-derived citrate from the mitochondria into the cytosol, confirming that citrate is required for reductive metabolism in the heart. We demonstrate that YAP inactivation facilitates ACL deficiency. Computational flux analysis and integrative multi-omics analysis indicate that loss of ACL induces alternative isocitrate dehydrogenase 1 flux to compensate. Conclusions: This study mechanistically delineates how cardiac metabolism compensates for suppressed citrate metabolism in response to ACL loss and uncovers metabolic vulnerabilities in the heart.

Sampling environmental acoustic recordings to determine bird species richness.

Acoustic sensors can be used to estimate species richness for vocal species such as birds. They can continuously and passively record large volumes of data over extended periods. These data must subsequently be analyzed to detect the presence of vocal species. Automated analysis of acoustic data for large numbers of species is complex and can be subject to high levels of false positive and false negative results. Manual analysis by experienced surveyors can produce accurate results; however the time and effort required to process even small volumes of data can make manual analysis prohibitive. This study examined the use of sampling methods to reduce the cost of analyzing large volumes of acoustic sensor data, while retaining high levels of species detection accuracy. Utilizing five days of manually analyzed acoustic sensor data from four sites, we examined a range of sampling frequencies and methods including random, stratified, and biologically informed. We found that randomly selecting 120 one-minute samples from the three hours immediately following dawn over five days of recordings, detected the highest number of species. On average, this method detected 62% of total species from 120 one-minute samples, compared to 34% of total species detected from traditional area search methods. Our results demonstrate that targeted sampling methods can provide an effective means for analyzing large volumes of acoustic sensor data efficiently and accurately. Development of automated and semi-automated techniques is required to assist in analyzing large volumes of acoustic sensor data.

Properties and self-assembled packing morphology of long alkyl-chained substituted polyhedral oligomeric silsesquioxanes (POSS) cages.

Polyhedral oligomeric silsesquioxane (POSS) cubic cage systems (octa-n-octadecyloctasilsesquioxane, (T8C18) and octakis(n-octadecyldimethylsiloxy)octasilsesquioxane, (Q8C18)) were synthesised with eight long n-alkyl chain (R = C18H37) substituent arms, as model nano-functionalized compounds. The crystalline packing morphology of the cages was studied using time-resolved Small- and Wide-angle X-ray scattering (SAXS/WAXS), thermal and optical techniques. From thermal analysis the melting and crystallization temperatures of the Q8 cage were significantly less than those for the T8 cage. X-ray scattering showed that both cage systems have long-range crystalline ordering where the alkyl chains align in a parallel axial disposition from the POSS core giving a 'rod-like' self-assembled packing morphology. The packing length-scale can be directly related to the overall dimensions of the POSS molecules. Compared to the T8 cages, the Q8 cages pack more efficiently allowing the interdigitation of the alkyl chain arms. Different packing modes and thermal behaviour observed for the T8 and Q8 cages is directly attributed to their structural chemistry. For the Q8 cage, the presence of the OSiMe2 spacer groups which tether the alkyl chain arms to the cage (absent in the T8 cages) allows greater flexibility of the arms letting them interdigitate with each other when packing which is not observed for the analogous T8 cages.

Autoinflation for hearing loss associated with otitis media with effusion.

BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2006.Otitis media with effusion (OME) or 'glue ear' is an accumulation of fluid in the middle ear, in the absence of acute inflammation or infection. It is the commonest cause of acquired hearing loss in childhood and the usual reason for insertion of 'grommets'. Potential treatments include decongestants, mucolytics, steroids, antihistamines and antibiotics. Autoinflation devices have been proposed as a simple mechanical means of improving 'glue ear'. OBJECTIVES: To assess the effectiveness of autoinflation compared with no treatment in children and adults with otitis media with effusion. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 12 April 2013. SELECTION CRITERIA: We selected randomised controlled trials that compared any form of autoinflation to no autoinflation in individuals with 'glue ear'. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, assessed risk of bias and extracted data from included studies. MAIN RESULTS: Eight studies, with a total of 702 participants, met the inclusion criteria. Overall, the studies were predominantly assessed as being at low or unclear risk of bias; unclear risk was mainly due lack of information. There was no evidence of selective reporting.Pooled estimates favoured the intervention, but did not show a significant effect on tympanometry (type C2 and B) at less than one month, nor at more than one month. Similarly, there were no significant changes for discrete pure-tone audiometry and non-discrete audiometry. Pooled estimates favoured, but not significantly, the intervention for the composite measure of tympanogram or audiometry at less than one month; at more than one month the result became significant (RRI 1.74, 95% CI 1.22 to 2.50). Subgroup analysis based on the type of intervention showed a significant effect using a Politzer device under one month (RRI 7.07, 95% CI 3.70 to 13.51) and over one month (RRI 2.25, 95% CI 1.67 to 3.04).None of the studies demonstrated a significant difference in the incidence of side effects between interventions. AUTHORS' CONCLUSIONS: All of the studies were small, of limited treatment duration and had short follow-up. However, because of the low cost and absence of adverse effects it is reasonable to consider autoinflation whilst awaiting natural resolution of otitis media with effusion. Primary care could prove a beneficial place to evaluate such interventions and there is ongoing research in this area. Further research should also consider the duration of treatment, the long-term impact on developmental outcomes in children and additional quality of life outcome measures for children and families.

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.

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.

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.

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.

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.

Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-{gamma}/JAK/STAT1 signaling is critical for the expression of PTN in macrophages.

Neovascularization is critical to destabilization of atheroma. We previously reported that the angiogenic growth factor pleiotrophin (PTN) coaxes monocytes to assume the phenotype of functional endothelial cells in vitro and in vivo. In this study we show that PTN expression is colocalized with capillaries of human atherosclerotic plaques. Among the various reagents that are critical to the pathogenesis of atherosclerosis, interferon (IFN)-gamma was found to markedly induce PTN mRNA expression in a dose-dependent manner in macrophages. Mechanistic studies revealed that the Janus kinase inhibitors, WHI-P154 and ATA, efficiently blocked STAT1 phosphorylation in a concentration- and time-dependent manner. Notably, the level of phosphorylated STAT1 was found to correlate directly with the PTN mRNA levels. In addition, STAT1/STAT3/p44/42 signaling molecules were found to be phosphorylated by IFN-gamma in macrophages, and they were translocated into the nucleus. Further, PTN promoter analysis showed that a gamma-activated sequence (GAS) located at -2086 to -2078 bp is essential for IFN-gamma-regulated promoter activity. Moreover, electrophoretic mobility shift, supershift, and chromatin immunoprecipitation analyses revealed that both STAT1 and STAT3 bind to the GAS at the chromatin level in the IFN-gamma stimulated cells. Finally, to test whether the combined effect of STAT1/STAT3/p44/42 signaling is required for the expression of PTN in macrophages, gene knockdowns of these transcription factors were performed using siRNA. Cells lacking STAT1, but not STAT3 or p42, have markedly reduced PTN mRNA levels. These data suggest that PTN expression in the human plaques may be in part regulated by IFN-gamma and that PTN is involved in the adaptive immunity.-Li, F., Tian, F., Wang, L., Williamson, I. K., Sharifi, B. G., Shah, P. K. Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-gamma/JAK/STAT1 signaling is critical for the expression of PTN in macrophages.