OrganoID: A versatile deep learning platform for tracking and analysis of single-organoid dynamics.

Organoids have immense potential as ex vivo disease models for drug discovery and personalized drug screening. Dynamic changes in individual organoid morphology, number, and size can indicate important drug responses. However, these metrics are difficult and labor-intensive to obtain for high-throughput image datasets. Here, we present OrganoID, a robust image analysis platform that automatically recognizes, labels, and tracks single organoids, pixel-by-pixel, in brightfield and phase-contrast microscopy experiments. The platform was trained on images of pancreatic cancer organoids and validated on separate images of pancreatic, lung, colon, and adenoid cystic carcinoma organoids, which showed excellent agreement with manual measurements of organoid count (95%) and size (97%) without any parameter adjustments. Single-organoid tracking accuracy remained above 89% over a four-day time-lapse microscopy study. Automated single-organoid morphology analysis of a chemotherapy dose-response experiment identified strong dose effect sizes on organoid circularity, solidity, and eccentricity. OrganoID enables straightforward, detailed, and accurate image analysis to accelerate the use of organoids in high-throughput, data-intensive biomedical applications.

Shot-noise limited homodyne detection for MHz quantum light characterisation in the 2 µm band.

Characterising quantum states of light in the 2 µm band requires high-performance shot-noise limited detectors. Here, we present the characterisation of a homodyne detector that we use to observe vacuum shot-noise via homodyne measurement with a 2.07 µm pulsed mode-locked laser. The device is designed primarily for pulsed illumination. It has a 3-dB bandwidth of 13.2 MHz, total conversion efficiency of 57% at 2.07 µm, and a common-mode rejection ratio of 48 dB at 39.5 MHz. The detector begins to saturate at 1.8 mW with 9 dB of shot-noise clearance at 5 MHz. This demonstration enables the characterisation of megahertz-quantum optical behaviour in the 2 µm band and provides a guide of how to design a 2 µm homodyne detector for quantum applications.

Advantage of Coherent States in Ring Resonators over Any Quantum Probe Single-Pass Absorption Estimation Strategy.

Quantum states of light have been shown to enhance precision in absorption estimation over classical strategies. By exploiting interference and resonant enhancement effects, we show that coherent-state probes in all-pass ring resonators can outperform any quantum probe single-pass strategy even when normalized by the mean input photon number. We also find that under optimal conditions coherent-state probes equal the performance of arbitrarily bright pure single-mode squeezed probes in all-pass ring resonators.

Widely-tunable mid-infrared ring cavity pump-enhanced OPO and application in photo-thermal interferometric trace ethane detection.

The development of a broadly and accurately tunable single-frequency mid-infrared laser source and its application to a sensitive laser absorption detection method are described. Photo-thermal interferometric spectroscopy is employed as a phase-sensitive method to detect the minute refractive index change caused by the heating of a gas under laser radiation. A separate probe beam allows for the spectrally-interesting mid-infrared region to be examined whilst utilizing low cost, high detectivity photodetectors in the visible/near-infrared region. We also describe the implementation of a Sagnac interferometer to minimize the effects of environmental perturbation and provide inherent passive stability. A continuous-wave ring-cavity pump-enhanced OPO has been developed to provide excitation light from 3-4 µm at 140 mW with the ability to mode-hop tune continuously over 90 cm-1 in 0.07 cm-1 steps. Complementary use of both detection apparatus and excitation source has allowed for presence of ethane to be detected down to 200 parts per billion.

Quantum Optical Metrology of Correlated Phase and Loss.

Optical absorption measurements characterize a wide variety of systems from atomic gases to in vivo diagnostics of living organisms. Here we study the potential of nonclassical techniques to reduce statistical noise below the shot-noise limit in absorption measurements with concomitant phase shifts imparted by a sample. We consider both cases where there is a known relationship between absorption and a phase shift, and where this relationship is unknown. For each case we derive the fundamental limit and provide a practical strategy to reduce statistical noise. Furthermore, we find an intuitive correspondence between measurements of absorption and of lossy phase shifts, which both show the same analytical form for precision enhancement for bright states. Our results demonstrate that nonclassical techniques can aid real-world tasks with present-day laboratory techniques.

Observation of nonlinear interference on a silicon photonic chip.

Photonic integrated circuits represent a promising platform for applying quantum information science to areas such as quantum computation, quantum communication, and quantum metrology. While the linear optical approach has greatly contributed to this field, it is often possible to improve the functionality and scalability by making use of nonlinear processes. One interesting phenomenon is the interference between two nonlinear optical processes, where the interference occurs by removing the information as to which of two processes have occurred. In this Letter, we demonstrate a nonlinear interferometer in the pair-photon generation regime by using spontaneous four-wave mixing in an integrated silicon photonic chip. We observe a nonlinear interference in the production rate of photon pairs generated from two different four-wave mixing waveguides. We obtain an interference visibility of 96.8%. This work shows the possibility of integrating and controlling nonlinear-optical-interference components for silicon quantum photonics.

Generation of random numbers by measuring phase fluctuations from a laser diode with a silicon-on-insulator chip.

Random numbers are a fundamental resource in science and technology. Among the different approaches to generating them, random numbers created by exploiting the laws of quantum mechanics have proven to be reliable and can be produced at enough rates for their practical use. While these demonstrations have shown very good performance, most of the implementations using free-space and fibre optics suffer from limitations due to their size, which strongly limits their practical use. Here we report a quantum random number generator based on phase fluctuations from a diode laser, where the other required optical components are integrated on a mm-scale monolithic silicon-on-insulator chip. The post-processing reported in this experiment is performed via software. However, our physical device shows the potential of operation at generation rates in the Gbps regime. Considering the device's size, its simple, robust and low power operation, and the rapid industrial uptake of silicon photonics, we foresee the widespread integration of the reported design in more complex systems.

An Embedded Device for Real-Time Noninvasive Intracranial Pressure Estimation.

OBJECTIVE: The monitoring of intracranial pressure (ICP) is indicated for diagnosing and guiding therapy in many neurological conditions. Current monitoring methods, however, are highly invasive, limiting their use to the most critically ill patients only. Our goal is to develop and test an embedded device that performs all necessary mathematical operations in real-time for noninvasive ICP (nICP) estimation based on a previously developed model-based approach that uses cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP) waveforms. MATERIALS AND METHODS: The nICP estimation algorithm along with the required preprocessing steps were implemented on an NXP LPC4337 microcontroller unit (MCU). A prototype device using the MCU was also developed, complete with display, recording functionality, and peripheral interfaces for ABP and CBFV monitoring hardware. RESULTS: The device produces an estimate of mean ICP once per minute and performs the necessary computations in 410 ms, on average. Real-time nICP estimates differed from the original batch-mode MATLAB implementation of theestimation algorithm by 0.63 mmHg (root-mean-square error). CONCLUSIONS: We have demonstrated that real-time nICP estimation is possible on a microprocessor platform, which offers the advantages of low cost, small size, and product modularity over a general-purpose computer. These attributes take a step toward the goal of real-time nICP estimation at the patient's bedside in a variety of clinical settings.

ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.

ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

Quantum Logic with Cavity Photons From Single Atoms.

We demonstrate quantum logic using narrow linewidth photons that are produced with an a priori nonprobabilistic scheme from a single ^{87}Rb atom strongly coupled to a high-finesse cavity. We use a controlled-not gate integrated into a photonic chip to entangle these photons, and we observe nonclassical correlations between photon detection events separated by periods exceeding the travel time across the chip by 3 orders of magnitude. This enables quantum technology that will use the properties of both narrow-band single photon sources and integrated quantum photonics.

Low testosterone has a similar prevalence among men with sexual dysfunction due to either Peyronie's disease or erectile dysfunction and does not correlate with Peyronie's disease severity.

INTRODUCTION: Low testosterone (T) has been suggested as a risk factor for Peyronie's disease (PD) that may correlate with disease severity. Low T is common in men with sexual dysfunction but its role in the pathogenesis of PD remains unclear. AIM: The aim of this study was to compare the prevalence of low T (<300 ng/dL) in patients presenting with PD or erectile dysfunction (ED), as well as disease severity between men with PD and either low T or normal T (≥300 ng/dL). METHODS: Retrospective review of 300 men with either PD or ED was conducted. Men were excluded for combined PD and ED, psychogenic ED, or prior T use. For men with PD, plaque size, degree of curvature, and surgical correction rate were compared. MAIN OUTCOME MEASURES: The main outcome measures were (i) mean T levels in men with PD or ED and (ii) plaque size, degree of curvature, and surgical correction rates among men with PD and either low T or normal T. RESULTS: Eighty-seven men with PD and 98 men with ED were identified. Men with PD had mean total T and free T of 328 ng/dL and 11.5 ng/dL, while men with ED had mean levels of 332 ng/dL and 12.1 ng/dL, respectively (P > 0.05). Of PD men, 52.9% had low T, compared with 45.9% of men with ED (P = 0.35). T levels did not correlate with plaque size or degree of curvature in the PD group (P > 0.05). CONCLUSIONS: Men with sexual dysfunction characterized by either PD or ED had similarly low T levels, and low T did not correlate with PD severity or surgical correction rate. The comparable prevalence of low T in men with PD or ED suggests the high rate of low T in PD men may be related to a common process among men with abnormal erectile physiology and not specifically causative in plaque formation.

Nutritional predictors of complications following radical cystectomy.

PURPOSE: To determine the impact of preoperative nutritional status on the development of surgical complications following cystectomy using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). METHODS: We performed a retrospective review of the NSQIP 2005-2012 Participant Use Data Files. ACS-NSQIP collects data on 135 variables, including pre- and intraoperative data and 30-day postoperative complications and mortality on all major surgical procedures at participating institutions. Preoperative albumin (<3.5 or >3.5 g/dl), weight loss 6 months before surgery (>10 %), and body mass index (BMI) were identified as nutritional variables within the database. The overall complication rate was calculated, and predictors of complications were identified using multivariable logistic regression models. RESULTS: A total of 1,213 patients underwent cystectomy for bladder cancer between 2005 and 2012. The overall 30-day complication rate was 55.1 % (n = 668). While 14.7 % (n = 102) had a preoperative albumin <3.5 g/dL, 3.4 % had >10 % weight loss in the 6 months prior to surgery and the mean BMI was 28 kg/m(2). After controlling for age, sex, medical comorbidities, medical resident involvement, operation year, operative time, and prior operation, only albumin <3.5 g/dl was a significant predictor of experiencing a postoperative complication (p = 0.03). This remained significant when albumin was evaluated as a continuous variable (p = 0.02). CONCLUSIONS: Poor nutritional status measured by serum albumin is predictive of an increased rate of surgical complications following radical cystectomy. This finding supports the importance of preoperative nutritional status in this population and highlights the need for the development of effective nutritional interventions in the preoperative setting.

Resident involvement and experience do not affect perioperative complications following robotic prostatectomy.

PURPOSE: Most urologic training programs use robotic prostatectomy (RP) as an introduction to teach residents appropriate robotic technique. However, concerns may exist regarding differences in RP outcomes with resident involvement. Our objective was therefore to evaluate whether resident involvement affects complications, operative time, or length of stay (LOS) following RP. METHODS: Using the National Surgical Quality Improvement Program database (2005-2011), we identified patients who underwent RP, stratified them by resident presence or absence during surgery, and compared hospital LOS, operative time, and postoperative complications using bivariable and multivariable analyses. A secondary analysis comparing outcomes of interest across postgraduate year (PGY) levels was also performed. RESULTS: A total of 5,087 patients who underwent RPs were identified, in which residents participated in 56%, during the study period. After controlling for potential confounders, resident present and absent groups were similar in 30-day mortality (0.0 vs. 0.2%, p = 0.08), serious morbidity (1.8 vs. 2.1%, p = 0.33), and overall morbidity (5.1 vs. 5.4%, p = 0.70). While resident involvement did not affect LOS, operative time was longer when residents were present (median 208 vs. 183 min, p < 0.001). Similar findings were noted when assessing individual PGY levels. CONCLUSIONS: Regardless of PGY level, resident involvement in RPs appears safe and does not appear to affect postoperative complications or LOS. While resident involvement in RPs does result in longer operative times, this is necessary for the learning process.

Sarcopenia as a predictor of complications and survival following radical cystectomy.

PURPOSE: Patients undergoing radical cystectomy face substantial but highly variable risks of major complications. Risk stratification may be enhanced by objective measures such as sarcopenia. Sarcopenia (loss of skeletal muscle mass) has emerged as a novel biomarker associated with adverse outcomes in many clinical contexts relevant to cystectomy. Based on these data we hypothesized that sarcopenia would be associated with increased 30-day major complications and mortality after radical cystectomy for bladder cancer. MATERIALS AND METHODS: We performed a retrospective study of patients treated with radical cystectomy at our institution from 2008 to 2011. Sarcopenia was assessed by measuring cross-sectional area of the psoas muscle (total psoas area) on preoperative computerized tomography. Cutoff points were developed and evaluated using ROC curves to determine predictive ability in men and women for outcomes of major complications and survival. RESULTS: Of 224 patients with bladder cancer 200 underwent preoperative computerized tomography within 1 month of surgery. Total psoas area was calculated with a mean score of 712 and 571 cm2/m2 in men and women, respectively. A clear association was noted between major complications and lower total psoas area in women using a cutoff of 523 cm2/m2 to define sarcopenia (AUC 0.70). Sarcopenia was not significantly associated with complications in men. There was a nonsignificant trend of sarcopenia with worse 2-year survival. CONCLUSIONS: Sarcopenia in women was a predictor of major complications after radical cystectomy. Further research confirming sarcopenia as a useful predictor of complications would support the development of targeted interventions to mitigate the untoward effects of sarcopenia before cancer surgery.

Quantum walks of correlated photon pairs in two-dimensional waveguide arrays.

We demonstrate quantum walks of correlated photons in a two-dimensional network of directly laser written waveguides coupled in a "swiss cross" arrangement. The correlated detection events show high-visibility quantum interference and unique composite behavior: strong correlation and independence of the quantum walkers, between and within the planes of the cross. Violations of a classically defined inequality, for photons injected in the same plane and in orthogonal planes, reveal nonclassical behavior in a nonplanar structure.

Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity.

OBJECTIVE: To determine whether neoadjuvant chemotherapy (NAC) is a predictor of postoperative complications, length of stay (LOS), or operating time after radical cystectomy (RC) for bladder cancer. PATIENTS AND METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC before RC from 2005 to 2011. Bivariable and multivariable analyses were used to determine whether NAC was associated with 30-day perioperative outcomes, e.g. complications, LOS, and operating time. RESULTS: Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC. In all, 457 of the 878 patients (52.1%) undergoing RC had at least one complication ≤30 days of RC, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (P = 0.58). On multivariable logistic regression, NAC was not a predictor of complications (P = 0.87), re-operation (P = 0.16), wound infection (P = 0.32), or wound dehiscence (P = 0.32). Using multiple linear regression, NAC was not a predictor of increased operating time (P = 0.24), and patients undergoing NAC had a decreased LOS (P = 0.02). CONCLUSIONS: Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC. Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC. Considering these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.

A Bi-CMOS electronic photonic integrated circuit quantum light detector.

Complimentary metal-oxide semiconductor (CMOS) integration of quantum technology provides a route to manufacture at volume, simplify assembly, reduce footprint, and increase performance. Quantum noise-limited homodyne detectors have applications across quantum technologies, and they comprise photonics and electronics. Here, we report a quantum noise-limited monolithic electronic-photonic integrated homodyne detector, with a footprint of 80 micrometers by 220 micrometers, fabricated in a 250-nanometer lithography bipolar CMOS process. We measure a 15.3-gigahertz 3-decibel bandwidth with a maximum shot noise clearance of 12 decibels and shot noise clearance out to 26.5 gigahertz, when measured with a 9-decibel-milliwatt power local oscillator. This performance is enabled by monolithic electronic-photonic integration, which goes below the capacitance limits of devices made up of separate integrated chips or discrete components. It exceeds the bandwidth of quantum detectors with macroscopic electronic interconnects, including wire and flip chip bonding. This demonstrates electronic-photonic integration enhancing quantum photonic device performance.

Heterogeneous Integration of Solid-State Quantum Systems with a Foundry Photonics Platform.

Diamond color centers are promising optically addressable solid-state spins that can be matter-qubits, mediate deterministic interaction between photons, and act as single photon emitters. Useful quantum computers will comprise millions of logical qubits. To become useful in constructing quantum computers, spin-photon interfaces must, therefore, become scalable and be compatible with mass-manufacturable photonics and electronics. Here, we demonstrate the heterogeneous integration of NV centers in nanodiamond with low-fluorescence silicon nitride photonics from a standard 180 nm CMOS foundry process. Nanodiamonds are positioned over predefined sites in a regular array on a waveguide in a single postprocessing step. Using an array of optical fibers, we excite NV centers selectively from an array of six integrated nanodiamond sites and collect the photoluminescence (PL) in each case into waveguide circuitry on-chip. We verify single photon emission by an on-chip Hanbury Brown and Twiss cross-correlation measurement, which is a key characterization experiment otherwise typically performed routinely with discrete optics. Our work opens up a simple and effective route to simultaneously address large arrays of individual optically active spins at scale, without requiring discrete bulk optical setups. This is enabled by the heterogeneous integration of NV center nanodiamonds with CMOS photonics.

Severe outcomes are associated with genogroup 2 genotype 4 norovirus outbreaks: a systematic literature review.

BACKGROUND: Noroviruses (NoVs) are the most common cause of epidemic gastroenteritis; however, the relative impacts of individual factors underlying severe illness are poorly understood. This report reviews published NoV outbreak reports to quantify hospitalization and mortality rates and assess their relationship with outbreak setting, transmission route, and strain. METHODS: Using a string of terms related to "norovirus" and "outbreak," we 2435 nonduplicate articles identified in PubMed, EMBASE, and Web of Knowledge published between January 1993 and June 2011. Inclusion criteria included outbreaks with a minimum of 2 ill persons with a common exposure and at least 1 reverse-transcription polymerase chain reaction-confirmed case of NoV disease. Univariate analyses were performed, and multivariable models were fitted to estimate the independent effect of each factor. RESULTS: We analyzed 843 NoV outbreaks reported in 233 published articles from 45 countries. Based upon 71724 illnesses, 501 hospitalizations, and 45 deaths, overall hospitalization and mortality rates were 0.54% and 0.06%, respectively. In multivariate analysis, genogroup 2 genotype 4 (GII.4) NoV strains were associated with higher hospitalization (incidence rate ratio [IRR], 9.4; 95% confidence interval [CI], 6.1-14.4; P< .001) and mortality rates (IRR, 3.1; 95% CI, 1.3-7.6; P = .01). Deaths were much more likely to occur in outbreaks occurring in healthcare facilities (IRR, 60; 95% CI, 6-109; P = .01). CONCLUSIONS: Our review suggests that hospitalizations and deaths were more likely in outbreaks associated with GII.4 viruses, independent of other factors, and underscores the importance of developing vaccines against GII.4 viruses to prevent severe disease outcomes.