Novel physiologic predictors of positive airway pressure effectiveness (NICEPAP) study: rationale, design and methods.

PURPOSE: Continuous positive airway pressure (CPAP) is the primary therapy for obstructive sleep apnea (OSA); however the effectiveness of CPAP remains suboptimal. We describe the Novel PhysIologiC prEdictors of Positive Airway Pressure Effectiveness (NICEPAP) study. Its purpose is to determine whether physiological traits of OSA contribute to CPAP effectiveness. METHODS: NICEPAP (NCT05067088) is a prospective, observational cohort study conducted at an academic sleep center. Adults newly diagnosed with OSA (n = 267) are assessed for OSA traits of loop gain, arousal threshold, pharyngeal collapsibility, and muscle compensation from baseline polysomnography. We perform a comprehensive assessment of covariates relevant to CPAP adherence, efficacy, and patient-centered outcomes. Participants are followed for 12 months. Primary outcomes include (1) CPAP adherence (hours/night), (2) CPAP efficacy (apneas-hypopneas/hour), and (3) quality of life at six months measured by objective CPAP data and Functional Outcomes of Sleep Questionnaire. Secondary outcomes include sleep quality, sleepiness, insomnia, and neurocognitive function. RESULTS: Data on covariates, including demographics, sleep symptoms, medical history, medications, sleep quality, OSA and treatment self-efficacy, decisional balance, and socio-economic and social and partner support, are collected using validated instruments. The analysis for primary outcomes includes a generalized linear mixed model for an outcome (e.g., CPAP adherence) with OSA traits as exposures followed by the addition of relevant covariates. CONCLUSION: The findings of the NICEPAP study will inform research aimed to enhance CPAP effectiveness. Understanding the role of physiological OSA traits in CPAP effectiveness is a crucial step toward a precision medicine approach to OSA.

Precise localization of corneal reflections in eye images using deep learning trained on synthetic data.

We present a deep learning method for accurately localizing the center of a single corneal reflection (CR) in an eye image. Unlike previous approaches, we use a convolutional neural network (CNN) that was trained solely using synthetic data. Using only synthetic data has the benefit of completely sidestepping the time-consuming process of manual annotation that is required for supervised training on real eye images. To systematically evaluate the accuracy of our method, we first tested it on images with synthetic CRs placed on different backgrounds and embedded in varying levels of noise. Second, we tested the method on two datasets consisting of high-quality videos captured from real eyes. Our method outperformed state-of-the-art algorithmic methods on real eye images with a 3-41.5% reduction in terms of spatial precision across data sets, and performed on par with state-of-the-art on synthetic images in terms of spatial accuracy. We conclude that our method provides a precise method for CR center localization and provides a solution to the data availability problem, which is one of the important common roadblocks in the development of deep learning models for gaze estimation. Due to the superior CR center localization and ease of application, our method has the potential to improve the accuracy and precision of CR-based eye trackers.

Nicotine, alcohol, and caffeine use among individuals with untreated obstructive sleep apnea.

BACKGROUND: Psychoactive substance use (i.e., nicotine, alcohol, and caffeine) has substantial effects on sleep architecture in healthy individuals, but their effects in those with obstructive sleep apnea (OSA) have not been well described. We aimed to describe the association between psychoactive substance use and sleep characteristics and daytime symptoms in individuals with untreated OSA. METHODS: We performed a secondary, cross-sectional analysis of The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Exposures included current smoking, alcohol and caffeine use in individuals with untreated OSA. Outcome domains included subjective and objective sleep characteristics, daytime symptoms, and comorbid conditions. Linear or logistic regression assessed the association between substance use and each domain (e.g., self-reported sleep duration, total polysomnographic sleep time, sleepiness, and anxiety). RESULTS: Of the 919 individuals with untreated OSA, 116 (12.6%) were current cigarette smokers, 585 (63.7%) were moderate or heavy alcohol users, and 769 (83.7%) were moderate or heavy caffeine users. Participants were on average 52.2±11.9 years old, 65.2% were male with a median BMI of 30.6 (IQR: 27.2, 35.9, kg/m2). Current smokers exhibited lower sleep duration (0.3 h), longer sleep latency (5 min) compared with non-smokers (all p-values < 0.05). People with heavy or moderate alcohol use exhibited more REM sleep (2.5 and 5% of total sleep time respectively), as did those with moderate caffeine use (2%, p-values < 0.05). The combined smoker plus caffeine group exhibited shorter sleep duration (0.4 h, p-value < 0.05) and higher risk for chronic pain [Odds Ratio (95%CI) = 4.83 (1.57, 14.9) compared with non-users. CONCLUSIONS: Psychoactive substance use is associated with sleep characteristics and clinically relevant correlates in people with untreated OSA. Further investigation into the effects that various substances have on this population may present opportunities to understand disease mechanisms more fully and increase the effectiveness of treatment in OSA.

Predicting choice behaviour in economic games using gaze data encoded as scanpath images.

Eye movement data has been extensively utilized by researchers interested in studying decision-making within the strategic setting of economic games. In this paper, we demonstrate that both deep learning and support vector machine classification methods are able to accurately identify participants' decision strategies before they commit to action while playing games. Our approach focuses on creating scanpath images that best capture the dynamics of a participant's gaze behaviour in a way that is meaningful for predictions to the machine learning models. Our results demonstrate a higher classification accuracy by 18% points compared to a baseline logistic regression model, which is traditionally used to analyse gaze data recorded during economic games. In a broader context, we aim to illustrate the potential for eye-tracking data to create information asymmetries in strategic environments in favour of those who collect and process the data. These information asymmetries could become especially relevant as eye-tracking is expected to become more widespread in user applications, with the seemingly imminent mass adoption of virtual reality systems and the development of devices with the ability to record eye movement outside of a laboratory setting.

SGC-CAMKK2-1: A Chemical Probe for CAMKK2.

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

Failure Modes of Platinized pn+-GaInP Photocathodes for Solar-Driven H2 Evolution.

The long-term stability for the hydrogen-evolution reaction (HER) of homojunction pn+-Ga0.52In0.48P photocathodes (band gap = 1.8 eV) with an electrodeposited Pt catalyst (pn+-GaInP/Pt) has been systematically evaluated in both acidic and alkaline electrolytes. Electrode dissolution during chronoamperometry was correlated with changes over time in the current density-potential (J-E) behavior to reveal the underlying failure mechanism. Pristine pn+-GaInP/Pt photocathodes yielded an open-circuit photopotential (Eoc) as positive as >1.0 V vs the potential of the reversible hydrogen electrode (RHE) and a light-limited current density (Jph) of >12 mA cm-2 (1-sun illumination). However, Eoc and Jph gradually degraded at either pH 0 or pH 14. The performance degradation was attributed to three different failure modes: (1) gradual thinning of the n+-emitter layer due to GaInP dissolution in acid; (2) active corrosion of the underlying GaAs substrate at positive potentials causing delamination of the upper GaInP epilayers; and (3) direct GaAs/electrolyte contact compromising the operational stability of the device. This work reveals the importance of both substrate stability and structural integrity of integrated photoelectrodes toward stable solar fuel generation.

The effect of planning time on penultimate and ultimate step kinematics and subsequent knee moments during sidestepping.

Frontal plane postures during the ultimate step of sidestepping are linked to increased anterior cruciate ligament injury risk. However, there is a lack of research detailing the kinematic strategies present in the penultimate step. This study, therefore, investigated penultimate and ultimate step kinematics of planned sidestepping (pSS) and unplanned sidestepping (upSS) to further understand the effect of planning time on known ultimate step kinematic and kinetic differences. Sixty male amateur Australian Rules football players performed three trials of straight-line running (RUN), pSS, and upSS in a randomized order. Mediolateral foot placement and three-dimensional joint kinematics for the knee, pelvis, and trunk were measured at final foot contact of the penultimate step and initial foot contact of the ultimate step. Peak knee moments were measured during the weight acceptance phase of the ultimate step. In pSS, at the penultimate step final foot contact, the support foot was placed across the midline of the center of mass, in the frontal plane, contralateral to the sidestep direction. Greater trunk lateral flexion toward the sidestep direction and greater negative pelvic lateral tilt were observed in pSS compared with upSS and RUN. Differences between pSS and upSS frontal plane kinematics at penultimate step final foot contact suggest preparatory reorientation strategies are likely constrained by the amount of planning time available. As there are clear differences in preparatory kinematics, we recommend that planning time be considered when training and assessing sidestepping maneuvers and planned and unplanned maneuvers not be treated as interchangeable skills.

Refolding of lid subdomain of SARS-CoV-2 nsp14 upon nsp10 interaction releases exonuclease activity.

During RNA replication, coronaviruses require proofreading to maintain the integrity of their large genomes. Nsp14 associates with viral polymerase complex to excise the mismatched nucleotides. Aside from the exonuclease activity, nsp14 methyltransferase domain mediates cap methylation, facilitating translation initiation and protecting viral RNA from recognition by the innate immune sensors. The nsp14 exonuclease activity is modulated by a protein co-factor nsp10. While the nsp10/nsp14 complex structure is available, the mechanistic basis for nsp10-mediated modulation remains unclear in the absence of the nsp14 structure. Here, we provide a crystal structure of nsp14 in an apo-form. Comparative analysis of the apo- and nsp10-bound structures explain the modulatory role of the co-factor protein and reveal the allosteric nsp14 control mechanism essential for drug discovery. Further, the flexibility of the N-terminal lid of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nsp14 structure presented in this study rationalizes the recently proposed idea of nsp14/nsp10/nsp16 ternary complex.

Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes.

CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency in vitro, while compounds 13g and 45 had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.

Photoactivated release of membrane impermeant sulfonates inside cells.

Photouncaging delivers compounds with high spatial and temporal control to induce or inhibit biological processes but the released compounds may diffuse out. We here demonstrate that sulfonate anions can be photocaged so that a membrane impermeable compound can enter cells, be uncaged by photoirradiation and trapped within the cell.

Concise, gram-scale synthesis of furo[2,3-b]pyridines with functional handles for chemoselective cross-coupling.

A concise 4-step synthesis of furo[2,3-b]pyridines, with handles in the 3- and 5-positions for palladium mediated cross-coupling reactions, is described. The synthetic route has been optimized, with only one step requiring purification by column chromatography. The route is amenable to scale-up, and was successfully executed on a multi-gram scale. Furopyridines are of growing interest in medicinal chemistry, and this route should enable easy access to the core for structure-activity relationship (SAR) studies.

In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds.

The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. The deregulation of CAMKK2 is linked to several diseases, suggesting the utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work, we demonstrate that STO-609, frequently described as a selective inhibitor for CAMKK2, potently inhibits a significant number of other kinases. Through an analysis of literature and public databases, we have identified other potent CAMKK2 inhibitors and verified their activities in differential scanning fluorimetry and enzyme inhibition assays. These inhibitors are potential starting points for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.

By failing to prepare, you are preparing your anterior cruciate ligament to fail.

There is strong evidence linking an athlete's movement technique during sidestepping with anterior cruciate ligament (ACL) injury risk. However, it is unclear how these injurious postures are influenced by prior movement. We aim to describe preparatory trunk and thigh kinematics at toe-off of the penultimate-step and flight-phase angular momenta, and explore their associations with frontal-plane risk factors during unplanned sidestepping maneuvers. We analyzed kinematic and kinetic data of 33 male Australian Football players performing unplanned sidestepping tasks (103 trials). Linear mixed models tested for reliable associations between ACL injury risk during weight acceptance of the execution-step, with preparatory kinematics and angular momenta of the trunk and thigh during the penultimate-step. Multi-planar flight-phase trunk momenta along with hip abduction angle at penultimate-step toe-off were significantly associated with peak knee valgus moments during the execution-step (R2  = .21, P < .01). Execution-step trunk lateral flexion was significantly predicted by frontal and sagittal-plane preparatory trunk positioning at toe-off of the penultimate-step (R2  = .44, P < .01). Multi-planar flight-phase trunk momenta as well as multi-planar trunk and hip positioning at penultimate-step toe-off were associated with hip abduction during the execution-step (R2  = .53, P < .01). Preparatory positioning of the trunk and hip, along with flight-phase trunk momentum adjusting this positioning are linked to known ACL injury risk factors. We recommend that during the penultimate-step athletes maintain an upright trunk, as well as minimize frontal-plane trunk momentum and transverse-plane trunk momentum toward the sidestep direction to reduce risk of ACL injury during unplanned sidesteps.

The applied impact of 'naïve' statistical modelling of clustered observations of motion data in injury biomechanics research.

OBJECTIVES: Appropriate statistical analysis of clustered data necessitates accounting for within-participant effects to ensure results are repeatable and translatable to real-world applications. This study aimed to compare statistical output and injury risk interpretation differences from two statistical regression models built from a clinical movement sidestepping database. A "naïve" regression model, which does not account for within-participant effects, was compared with an appropriately applied mixed effects model. DESIGN: Comparative study. METHODS: Three-dimensional unplanned sidestepping joint angle data (trunk, hip, and knee) from 35 males (112 observations) were used to model peak knee valgus moments and anterior cruciate ligament injury risk during the impact phase of stance. Both statistical models were cross-validated using a k-fold analysis. RESULTS: The naïve regression returned inflated goodness of fit statistics (R2=0.50), which was evident following cross-validation (predicted R2=0.43). Following cross-validation, the mixed effects model (predicted R2=0.40) explained a similar amount of variance, despite containing three less predictors. The naïve model produced inaccurate parameter estimates, overestimating the effects of certain kinematic parameters by as much as 79 %. CONCLUSIONS: A regression model naïvely applied to clustered observations of sidestepping data resulted in erroneous parameter estimates and goodness of fit statistics which have the potential to mislead future research and real-world applications. It is important for sport and clinical scientists to use statistically appropriate mixed effects models when modelling clustered motion capture data for injury biomechanics research to protect the translatability of the findings.

1.6 MHz scanning rate direct absorption temperature measurements using a single vertical-cavity surface-emitting laser diode.

This paper presents 1.6 MHz scan rate, non-intrusive, time-resolved temperature measurements of a normal shock reflection from a plane end wall within a shock tube. A vertical-cavity surface-emitting laser (VCSEL) was used to conduct tunable diode laser absorption spectroscopy with water vapor as the probe species. The results are compared with analytical predictions. Temperatures measured with this technique agree within a single-scan standard deviation of ±33 K with calculated temperatures at a VCSEL modulation frequency of 800 kHz, which is sufficiently rapid enough to be used to investigate highly transient shock wave interaction processes.

Effect of noise-induced wavelength fluctuation in tunable diode lasers on narrow-linewidth absorption measurements.

Tunable diode laser absorption spectroscopy is being widely used to make sensors for diagnostic purposes in various engineering applications. Since the wavelength of many diode lasers used in such sensors is sensitive to the driving current, even noise as small as a few µArms in the driving current can cause a wavelength fluctuation of ∼±0.5 pm, which is large enough to interfere with sensitive absorption measurements. Although these fluctuations are small, they can cause significant systematic error in measured absorption spectra in applications where the absorption line probed is narrow, as is the case for low-density hypersonic flows. As an example, at a pressure of 300 Pa and 297 K, the error in the full width at half-maximum was ±6.5% in an absorption spectrum obtained using a system based on a vertical-cavity surface-emitting laser scanned at 10 kHz. This paper analyzes the effect of such systematic errors on measured temperature and velocity and suggests some remedial measures.

Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties.

Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of "metastatic inefficiency." Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. Cancer Prev Res; 10(9); 514-24. ©2017 AACRSee related editorial by Hynds and Janes, p. 491.

Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities.

BACKGROUND & AIMS: We conducted a phase 4, open-label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies. METHODS: We performed a prospective study of treatment-naive (n = 47) and treatment-experienced (n = 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000-1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy. RESULTS: Fifty-two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%-88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%-97%) and 36 were treatment naive (77%; 95% confidence interval, 62%-88%). All patients had at least 1 comorbidity. Thirty-five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment. CONCLUSIONS: In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542.

Multiparameter mechanical and morphometric screening of cells.

We introduce a label-free method to rapidly phenotype and classify cells purely based on physical properties. We extract 15 biophysical parameters from cells as they deform in a microfluidic stretching flow field via high-speed microscopy and apply machine-learning approaches to discriminate different cell types and states. When employing the full 15 dimensional dataset, the technique robustly classifies individual cells based on their pluripotency, with accuracy above 95%. Rheological and morphological properties of cells while deforming were critical for this classification. We also show the application of this method in accurate classifying cells based on their viability, drug screening and detecting populations of malignant cells in mixed samples. We show that some of the extracted parameters are not linearly independent, and in fact we reach maximum classification accuracy by using only a subset of parameters. However, the informative subsets could vary depending on cell types in the sample. This work shows the utility of an assay purely based on intrinsic biophysical properties of cells to identify changes in cell state. In addition to a label-free alternative to flow cytometry in certain applications, this work, also can provide novel intracellular metrics that would not be feasible with labeled approaches (i.e. flow cytometry).

Multiple receivers in a high-resolution near-infrared heterodyne spectrometer.

The paper describes a modification of a high-resolution heterodyne NIR spectrometer described by Rodin, et al. in Opt. Express22, 13825 (2014), wherein the noise amplitude of the heterodyne signal squared was proportional to the power of the incoherent radiation source (the sun). The addition of a second receiver collecting radiation from the sun into a second single-mode fiber created up to a factor of two increase in detected source power spectrum. The ability to add uncorrelated heterodyne IF signals as Gaussian noise (variance) provides the means by which multiple heterodyne receivers of signal from an incoherent source can increase the detected source power by the same multiple, thus avoiding the limit imposed by the antenna theorem for a single receiver (A. E. Siegman, Appl. Opt.5, 1588 (1966)).