The fast committor machine: Interpretable prediction with kernels.

In the study of stochastic systems, the committor function describes the probability that a system starting from an initial configuration x will reach a set B before a set A. This paper introduces an efficient and interpretable algorithm for approximating the committor, called the "fast committor machine" (FCM). The FCM uses simulated trajectory data to build a kernel-based model of the committor. The kernel function is constructed to emphasize low-dimensional subspaces that optimally describe the A to B transitions. The coefficients in the kernel model are determined using randomized linear algebra, leading to a runtime that scales linearly with the number of data points. In numerical experiments involving a triple-well potential and alanine dipeptide, the FCM yields higher accuracy and trains more quickly than a neural network with the same number of parameters. The FCM is also more interpretable than the neural net.

Development and Implementation of an Online Pain Management Continuing Education Program.

BACKGROUND: Multiple studies indicate a lack of pain management training across a range of healthcare specialties. The online Joint Pain Education Program (OJPEP) was created to provide content covering various topics that range from general pain science to integrative care to pain management. The present study evaluates the feasibility of an interdisciplinary, self-guided, online pain management continuing education program, the OJPEP. PARTICIPANTS/SUBJECTS: A total of 228 learners participted in this study. Of the 228 learners, 58 learners identified as registered nurses and 12 learners identified as nurse practitioners. DESIGN: Prospective single-arm education feasibility study. METHODS: Potential learners were provided invitations to participate via emails from clinic leadership and postings to hospital intranet websites. Learners registered online and could select up to eight modules, based on the materials developed from a Department of Defense/Veterans Administration project. Learners evaluated their satisfaction with module quality and applicability. RESULTS: A variety of providers, predominately non-prescribers, across many health care specialties, registered for modules. Across all modules except one, less than half of participants who registered completed the selected module. Time stamps indicated many learners skipped module content. Of those who completed the continuing education evaluation to obtain certificates, the majority indicated the content was of high-quality, appropriate, and evidence-based. One-third to approximately one-half of learners indicated that they would apply content in their clinical practice. Completion of the intended 3-month follow-up survey was poor. CONCLUSIONS: Though modules were acceptable per learner responses, future work is needed to: develop modules that are more engaging (e.g., interactive) and applicable to learners; and improve implementation methods to include dissemination and evaluation metrics.

Circulating Microvesicle-Associated Inducible Nitric Oxide Synthase Is a Novel Therapeutic Target to Treat Sepsis: Current Status and Future Considerations.

To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD80 dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan-Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb's efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship.

Practical rare event sampling for extreme mesoscale weather.

Extreme mesoscale weather, including tropical cyclones, squall lines, and floods, can be enormously damaging and yet challenging to simulate; hence, there is a pressing need for more efficient simulation strategies. Here, we present a new rare event sampling algorithm called quantile diffusion Monte Carlo (quantile DMC). Quantile DMC is a simple-to-use algorithm that can sample extreme tail behavior for a wide class of processes. We demonstrate the advantages of quantile DMC compared to other sampling methods and discuss practical aspects of implementing quantile DMC. To test the feasibility of quantile DMC for extreme mesoscale weather, we sample extremely intense realizations of two historical tropical cyclones, 2010 Hurricane Earl and 2015 Hurricane Joaquin. Our results demonstrate quantile DMC's potential to provide low-variance extreme weather statistics while highlighting the work that is necessary for quantile DMC to attain greater efficiency in future applications.

Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is a life-long, potentially fatal IgG autoantibody-mediated blistering disease targeting mucocutaneous keratinocytes (KCs). PV patients develop pathogenic anti-desmoglein (Dsg) 3 ± 1 and antimitochondrial antibodies (AMA), but it remained unknown whether and how AMA enter KCs and why other cell types are not affected in PV. Therefore, we sought to elucidate mechanisms of cell entry, trafficking, and pathogenic action of AMA in PV. We found that PVIgGs associated with neonatal Fc receptor (FcRn) on the cell membrane, and the PVIgG-FcRn complexes entered KCs and reached mitochondria where they dissociated. The liberated AMA altered mitochondrial membrane potential, respiration, and ATP production and induced cytochrome c release, although the lack or inactivation of FcRn abolished the ability of PVIgG to reach and damage mitochondria and to cause detachment of KCs. The assays of mitochondrial functions and keratinocyte adhesion demonstrated that although the pathobiological effects of AMA on KCs are reversible, they become irreversible, leading to epidermal blistering (acantholysis), when AMA synergize with anti-Dsg antibodies. Thus, it appears that AMA enter a keratinocyte in a complex with FcRn, become liberated from the endosome in the cytosol, and are trafficked to the mitochondria, wherein they trigger pro-apoptotic events leading to shrinkage of basal KCs uniquely expressing FcRn in epidermis. During recovery, KCs extend their cytoplasmic aprons toward neighboring cells, but anti-Dsg antibodies prevent assembly of nascent desmosomes due to steric hindrance, thus rendering acantholysis irreversible. In conclusion, FcRn is a common acceptor protein for internalization of AMA and, perhaps, for PV autoantibodies to other intracellular antigens, and PV is a novel disease paradigm for investigating and elucidating the role of FcRn in this autoimmune disease and possibly other autoimmune diseases.

Full Configuration Interaction Excited-State Energies in Large Active Spaces from Subspace Iteration with Repeated Random Sparsification.

We present a stable and systematically improvable quantum Monte Carlo (QMC) approach to calculating excited-state energies, which we implement using our fast randomized iteration method for the full configuration interaction problem (FCI-FRI). Unlike previous excited-state quantum Monte Carlo methods, our approach, which is based on an asymmetric variant of subspace iteration, avoids the use of dot products of random vectors and instead relies upon trial vectors to maintain orthogonality and estimate eigenvalues. By leveraging recent advances, we apply our method to calculate ground- and excited-state energies of challenging molecular systems in large active spaces, including the carbon dimer with 8 electrons in 108 orbitals (8e,108o), an oxo-Mn(salen) transition metal complex (28e,28o), ozone (18e,87o), and butadiene (22e,82o). In the majority of these test cases, our approach yields total excited-state energies that agree with those from state-of-the-art methods─including heat-bath CI, the density matrix renormalization group approach, and FCIQMC─to within sub-milliHartree accuracy. In all cases, estimated excitation energies agree to within about 0.1 eV.

Procedural Benzodiazepine and Post-Vasectomy Opioid and Nonopioid Prescribing Variation in a Large Health Care System.

INTRODUCTION: Our goal was to describe variation in procedural benzodiazepine and post-vasectomy nonopioid pain and opioid prescription dispense events, and multilevel factors associated with the probability of an opioid refill. METHODS: Patients (40,584) undergoing vasectomies in the U.S. Military Health System between January 2016-January 2020 were included in this observational retrospective study. The main outcome was the probability of being dispensed an opioid prescription refill within 30 days post-vasectomy. Bivariate analyses examined the relationships between patient- and care-level characteristics, prescription dispense and 30-day opioid prescription refill. A generalized additive mixed-effects model and sensitivity analyses examined factors associated with opioid refill. RESULTS: There was wide variation in procedural benzodiazepine (32%) and post-vasectomy nonopioid (71%) and opioid (73%) prescription dispense patterns across facilities. Only 5% of the patients dispensed opioids received a refill. Probability of an opioid refill was associated with race (White), younger age, opioid dispense history, documented mental health or pain condition, lack of post-vasectomy nonopioid pain medication dispense events and higher dispensed post-vasectomy opioid prescription dose; albeit the effect of dose did not replicate in sensitivity analyses. CONCLUSIONS: Despite the wide variation in vasectomy-related pharmacological pathways across a large health care system, most patients do not require an opioid refill. Significant variation in prescribing practices indicated racial inequities. Given the low rates of opioid prescription refill, combined with the wide variation in opioid prescription dispense events and American Urological Association recommendations for conservative opioid prescribing after vasectomy, intervention to address excessive opioid prescribing is warranted.

Error Bounds for Dynamical Spectral Estimation.

Dynamical spectral estimation is a well-established numerical approach for estimating eigenvalues and eigenfunctions of the Markov transition operator from trajectory data. Although the approach has been widely applied in biomolecular simulations, its error properties remain poorly understood. Here we analyze the error of a dynamical spectral estimation method called "the variational approach to conformational dynamics" (VAC). We bound the approximation error and estimation error for VAC estimates. Our analysis establishes VAC's convergence properties and suggests new strategies for tuning VAC to improve accuracy.

Integrated Variational Approach to Conformational Dynamics: A Robust Strategy for Identifying Eigenfunctions of Dynamical Operators.

One approach to analyzing the dynamics of a physical system is to search for long-lived patterns in its motions. This approach has been particularly successful for molecular dynamics data, where slowly decorrelating patterns can indicate large-scale conformational changes. Detecting such patterns is the central objective of the variational approach to conformational dynamics (VAC), as well as the related methods of time-lagged independent component analysis and Markov state modeling. In VAC, the search for slowly decorrelating patterns is formalized as a variational problem solved by the eigenfunctions of the system's transition operator. VAC computes solutions to this variational problem by optimizing a linear or nonlinear model of the eigenfunctions using time series data. Here, we build on VAC's success by addressing two practical limitations. First, VAC can give poor eigenfunction estimates when the lag time parameter is chosen poorly. Second, VAC can overfit when using flexible parametrizations such as artificial neural networks with insufficient regularization. To address these issues, we propose an extension that we call integrated VAC (IVAC). IVAC integrates over multiple lag times before solving the variational problem, making its results more robust and reproducible than VAC's.

Improved Fast Randomized Iteration Approach to Full Configuration Interaction.

We present three modifications to our recently introduced fast randomized iteration method for full configuration interaction (FCI-FRI) and investigate their effects on the method's performance for Ne, H2O, and N2. The initiator approximation, originally developed for full configuration interaction quantum Monte Carlo, significantly reduces statistical error in FCI-FRI when few samples are used in compression operations, enabling its application to larger chemical systems. The semistochastic extension, which involves exactly preserving a fixed subset of elements in each compression, improves statistical efficiency in some cases but reduces it in others. We also developed a new approach to sampling excitations that yields consistent improvements in statistical efficiency and reductions in computational cost. We discuss possible strategies based on our findings for improving the performance of stochastic quantum chemistry methods more generally.

Inducible Nitric Oxide Synthase in Circulating Microvesicles: Discovery, Evolution, and Evidence as a Novel Biomarker and the Probable Causative Agent for Sepsis.

Background: The sepsis pathology remains an enormous medical problem globally because morbidity and mortality remain unacceptably high in septic patients despite intense research efforts. The economic and societal burden of sepsis makes it the most pressing patient care issue in the United States and worldwide. Sepsis is a dysregulated immune response normally initiated by an infection. The need for an early, accurate, and reliable biomarker test to detect the onset of sepsis and for a targeted sepsis therapy are widely recognized in the biomedical community. Content: This report reviews the published findings relevant to microvesicle-associated inducible nitric oxide synthase (MV-A iNOS) as a novel plasma biomarker for the onset of sepsis including human clinical studies and animal studies. Plasma iNOS as a standalone test and as one of the components of a novel panel of biomarkers to stage the progression of sepsis are presented and discussed in comparison to other biomarkers and other proposed panels of biomarkers for sepsis. Summary: The data strongly support the concept that extracellular plasma MV-A iNOS in circulating microvesicles is centrally involved in the initiation of sepsis, and a diagnostic test based upon plasma iNOS can serve as an early pre-symptomatic warning signal for the onset of sepsis. A novel panel of plasma biomarkers comprised of iNOS, pro-IL-18, pro-IL-33, and Reg-1α is proposed as a multianalyte pre-symptomatic method to stage the onset of sepsis for improved prompt data driven patient care.

Beyond Walkers in Stochastic Quantum Chemistry: Reducing Error Using Fast Randomized Iteration.

We introduce a family of methods for the full configuration interaction problem in quantum chemistry, based on the fast randomized iteration (FRI) framework [Lim, L.-H.; Weare, J. SIAM Rev. 2017, 59, 547; DOI: 10.1137/15M1040827 ]. These methods, which we term "FCI-FRI", stochastically impose sparsity during iterations of the power method and can be viewed as a generalization of full configuration interaction quantum Monte Carlo (FCIQMC) without walkers. In addition to the multinomial scheme commonly used to sample excitations in FCIQMC, we present a systematic scheme where excitations are not sampled independently. Performing ground-state calculations on five small molecules at fixed cost, we find that the systematic FCI-FRI scheme is 11-45 times more statistically efficient than the multinomial FCI-FRI scheme, which is in turn 1.4-178 times more statistically efficient than the original FCIQMC algorithm.

Educating Parents About Infant Language Development: A Randomized Controlled Trial.

A total of 427 women (aged 18-45 years) who delivered a singleton neonate without serious medical complications were randomized to watch either an educational intervention (n = 225) or the sudden infant death syndrome (n = 202) video. Linear mixed models showed that the intervention women significantly gained knowledge over time. Knowledge gain was largest among high-socioeconomic status (high-SES) and middle-SES English-speaking, smaller among low-SES Spanish-speaking, and nonsignificant among low-SES English-speaking women. Analysis of deviance revealed that the intervention women of all SES learned strategies fostering secure attachment and language acquisition. Participants considered watching an educational video alongside the universal newborn hearing screening (UNHS) conveniently timed. The intervention women were more likely than the control women to recognize the importance of timely UNHS follow-up.

Project ASPIRE: Spoken Language Intervention Curriculum for Parents of Low-socioeconomic Status and Their Deaf and Hard-of-Hearing Children.

OBJECTIVE: To investigate the impact of a spoken language intervention curriculum aiming to improve the language environments caregivers of low socioeconomic status (SES) provide for their D/HH children with CI & HA to support children's spoken language development. STUDY DESIGN: Quasiexperimental. SETTING: Tertiary. PATIENTS: Thirty-two caregiver-child dyads of low-SES (as defined by caregiver education ≤ MA/MS and the income proxies = Medicaid or WIC/LINK) and children aged < 4.5 years, hearing loss of ≥ 30 dB, between 500 and 4000 Hz, using at least one amplification device with adequate amplification (hearing aid, cochlear implant, osseo-integrated device). INTERVENTION: Behavioral. Caregiver-directed educational intervention curriculum designed to improve D/HH children's early language environments. MAIN OUTCOME MEASURES: Changes in caregiver knowledge of child language development (questionnaire scores) and language behavior (word types, word tokens, utterances, mean length of utterance [MLU], LENA Adult Word Count (AWC), Conversational Turn Count (CTC)). RESULTS: Significant increases in caregiver questionnaire scores as well as utterances, word types, word tokens, and MLU in the treatment but not the control group. No significant changes in LENA outcomes. CONCLUSION: Results partially support the notion that caregiver-directed language enrichment interventions can change home language environments of D/HH children from low-SES backgrounds. Further longitudinal studies are necessary.

Biological effects of SLURP-1 on human keratinocytes.

A novel paradigm of keratinocyte (KC) regulation via nicotinic acetylcholine receptors (nAChR) has been discovered in studies of SLURP (secreted mammalian Ly-6/urokinase-type plasminogen activator receptor-related protein)-1 in Mal de Meleda. We cloned human SLURP-1 and produced recombinant protein and the monoclonal antibody 336H12-1A3 that visualized native SLURP-1. SLURP-1 ligated the conventional ligand-binding site of KC nAChR, showing a higher affinity to the [(3)H]nicotine-, compared with the [(3)H]epibatidine-sensitive nAChR. SLURP-1 significantly (p<0.05) increased the activities of caspases 3 and 8, and the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling-positive cells. The pro-apoptotic activity of SLURP-1 exceeded that of tumor necrosis factor-alpha, suggesting the involvement of separate pathways. In a series of real-time PCR and in-cell western experiments, SLURP-1 significantly (p<0.05) upregulated expression of transglutaminase type I cytokeratin 10, p21, and caspase-3. In the presence of the agonist carbachol, the effects of SLURP-1 on gene expression were augmented, which is in keeping with the notion that SLURP-1 acts as an allosteric agonist at the KC nAChR. Thus, the changes in the cell state induced by SLURP-1 could result from nAChR-mediated effects on the KC gene expression. These results suggest that the biological role of SLURP-1 in the epidermis is to provide fine tuning of the physiologic regulation of KC functions through the cholinergic pathways.

SLURP-2: A novel cholinergic signaling peptide in human mucocutaneous epithelium.

The biologic role of novel cholinergic toxin-like signaling peptides termed SLURP (secreted mammalian Ly-6/uPAR-related protein) in the mucocutaneous epithelium is a subject of intense research. Previous studies demonstrated that SLURP-1 activates the alpha7 subtype of keratinocyte nicotinic acetylcholine receptors (nAChRs) and facilitates keratinization and programmed cell death, and that the level of SLURP-2 was found to be upregulated several fold in the hyperproliferative skin of patients with psoriasis. In this study, we demonstrated for the first time that human epidermal and oral keratinocytes secrete SLURP-2. We cloned human SLURP-2 and produced the mouse monoclonal antibody 341F10-1F12 that visualized SLURP-2 in the cytoplasm of normal human epidermal and oral keratinocytes grown in culture. In epidermis, SLURP-2 was found predominantly in the suprabasal compartment, whereas in the attached gingiva-in the lowermost epithelial layers. Recombinant SLURP-2 (rSLURP-2) competed with nicotinic radioligands for binding to keratinocytes, showing a higher affinity to the [3H]epibatidine- than [3H]nicotine-labeled sites. Treatment with rSLURP-2 significantly (P < 0.05) increased the number of keratinocytes in culture and their resistance to apoptosis, which could be abolished by mecamylamine more efficiently than alpha-bungarotoxin. By real-time PCR and in-cell western, rSLURP-2 significantly (P < 0.05) downregulated gene expression of the differentiation markers loricrin, filaggrin, and cytokeratins 1 and 10, and pro-apoptotic Bax, Bad, and caspase 3 which were elevated by high extracellular calcium, and rSLURP-2 also abolished activation of caspases 3 and 8 caused by camptothecin. These results indicated that SLURP-2 competes with acetylcholine predominantly at the alpha3 nAChR, and that receptor ligation with SLURP-2 delays keratinocyte differentiation and prevents apoptosis. Thus, the different effects observed for SLURP-1 and -2 can be explained by their differential binding to the nAChR subtypes expressed in keratinocytes. These findings present a novel paradigm of the physiologic regulation of mucocutaneous epithelial cells by locally produced small hormone-like peptide molecules, and open novel directions toward better understanding and treating of skin and mucosal diseases.

Development, characterization, and epitope mapping of a panel of twenty-four monoclonal antibodies specific for human inducible nitric oxide synthase.

A panel of monoclonal antibodies (MAbs) to human inducible nitric oxide synthase (hiNOS) has been developed. By isotype analysis of the MAbs cloned from the 24 different positive hybridomas, 13 were determined to be mouse IgG1, two were mouse IgG2a, two were mouse IgG2b, and the seven others were mouse IgM antibodies: all contained kappa light chains. The anti-hiNOS MAbs were initially characterized by ELISA, RIA, Western blot, and immunocytochemistry, and then they were epitope mapped using synthetic peptides and a three-step mapping procedure. In the first step, each of the 24 MAbs was tested by indirect ELISA for binding to 96 overlapping 18-amino acid-long peptides that span the entire 1153-amino acid length of hiNOS. Eight IgG class anti-hiNOS MAbs were found to bind to one of five different peptides. In the second step, a series of amino terminal and carboxyl terminal truncated peptides were synthesized for each of the five peptides to which one or more of the MAbs bound. Each of the eight anti-hiNOS MAbs was found to bind to the truncated peptides with a unique specificity that identified the amino acid segment involved in binding. The third step in the epitope mapping process utilized three series of overlapping 5-, 6-, 7-, 8-, and 9-amino acid-long peptides for each of these segments and identified the exact amino acids of hiNOS involved in antibody binding. Anti-hiNOS MAbs 2A1-F8, 2D2-B2, 21C10-1D10, and 24B10-2C7 were found to be especially useful in different immunoassays.