Closed-loop transfer enables artificial intelligence to yield chemical knowledge.

Artificial intelligence-guided closed-loop experimentation has emerged as a promising method for optimization of objective functions1,2, but the substantial potential of this traditionally black-box approach to uncovering new chemical knowledge has remained largely untapped. Here we report the integration of closed-loop experiments with physics-based feature selection and supervised learning, denoted as closed-loop transfer (CLT), to yield chemical insights in parallel with optimization of objective functions. CLT was used to examine the factors dictating the photostability in solution of light-harvesting donor-acceptor molecules used in a variety of organic electronics applications, and showed fundamental insights including the importance of high-energy regions of the triplet state manifold. This was possible following automated modular synthesis and experimental characterization of only around 1.5% of the theoretical chemical space. This physics-informed model for photostability was strengthened using multiple experimental test sets and validated by tuning the triplet excited-state energy of the solvent to break out of the observed plateau in the closed-loop photostability optimization process. Further applications of CLT to additional materials systems support the generalizability of this strategy for augmenting closed-loop strategies. Broadly, these findings show that combining interpretable supervised learning models and physics-based features with closed-loop discovery processes can rapidly provide fundamental chemical insights.

Secondary structure determines electron transport in peptides.

Proteins play a key role in biological electron transport, but the structure-function relationships governing the electronic properties of peptides are not fully understood. Despite recent progress, understanding the link between peptide conformational flexibility, hierarchical structures, and electron transport pathways has been challenging. Here, we use single-molecule experiments, molecular dynamics (MD) simulations, nonequilibrium Green's function-density functional theory (NEGF-DFT), and unsupervised machine learning to understand the role of secondary structure on electron transport in peptides. Our results reveal a two-state molecular conductance behavior for peptides across several different amino acid sequences. MD simulations and Gaussian mixture modeling are used to show that this two-state molecular conductance behavior arises due to the conformational flexibility of peptide backbones, with a high-conductance state arising due to a more defined secondary structure (beta turn or 310 helices) and a low-conductance state occurring for extended peptide structures. These results highlight the importance of helical conformations on electron transport in peptides. Conformer selection for the peptide structures is rationalized using principal component analysis of intramolecular hydrogen bonding distances along peptide backbones. Molecular conformations from MD simulations are used to model charge transport in NEGF-DFT calculations, and the results are in reasonable qualitative agreement with experiments. Projected density of states calculations and molecular orbital visualizations are further used to understand the role of amino acid side chains on transport. Overall, our results show that secondary structure plays a key role in electron transport in peptides, which provides broad avenues for understanding the electronic properties of proteins.

Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

Fasting vs no fasting prior to catheterisation laboratory procedures: the SCOFF trial.

BACKGROUND AND AIMS: Current guidelines recommend 6 hours of solid food and 2 hours of clear liquid fasting for patients undergoing cardiac procedures with conscious sedation. There are no data to support this practice, and previous single centre studies support the safety of removing fasting requirements. The objective of this study was to determine the non-inferiority of a no fasting strategy to fasting prior to cardiac catheterisation procedures which require conscious sedation. METHODS: This is a multicentre, investigator-initiated, non-inferiority randomised trial conduced in Australia with a prospective open label blinded endpoint design. Patients referred for coronary angiography, percutaneous coronary intervention or cardiac implantable electronic device (CIED) related procedures were enrolled. Patients were randomised 1:1 to fasting as normal (6 hours solid food and 2 hours clear liquid) or no fasting requirements (encouraged to have regular meals but not mandated to do so). Recruitment occurred from 2022 to 2023. The primary outcome was a composite of aspiration pneumonia, hypotension, hyperglycaemia and hypoglycaemia assessed with a Bayesian approach. Secondary outcomes included patient satisfaction score, new ventilation requirement (non-invasive and invasive), new intensive care unit admission, 30-day readmission, 30-day mortality, 30-day pneumonia. RESULTS: 716 patients were randomised with 358 in each group. Those in the fasting arm had significantly longer solid food fasting (13.2 versus 3.0 hours, Bayes factor >100 indicating extreme evidence of difference) and clear liquid fasting times (7.0 versus 2.4 hours, Bayes factor >100). The primary composite outcome occurred in 19.1% of patients in the fasting arm and 12.0% of patients in the no fasting arm. The estimate of the mean posterior difference in proportions in the primary composite outcome was -5.2% (95% CI -9.6 to -0.9, ) favouring no fasting. This result confirms non-inferiority (posterior probability >99.5%) and superiority (posterior probability 99.1%) of no fasting for the primary composite outcome. The no fasting arm had improved patient satisfaction scores with a posterior mean difference of 4.02 points (95% CI 3.36 to 4.67, Bayes factor >100). Secondary outcome events were similar. CONCLUSIONS: In patients undergoing cardiac catheterisation and CIED related procedures, no fasting was non-inferior and superior to fasting for the primary composite outcome of aspiration pneumonia, hypotension, hyperglycaemia and hypoglycaemia. Patient satisfaction scores were significantly better with no fasting. This supports removing fasting requirements for patients undergoing cardiac catheterisation laboratory procedures that require conscious sedation.

Marrow Fat-Cortical Bone Relationship in ß-Thalassemia: A Study Using MRI.

BACKGROUND: Growing evidence suggests that marrow adipocytes play an active role in the regulation of bone metabolism and hematopoiesis. However, research on the relationship between bone and fat in the context of hematological diseases, particularly ß-thalassemia, remains limited. PURPOSE: To investigate the relationship between marrow fat and cortical bone thickness in ß-thalassemia and to identify key determinants influencing these variables. STUDY TYPE: Prospective. SUBJECTS: Thirty-five subjects in four subject groups of increasing disease severity: 6 healthy control (25.0 ± 5.3 years, 2 male), 4 ß-thalassemia minor, 13 intermedia, and 12 major (29.1 ± 6.4 years, 15 male). FIELD STRENGTH/SEQUENCE: 3.0 T, 3D fast low angle shot sequence and T1-weighted turbo spin echo. ASSESSMENT: Analyses on proton density fat fraction (PDFF) and R2* values in femur subregions (femoral head, greater trochanter, intertrochanteric, diaphysis, distal) and cortical thickness (CBI) of the subjects' left femur. Clinical data such as age, sex, body mass index (BMI), and disease severity were also included. STATISTICAL TESTS: One-way analysis of variance (ANOVA), mixed ANOVA, Pearson correlation and multiple regression. P-values <0.05 were considered significant. RESULTS: Bone marrow PDFF significantly varied between the femur subregions, F(2.89,89.63) = 44.185 and disease severity, F(1,3) = 12.357. A significant interaction between subject groups and femur subregions on bone marrow PDFF was observed, F(8.67,89.63) = 3.723. Notably, a moderate positive correlation was observed between PDFF and CBI (r = 0.33-0.45). Multiple regression models for both PDFF (R2 = 0.476, F(13,151) = 10.547) and CBI (R2 = 0.477, F(13,151) = 10.580) were significant. Significant predictors for PDFF were disease severity (ßTMi = 0.36, ßTMa = 0.17), CBI (ß = 0.24), R2* (ß = -0.32), and height (ß = -0.29) while for CBI, the significant determinants were sex (ß = -0.27), BMI (ß = 0.55), disease severity (ßTMi = 2.15), and PDFF (ß = 0.25). DATA CONCLUSION: This study revealed a positive correlation between bone marrow fat fraction and cortical bone thickness in ß-thalassemia with varying disease severity, potentially indicating a complex interplay between bone health and marrow composition. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

A systematic review and meta-analysis of pathologic complete response rates for patients with cholangiocarcinoma treated on liver transplant protocols.

BACKGROUND AND OBJECTIVES: Many heterogenous orthotopic liver transplant (OLT) protocols exist for patients with unresectable cholangiocarcinoma. Little is known about the incidence, predictors for, and the significance of achieving a pathologic complete response (pCR). METHODS: We performed a systematic review through September 2022 of the PubMed, Embase, and Web of Science databases. A random-effect meta-analysis was conducted to pool data across studies with reported pCR rates. Heterogeneity between treatment protocols was assessed via subgroup analysis. The pCR and 1-, 3-, and 5-year recurrence-free survival (RFS) and overall survival (OS) rates were extracted as outcomes of interest. RESULTS: A total of 15 studies reported pCR rates and were grouped by use of the Mayo protocol (4/15), stereotactic body radiation therapy (2/15), and an Other category (9/15). The pooled pCR rate among all studies was 32%. Both radiation technique and duration of CHT showed no significant association with pCR (p = 0.05 and 0.13, respectively). Pooled 1-year RFS and OS after any neoadjuvant therapy and OLT was 80% (95% confidence interval [CI], 0.61-0.91), and 91% (95% CI, 0.87-0.94), respectively. There was no 1-year OS difference detected among the three groups. pCR was not associated with OS in the meta-regression. Pooled 3- and 5-year OS among all studies was 72% and 61%, respectively. CONCLUSIONS: The pooled incidence of pCR was 32%. Differences in radiation technique did not appear to influence pCR rates and upon meta-regression, pCR was not a surrogate marker for survival.

Assessing molecular doping efficiency in organic semiconductors with reactive Monte Carlo.

The addition of molecular dopants into organic semiconductors (OSCs) is a ubiquitous augmentation strategy to enhance the electrical conductivity of OSCs. Although the importance of optimizing OSC-dopant interactions is well-recognized, chemically generalizable structure-function relationships are difficult to extract due to the sensitivity and dependence of doping efficiency on chemistry, processing conditions, and morphology. Computational modeling for an integrated OSC-dopant design is an attractive approach to systematically isolate fundamental relationships, but requires the challenging simultaneous treatment of molecular reactivity and morphology evolution. We present the first computational study to couple molecular reactivity with morphology evolution in a molecularly doped OSC. Reactive Monte Carlo is employed to examine the evolution of OSC-dopant morphologies and doping efficiency with respect to dielectric, the thermodynamic driving for the doping reaction, and dopant aggregation. We observe that for well-mixed systems with experimentally relevant dielectric constants, doping efficiency is near unity with a very weak dependence on the ionization potential and electron affinity of OSC and dopant, respectively. At experimental dielectric constants, reaction-induced aggregation is observed, corresponding to the well-known insolubility of solution-doped materials. Simulations are qualitatively consistent with a number of experimental studies showing a decrease of doping efficiency with increasing dopant concentration. Finally, we observe that the aggregation of dopants lowers doping efficiency and thus presents a rational design strategy for maximizing doping efficiency in molecularly doped OSCs. This work represents an important first step toward the systematic integration of molecular reactivity and morphology evolution into the characterization of multi-scale structure-function relationships in molecularly doped OSCs.

Distilling coarse-grained representations of molecular electronic structure with continuously gated message passing.

Bottom-up methods for coarse-grained (CG) molecular modeling are critically needed to establish rigorous links between atomistic reference data and reduced molecular representations. For a target molecule, the ideal reduced CG representation is a function of both the conformational ensemble of the system and the target physical observable(s) to be reproduced at the CG resolution. However, there is an absence of algorithms for selecting CG representations of molecules from which complex properties, including molecular electronic structure, can be accurately modeled. We introduce continuously gated message passing (CGMP), a graph neural network (GNN) method for atomically decomposing molecular electronic structure sampled over conformational ensembles. CGMP integrates 3D-invariant GNNs and a novel gated message passing system to continuously reduce the atomic degrees of freedom accessible for electronic predictions, resulting in a one-shot importance ranking of atoms contributing to a target molecular property. Moreover, CGMP provides the first approach by which to quantify the degeneracy of "good" CG representations conditioned on specific prediction targets, facilitating the development of more transferable CG representations. We further show how CGMP can be used to highlight multiatom correlations, illuminating a path to developing CG electronic Hamiltonians in terms of interpretable collective variables for arbitrarily complex molecules.

Validation of Distinct Bladder Pain Phenotypes Utilizing the MAPP Research Network Cohort.

INTRODUCTION AND HYPOTHESIS: As interstitial cystitis/bladder pain syndrome (IC/BPS) likely represents multiple pathophysiologies, we sought to validate three clinical phenotypes of IC/BPS patients in a large, multi-center cohort using unsupervised machine learning (ML) analysis. METHODS: Using the female Genitourinary Pain Index and O'Leary-Sant Indices, k-means unsupervised clustering was utilized to define symptomatic phenotypes in 130 premenopausal IC/BPS participants recruited through the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network. Patient-reported symptoms were directly compared between MAPP ML-derived phenotypic clusters to previously defined phenotypes from a single center (SC) cohort. RESULTS: Unsupervised ML categorized IC/BPS participants into three phenotypes with distinct pain and urinary symptom patterns: myofascial pain, non-urologic pelvic pain, and bladder-specific pain. Defining characteristics included presence of myofascial pain or trigger points on examination for myofascial pain patients (p = 0.003) and bladder pain/burning for bladder-specific pain patients (p < 0.001). The three phenotypes were derived using only 11 features (fGUPI subscales and ICSI/ICPI items), in contrast to 49 items required previously. Despite substantial reduction in classification features, unsupervised ML independently generated similar symptomatic clusters in the MAPP cohort with equivalent symptomatic patterns and physical examination findings as the SC cohort. CONCLUSIONS: The reproducible identification of IC/BPS phenotypes, distinguishing bladder-specific pain from myofascial and genital pain, using independent ML analysis of a multicenter database suggests these phenotypes reflect true pathophysiologic differences in IC/BPS patients.

The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Screening college athletes for sexual violence: athletes' experiences and opinions on best practices.

OBJECTIVES: College athletes are at elevated risk for sexual violence, yet few formally report it and screening for sexual violence is uncommon. This study aimed to evaluate the nature of screening occurring among college athletes and collect athletes' opinions on how best to screen for sexual violence. METHODS: This was a mixed-methods study combining a cross-sectional survey with small group interviews. Intercollegiate and club athletes 18 years and older at a division I institution were recruited to complete an online, anonymous survey. Those who completed the survey were invited to participate in follow-up interviews. Quantitative data were analysed using descriptive statistics and qualitative data were analysed inductively using thematic analysis. RESULTS: 165 athletes completed the survey. Only 25% of respondents reported past screening for any type of interpersonal violence, and only 22% reported past screening for sexual abuse and 21% for sexual harassment. 12 student-athletes participated in follow-up interviews. Athletes suggested several best practices including normalising conversation about sexual violence, empowering athletes to maintain a sense of control around disclosure, building trust and providing multiple opportunities for discussion and disclosure. CONCLUSION: Less than one-quarter of athletes in this study have been screened for sexual violence. Sensitive and effective screening practices should include providing safe environments, initiating the conversation, offering multiple opportunities for disclosure, and ensuring personnel completing screening are knowledgeable on what to do in case of a disclosure. These can inform screening and educational practices to decrease stigma, support those affected and ultimately decrease the incidence of sexual violence victimisation.

The Persistency Index: a novel screening tool for identifying myofascial pelvic floor dysfunction in patients seeking care for lower urinary tract symptoms.

BACKGROUND: Patients with myofascial pelvic floor dysfunction often present with lower urinary tract symptoms, such as urinary frequency, urgency, and bladder pressure. Often confused with other lower urinary tract disorders, this constellation of symptoms, recently termed myofascial urinary frequency syndrome, is distinct from other lower urinary tract symptoms and optimally responds to pelvic floor physical therapy. A detailed pelvic floor myofascial examination performed by a skilled provider is currently the only method to identify myofascial urinary frequency syndrome. Despite a high influence on quality of life, low awareness of this condition combined with no objective diagnostic testing leads to the frequent misdiagnosis or underdiagnosis of myofascial urinary frequency syndrome. OBJECTIVE: This study aimed to develop a screening measure to identify patients with myofascial urinary frequency syndrome (bothersome lower urinary tract symptoms secondary to myofascial pelvic floor dysfunction) from patient-reported symptoms. STUDY DESIGN: A population of patients with isolated myofascial urinary frequency syndrome was identified by provider diagnosis from a tertiary urology practice and verified by standardized pelvic floor myofascial examination and perineal surface pelvic floor electromyography. Least Angle Shrinkage and Selection Operator was used to identify candidate features from the Overactive Bladder Questionnaire, Female Genitourinary Pain Index, and Pelvic Floor Distress Index predictive of myofascial urinary frequency syndrome in a pooled population also containing subjects with overactive bladder (n=42), interstitial cystitis/bladder pain syndrome (n=51), and asymptomatic controls (n=54) (derivation cohort). A simple, summated score of the most discriminatory questions using the original scaling of the Pelvic Floor Distress Index 5 (0-4) and Genitourinary Pain Index 5 (0-5) and modified scaling of Female Genitourinary Pain Index 2b (0-3) had an area under the curve of 0.75. As myofascial urinary frequency syndrome was more prevalent in younger subjects, the inclusion of an age penalty (3 points added if under the age of 50 years) improved the area under the curve to 0.8. This score was defined as the Persistency Index (possible score of 0-15). The Youden Index was used to identify the optimal cut point Persistency Index score for maximizing sensitivity and specificity. RESULTS: Using a development cohort of 215 subjects, the severity (Pelvic Floor Distress Index 5) and persistent nature (Female Genitourinary Pain Index 5) of the sensation of incomplete bladder emptying and dyspareunia (Female Genitourinary Pain Index 2b) were the most discriminatory characteristics of the myofascial urinary frequency syndrome group, which were combined with age to create the Persistency Index. The Persistency Index performed well in a validation cohort of 719 patients with various lower urinary tract symptoms, including overactive bladder (n=285), interstitial cystitis/bladder pain syndrome (n=53), myofascial urinary frequency syndrome (n=111), controls (n=209), and unknown diagnoses (n=61), exhibiting an area under the curve of 0.74. A Persistency Index score ≥7 accurately identified patients with myofascial urinary frequency syndrome from an unselected population of individuals with lower urinary tract symptoms with 80% sensitivity and 61% specificity. A combination of the Persistency Index with the previously defined Bladder Pain Composite Index and Urge Incontinence Composite Index separated a population of women seeking care for lower urinary tract symptoms into groups consistent with overactive bladder, interstitial cystitis/bladder pain syndrome, and myofascial urinary frequency syndrome phenotypes with an overall diagnostic accuracy of 82%. CONCLUSION: Our study recommends a novel screening method for patients presenting with lower urinary tract symptoms to identify patients with myofascial urinary frequency syndrome. As telemedicine becomes more common, this index provides a way of screening for myofascial urinary frequency syndrome and initiating pelvic floor physical therapy even before a confirmatory pelvic examination.

A Systematic Review of the Safety and Efficacy of Inferior Vena Cava Stenting.

OBJECTIVE: Inferior vena cava (IVC) stenting may provide benefit to patients with symptomatic obstruction; however, there are no devices currently licensed for use in the IVC and systematic reviews on the topic are lacking. The aim of this study was to carry out a systematic review of the literature and meta-analysis to investigate the safety and efficacy of IVC stenting in all adult patient groups. DATA SOURCES: The Medline and Embase databases were searched for studies reporting outcomes for safety and effectiveness of IVC stenting for any indication in series of 10 or more patients. REVIEW METHODS: A systematic review of the literature was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Thirty-three studies were included describing 1 575 patients. Indications for stenting were malignant IVC syndrome (229 patients), thrombotic disease (807 patients), Budd-Chiari syndrome (501 patients), and IVC stenosis post liver transplantation (47 patients). The male:female ratio was 2:1 and the median age ranged from 30 to 61 years. The studies included were not suitable for formal meta-analysis as 30/33 were single centre retrospective studies with no control groups and there was considerable inconsistency in outcome reporting. There was significant risk of bias in 94% of studies. Median reported technical success was 100% (range 78 - 100%), primary patency was 75% (38 - 98%), and secondary patency was 91.5% (77 - 100%). Major complications were pulmonary embolism (three cases), stent migration (12 cases), and major bleeding (15 cases), and there were three deaths in the immediate post-operative period. Most studies reported improvement in clinical symptoms but formal reporting tools were not used consistently. CONCLUSION: The evidence base for IVC stenting consists of predominantly single centre, retrospective, observational studies that have a high risk of bias. Nonetheless the procedure appears safe with few major adverse events, and studies that reported clinical outcomes demonstrate improvement in symptoms and quality of life. Randomised controlled trials and prospective registry based studies with larger patient numbers and standardised outcome are required to improve the evidence base for this procedure.

Excited State Dynamics of a Conformationally Fluxional Copper Coordination Complex.

The conversion of solar energy into chemical fuel represents a capstone goal of the 21st century and has the potential to supply terawatts of power in a globally distributed manner. However, the disparate time scales of photodriven charge separation (∼fs) and steps in chemical reactions (∼µs) represent an inherent bottleneck in solar-to-fuels technology. To address this discrepancy, we are developing earth-abundant coordination complexes that undergo light-induced conformational rearrangements such that charge separation (CS) is hastened, while charge recombination (CR) is slowed. To these ends, we report the preparation and characterization of a new series of conformationally fluxional copper coordination complexes that contain a twisted intramolecular charge transfer (TICT) fluorophore as part of their ligand scaffold. Structural and spectroscopic characterization of the Cu(I) and Cu(II) complexes formed with these ligands in their ground states establish oxidation state-dependent conformational dynamicity, while time-resolved emission and transient absorption spectroscopies define the photophysical parameters of photo-induced excited states. Building on initial reports with a related set of molecules, the improved ligand design presented here greatly simplifies the observed photophysics, effectively shutting down unwanted ligand-centered excited states previously observed. Time-dependent density functional theory (TDDFT) analyses reveal an unusual metal-to-TICT electronic transition only reported once before, and though the formation of a CS state is not observed directly through experiments, TDDFT geometry optimizations in the excited states support the formation of transient Cu(II) CS species, lending credence to the potential success of our approach. These studies establish a clear model for the excited state dynamics at play in proof-of-concept systems and clarify key design parameters for future optimizations toward achieving long-lived CS via photoinduced conformational gating.

Barriers to Lactulose Adherence in Patients with Cirrhosis and Hepatic Encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a major cause of mortality and morbidity in patients with cirrhosis. Lactulose non-adherence is one of the most frequently reported precipitants of hospital admission for HE. AIMS: We aimed to identify which factors contribute most to lactulose non-adherence and propose strategies to promote greater adherence and utilization of lactulose. METHODS: Participants in this study consisted of patients with cirrhosis who were taking lactulose for prevention of HE. Subjects were administered the Morisky Adherence Scale 8 (MAS-8) and a customized 16-question survey that assessed barriers to lactulose adherence. Results from the MAS-8 were used to stratify subjects into "adherent" and "non-adherent" groups. Survey responses were compared between groups. RESULTS: We enrolled 129 patients in our study, of whom 45 were categorized as "adherent and 72 were categorized as "non-adherent." Barriers to adherence included large volumes of lactulose, high frequency of dosing, difficulty remembering to take the medication, unpleasant taste, and medication side-effects. Most patients (97%) expressed understanding of the importance of lactulose, and 71% of patients felt that lactulose was working to manage their HE. Hospital admission rates for HE was higher in non-adherent patients, although this difference was not statistically significant. CONCLUSION: We identified several factors that contribute to lactulose non-adherence among patients treated for HE. Many of these factors are potentially modifiable. Patient and care-giver education are critical to assure adherence. Pharmacists and nurses are an essential but underutilized aspect of education regarding proper medication use.

AL4GAP: Active learning workflow for generating DFT-SCAN accurate machine-learning potentials for combinatorial molten salt mixtures.

Machine learning interatomic potentials have emerged as a powerful tool for bypassing the spatiotemporal limitations of ab initio simulations, but major challenges remain in their efficient parameterization. We present AL4GAP, an ensemble active learning software workflow for generating multicomposition Gaussian approximation potentials (GAP) for arbitrary molten salt mixtures. The workflow capabilities include: (1) setting up user-defined combinatorial chemical spaces of charge neutral mixtures of arbitrary molten mixtures spanning 11 cations (Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba and two heavy species, Nd, and Th) and 4 anions (F, Cl, Br, and I), (2) configurational sampling using low-cost empirical parameterizations, (3) active learning for down-selecting configurational samples for single point density functional theory calculations at the level of Strongly Constrained and Appropriately Normed (SCAN) exchange-correlation functional, and (4) Bayesian optimization for hyperparameter tuning of two-body and many-body GAP models. We apply the AL4GAP workflow to showcase high throughput generation of five independent GAP models for multicomposition binary-mixture melts, each of increasing complexity with respect to charge valency and electronic structure, namely: LiCl-KCl, NaCl-CaCl2, KCl-NdCl3, CaCl2-NdCl3, and KCl-ThCl4. Our results indicate that GAP models can accurately predict structure for diverse molten salt mixture with density functional theory (DFT)-SCAN accuracy, capturing the intermediate range ordering characteristic of the multivalent cationic melts.

Pelvic organ prolapse recurrence after pregnancy following uterine-sparing prolapse repair: a systematic review and meta-analysis.

INTRODUCTION: We sought to determine rates of pelvic organ prolapse (POP) recurrence following pregnancy and delivery in reproductive-age women with prior hysteropexy. METHODS: Scopus, MEDLine, EMBASE, Cochrane Library, and ClinicalTrials.gov databases were searched from inception to May 2020 for combinations of any of the keywords: "pregnancy", "delivery", "fertility", or "cesarean" with a comprehensive list of uterine-sparing surgical procedures for POP repair. Using approach, 1,817 articles were identified describing surgical, uterine-sparing POP repair techniques and subsequent pregnancy and delivery outcomes in reproductive-age women.   RESULTS: Twenty-seven studies describing 218 pregnancies, including 215 deliveries and 3 abortions, were summarized using narrative review and descriptive statistics. Successful pregnancies were reported following a diverse range of uterine-sparing prolapse repairs, both native tissue and mesh-augmented, that utilized vaginal, open abdominal, and laparoscopic approaches. We observed shifts from native tissue repairs to mesh-augmented laparoscopic repairs over time. POP recurrence occurred in 12% of subjects overall, 15% after vaginal and 10% after abdominal prolapse repairs. While meta-analysis identified higher recurrence rates after vaginal delivery (15%) than cesarean section (10%), due to small study numbers, multiple confounders, and heterogeneity between studies, no significant differences in recurrence rates could be identified between vaginal and abdominal surgical approaches, utilization of mesh augmentation, or mode of delivery. CONCLUSION: Although literature on pregnancy following uterine-sparing POP repair is limited, available data suggest that prolapse recurrence after pregnancy and delivery remains similar to that after prolapse repair without subsequent pregnancies with few documented perinatal complications. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021247722.

Effect of external eyelid weighting on eyelid and eyebrow position in normal and ptosis patients.

PURPOSE: This study aims to characterize the physiologic response of both eyelid and eyebrow position to increasing downward forces simulated by external weights. METHODS: In this prospective observational study, both normal individuals and patients affected by ptosis were tested. External eyelid weights were placed on one upper eyelid with incrementally increasing weight from 0.2 to 2.4 g. The eyelid carrying the weight was randomly selected for normal subjects and patients with bilateral ptosis, whereas for unilateral ptosis, the ptotic eyelid was utilized. Photographs were obtained at baseline and with increasing weight until MRD1 reached 0 on the weighted side or, until 2.4 g was reached. Eyelid and brow position on the weighted and unweighted sides were digitally measured in millimeter. Primary outcome measures were change in the margin to reflex distance (MRD1) and pupil to brow distance (PTB) with weight on the weighted and unweighted sides for normal and ptosis subjects. RESULTS: The weighted eyelid MRD1 decreased linearly with increasing weight. This was true for normal and ptosis subjects. The unweighted eyelid MRD1 increased linearly with increasing weight. This was also the case for both normal and ptosis subjects. With increasing weight, PTB increased linearly on the weighted side. No significant intergroup differences were noted. CONCLUSIONS: In normal and ptosis subjects, when external weight on the eyelid is incrementally increased, the weighted eyelid MRD1 decreases, the unweighted eyelid MRD1 increases, and both brows elevate in a linear fashion.

Controlled Ankle Movement (CAM) Boot Provides Improved Outcomes With Lower Complications Than Short Leg Walking Cast in Low-energy Pediatric Lateral Ankle Injuries: A Prospective, Randomized Study.

BACKGROUND: Low-energy lateral ankle injuries (Salter-Harris 1 distal fibula, distal fibula avulsion fractures, and radiograph-negative lateral ankle injuries) are common in pediatric patients. Patient-based outcomes for the 2 treatment options, short leg walking cast (CAST) and controlled ankle motion (CAM) boot, are unknown. This study aims to determine differences between 2 treatments of low-energy lateral ankle injuries in pediatric patients. METHODS: A prospective, randomized controlled trial comparing the acute outcomes of CAST and CAM treatment for low-energy lateral ankle injuries in pediatric patients was completed. Patients were evaluated in-person at presentation and 4 weeks for ankle range of motion and Oxford foot and ankle score. A novel survey defining patient and parent satisfaction and time away from school/work was also completed. Treatment complications were documented. Patients were called at 8 weeks postinjury to determine other complications and the final time of return to sport. Mixed effects linear regression models evaluated change over time between the 2 treatment groups. RESULTS: After 60 patients were enrolled, 28 patients in the CAST group and 27 patients in the CAM group completed the study. Males comprised 51% (28), with 38 (69%) patients identifying as Hispanic. The patient's average age was 11.3±2.9 years and the average body mass index was 23.At the 4-week evaluation, the CAM group had improved range of motion, higher satisfaction scores (5.26 CAM vs. 4.25 CAST, P <0.05), similar pain scores (0.32 CAST vs. 0.41 CAM, P =0.75), and lower complications (0.54/patient CAST vs. 0.04/patient CAM, P <0.0001) than the CAST group. Female patients had improved inversion with CAM treatment than males ( P <0.05). Patients over age 12 in the CAST group had significantly decreased plantarflexion at week 4 ( P =0.002). Improvement in Oxford scores was similar between the CAST and CAM groups between the initial presentation and 4 weeks, except for increased improvement in CAM group Oxford scores for difficulty running and symptoms with walking/walking. At the 8-week evaluation, patients in the CAST group had a higher rate of continued symptoms than the CAM group (15.4% vs. 0%). CONCLUSIONS: CAM boot treatment of low-energy lateral ankle injuries in pediatric patients results in improved results and lower complications than CAST treatment. LEVEL OF EVIDENCE: Level I -randomized, controlled trial with a statistically significant difference.

Decrement Evoked Potential (DEEP) Mapping of the Atria: Unmasking Atrial Fibrillation Substrate.

BACKGROUND: Atrial myopathy may underlie the progression of atrial fibrillation (AF) from a treatable disease to an irreversible condition with poor ablation outcomes. Electrophysiological methods to unmask areas prone to re-entry initiation could be key to defining latent atrial myopathy. METHODS: Consecutive patients referred for AF ablation were prospectively included at four institutions. Decrement evoked potential mapping (DEEP) was performed in eight left atrial sites and five right atrial sites, from two different pacing locations (endocardially from the left atrial appendage, epicardially from the proximal coronary sinus). The electrograms (EGMs) during S1 600 ms drive and after an extra stimulus (S2 at +30 ms above atrial refractoriness) were studied at each location and assessed for decremental properties. Follow-up was 12 months. RESULTS: Seventy-four patients were included and 85% had persistent AF. A total of 17,614 EGMs were individually analysed and measured. Nine percent of the EGMs showed DEEP properties (local delay of >10 ms after S2) with a mean decrement of 33±26 ms. DEEPs were more frequent in the left atrium than the right atrium (9.4% vs 8.0%; p<0.001) and more prevalent in persistent AF patients than paroxysmal AF patients (9.8% vs 4.6% p=0.001). Atrial DEEPs were more frequently unmasked in normal bipolar voltage areas and by epicardial pacing than endocardial pacing (9.6% vs 8.4%, respectively; p=0.004). Within the left atrium, the roof had the highest prevalence of DEEP EGMs. CONCLUSIONS: DEEP mapping of both atria is useful for highlighting areas with a tendency for unidirectional block and re-entry initiation. Those areas are more easily unmasked by epicardial pacing from the coronary sinus and more prevalent in persistent AF patients than in paroxysmal AF patients.