Acceleration of Solvation Free Energy Calculation via Thermodynamic Integration Coupled with Gaussian Process Regression and Improved Gelman-Rubin Convergence Diagnostics.

The determination of the solvation free energy of ions and molecules holds profound importance across a spectrum of applications spanning chemistry, biology, energy storage, and the environment. Molecular dynamics simulations are powerful tools for computing this critical parameter. Nevertheless, the accurate and efficient calculation of the solvation free energy becomes a formidable endeavor when dealing with complex systems characterized by potent Coulombic interactions and sluggish ion dynamics and, consequently, slow transition across various metastable states. In the present study, we expose limitations stemming from the conventional calculation of the statistical inefficiency g in the thermodynamic integration method, a factor that can hinder the determination of convergence of the solvation free energy and its associated uncertainty. Instead, we propose a robust scheme based on Gelman-Rubin convergence diagnostics. We leverage this improved estimation of uncertainties to introduce an innovative accelerated thermodynamic integration method based on the Gaussian Process regression. This methodology is applied to the calculation of the solvation free energy of trivalent rare-earth elements immersed in ionic liquids, a scenario in which the aforementioned challenges render standard approaches ineffective. The proposed method proves to be effective in computing solvation free energy in situations where traditional thermodynamic integration methods fall short.

MolSieve: A Progressive Visual Analytics System for Molecular Dynamics Simulations.

Molecular Dynamics (MD) simulations are ubiquitous in cutting-edge physio-chemical research. They provide critical insights into how a physical system evolves over time given a model of interatomic interactions. Understanding a system's evolution is key to selecting the best candidates for new drugs, materials for manufacturing, and countless other practical applications. With today's technology, these simulations can encompass millions of unit transitions between discrete molecular structures, spanning up to several milliseconds of real time. Attempting to perform a brute-force analysis with data-sets of this size is not only computationally impractical, but would not shed light on the physically-relevant features of the data. Moreover, there is a need to analyze simulation ensembles in order to compare similar processes in differing environments. These problems call for an approach that is analytically transparent, computationally efficient, and flexible enough to handle the variety found in materials-based research. In order to address these problems, we introduce MolSieve, a progressive visual analytics system that enables the comparison of multiple long-duration simulations. Using MolSieve, analysts are able to quickly identify and compare regions of interest within immense simulations through its combination of control charts, data-reduction techniques, and highly informative visual components. A simple programming interface is provided which allows experts to fit MolSieve to their needs. To demonstrate the efficacy of our approach, we present two case studies of MolSieve and report on findings from domain collaborators.

Improving Estimation of the Koopman Operator with Kolmogorov-Smirnov Indicator Functions.

It has become common to perform kinetic analysis using approximate Koopman operators that transform high-dimensional timeseries of observables into ranked dynamical modes. The key to the practical success of the approach is the identification of a set of observables that form a good basis on which to expand the slow relaxation modes. Good observables are, however, difficult to identify a priori and suboptimal choices can lead to significant underestimations of characteristic time scales. Leveraging the representation of slow dynamics in terms of Hidden Markov Models (HMM), we propose a simple and computationally efficient clustering procedure to infer surrogate observables that form a good basis for slow modes. We apply the approach to an analytically solvable model system as well as on three protein systems of different complexities. We consistently demonstrate that the inferred indicator functions can significantly improve the estimation of the leading eigenvalues of Koopman operators and correctly identify key states and transition time scales of stochastic systems, even when good observables are not known a priori.

Architector for high-throughput cross-periodic table 3D complex building.

Rare-earth and actinide complexes are critical for a wealth of clean-energy applications. Three-dimensional (3D) structural generation and prediction for these organometallic systems remains a challenge, limiting opportunities for computational chemical discovery. Here, we introduce Architector, a high-throughput in-silico synthesis code for s-, p-, d-, and f-block mononuclear organometallic complexes capable of capturing nearly the full diversity of the known experimental chemical space. Beyond known chemical space, Architector performs in-silico design of new complexes including any chemically accessible metal-ligand combinations. Architector leverages metal-center symmetry, interatomic force fields, and tight binding methods to build many possible 3D conformers from minimal 2D inputs including metal oxidation and spin state. Over a set of more than 6,000 x-ray diffraction (XRD)-determined complexes spanning the periodic table, we demonstrate quantitative agreement between Architector-predicted and experimentally observed structures. Further, we demonstrate out-of-the box conformer generation and energetic rankings of non-minimum energy conformers produced from Architector, which are critical for exploring potential energy surfaces and training force fields. Overall, Architector represents a transformative step towards cross-periodic table computational design of metal complex chemistry.

Complete Endoscopic Resection of an Osteoid Osteoma in the Body of a Thoracic Vertebra: A Case Report.

CASE: A 29-year-old man presented nontraumatic diffuse thoracic pain. Magnetic resonance imaging of the spine showed a cortical lesion with peripheral hyperintensity, a central sclerotic hypointense nidus, and surrounding paraspinal inflammatory changes at the T3 vertebral body. Clinical and radiologic findings were consistent with an osteoid osteoma. The patient successfully underwent an endoscopic partial corpectomy and mass resection. At the 6-month follow-up, radiographs showed complete tumor resolution. CONCLUSION: Endoscopic resection is an adequate and minimally invasive technique for the complete resection of osteoid osteomas.

Patient Experience and Perspective on Medical Cannabis as an Alternative for Musculoskeletal Pain Management.

INTRODUCTION: The current rate of opioid prescription is disquieting because of their high abuse potential, adverse effects, and thousands of overdose deaths. This situation imposes urgency in seeking alternatives for adequate pain management. From this perspective, this study aimed to evaluate the experience and the perceived analgesic efficacy of medical cannabis in managing the pain associated with musculoskeletal conditions. METHODS: A 28-question survey was distributed to patients at a major medical cannabis center in Puerto Rico for 2 months. Demographics, medical history, cannabis usage, cannabis use perspective, and analgesic efficacy were assessed in the questionnaire. RESULTS: One hundred eighty-four patients completed our survey. The majority (67%) were males, and the participants' average age was 38 years. This study showed an average pain reduction score of 4.02 points on the Numeric Rating Scale among all the participants. Those with musculoskeletal conditions reported a notable average pain reduction score of 4.47 points. In addition, 89% of the participants considered medical cannabis to be more effective than narcotics for adequate pain management. CONCLUSIONS: This study demonstrated that the use of medical cannabis among patients with musculoskeletal conditions effectively reduced pain levels based on their Numeric Rating Scale reported scores.

Atomistic Mechanisms of Binary Alloy Surface Segregation from Nanoseconds to Seconds Using Accelerated Dynamics.

Although the equilibrium composition of many alloy surfaces is well understood, the rate of transient surface segregation during annealing is not known, despite its crucial effect on alloy corrosion and catalytic reactions occurring on overlapping timescales. In this work, CuNi bimetallic alloys representing (100) surface facets are annealed in vacuum using atomistic simulations to observe the effect of vacancy diffusion on surface separation. We employ multi-timescale methods to sample the early transient, intermediate, and equilibrium states of slab surfaces during the separation process, including standard MD as well as three methods to perform atomistic, long-time dynamics: parallel trajectory splicing (ParSplice), adaptive kinetic Monte Carlo (AKMC), and kinetic Monte Carlo (KMC). From nanosecond (ns) to second timescales, our multiscale computational methodology can observe rare stochastic events not typically seen with standard MD, closing the gap between computational and experimental timescales for surface segregation. Rapid diffusion of a vacancy to the slab is resolved by all four methods in tens of nanoseconds. Stochastic re-entry of vacancies into the subsurface, however, is only seen on the microsecond timescale in the two KMC methods. Kinetic vacancy trapping on the surface and its effect on the segregation rate are discussed. The equilibrium composition profile of CuNi after segregation during annealing is estimated to occur on a timescale of seconds as determined by KMC, a result directly comparable to nanoscale experiments.

Orthopaedic trauma epidemiology after Hurricane Maria in the Puerto Rico Trauma Centre.

PURPOSE: Hurricane Maria is the most devastating natural phenomenon in the recent history of Puerto Rico. Due to its destructive path through the island, the Puerto Rico Trauma Center (PRTC) remained the only hospital managing orthopaedic trauma in the immediate post-disaster period. We investigated the impact of this hurricane on the orthopaedic trauma epidemiology in the PRTC. METHODS: We evaluated the admissions by the orthopaedic surgery service in terms of demographics, mechanisms of injury, and orthopaedic diagnoses for two months after the impact of Hurricane Maria (HM) on September 20, 2017. We compared our study group with the same two month period for two years prior (2015 and 2016) and after (2018 and 2019) as control periods. A p value of < 0.05 was considered statistically significant. RESULTS: We included 384 admissions from September 20 to November 20, 2017. The majority were males (63%) and had an average age of 54 years. The most-reported mechanism of injury was fall from standing height (FFSH), showing a significant increment compared with the control periods. Contrarily, motor vehicle accidents (MVA) showed a significant reduction. Among the orthopaedic diagnoses, the hip + pelvis category showed a significant decline within the study group. CONCLUSIONS: This study highlighted the impact of HM on the orthopaedic trauma epidemiology at the PRTC. Our findings provide valuable evidence to healthcare institutions to better prepare to manage the potential changes in the orthopaedic trauma epidemiology after a major atmospheric event.

Pairwise Difference Regression: A Machine Learning Meta-algorithm for Improved Prediction and Uncertainty Quantification in Chemical Search.

Machine learning (ML) plays a growing role in the design and discovery of chemicals, aiming to reduce the need to perform expensive experiments and simulations. ML for such applications is promising but difficult, as models must generalize to vast chemical spaces from small training sets and must have reliable uncertainty quantification metrics to identify and prioritize unexplored regions. Ab initio computational chemistry and chemical intuition alike often take advantage of differences between chemical conditions, rather than their absolute structure or state, to generate more reliable results. We have developed an analogous comparison-based approach for ML regression, called pairwise difference regression (PADRE), which is applicable to arbitrary underlying learning models and operates on pairs of input data points. During training, the model learns to predict differences between all possible pairs of input points. During prediction, the test points are paired with all training set points, giving rise to a set of predictions that can be treated as a distribution of which the mean is treated as a final prediction and the dispersion is treated as an uncertainty measure. Pairwise difference regression was shown to reliably improve the performance of the random forest algorithm across five chemical ML tasks. Additionally, the pair-derived dispersion is both well correlated with model error and performs well in active learning. We also show that this method is competitive with state-of-the-art neural network techniques. Thus, pairwise difference regression is a promising tool for candidate selection algorithms used in chemical discovery.

E2-CD154 vaccine candidate is safe and immunogenic in pregnant sows, and the maternal derived neutralizing antibodies protect piglets from classical swine fever virus challenge.

E2-CD154 subunit vaccine candidate is safe and protects swine from Classical Swine Fever (CSF). However, its safety and immunogenicity in pregnant sows, and the capacity of maternal derived neutralizing antibodies (MDNA) to protect the offspring is yet to be demonstrated. The aim of this study was to evaluate the safety and immunogenicity of E2-CD154 in pregnant sows, and the capacity of MDNA to protect the offspring. Seventeen pregnant sows were vaccinated twice with E2-CD154 in either the first or the second third of pregnancy. Pregnancy and litter parameters were compared with a control group of non-vaccinated sows. Neutralizing antibodies (NAb) were monitored. The time course of MDNA was assessed in a group of six piglets born to an E2-CD154 immunized sow, and the animals were challenged with CSFV at day 63 after birth. No local or systemic adverse effects were found. Neither abortions, nor congenital malformations, nor stillbirths were observed. All sows develop high NAb titers after the first immunization. Piglets born to an E2-CD154 vaccinated sow still showed MDNA titers of 1:100 at day 63 after birth. Five animals were negative for virus isolation after challenge, and showed neither signs of CSF, nor macroscopic lesions in the organs. The other piglet was positive for CSFV isolation, and macroscopic lesions were observed in the spleen, although no clinical signs of CSF other than fever were detected. E2-CD154 vaccine candidate was safe and immunogenic in pregnant sows, and the passive immunity transmitted to the offspring was still protective by day 63 after birth.

Blunt Abdominopelvic Trauma Complicated by Traumatic Testicular Dislocation in a 19-Year-Old Male Patient: A Case Report.

CASE: A 19 year-old male patient presented with testicular dislocation after abdominopelvic trauma. During open reduction and internal fixation, consult to urology was placed after discovering the presence of the intra-abdominal testicle. The testicle was repositioned into the scrotum with orchiopexy, and pelvic fixation was completed with 1 sacroiliac percutaneous screw and pubic symphysis fixation. Postoperative recovery was uneventful, and the patient was discharged home on postoperative day 3. CONCLUSION: Testicular dislocation is an uncommon finding after blunt abdominopelvic trauma; hence, it may be overlooked. Prompt diagnosis of testicular dislocation given the need for operative management to preserve testicle viability is crucial.

Concordance between self-sampling and standar endocervical sample collection to identify sexual transmission infections in an urban-rural area of Peru. / Concordancia entre autotoma y colección estándar de muestras endocervicales para identificar infecciones de trasmisión sexual en un área urbano-rural del Perú.

With the objective of evaluating the concordance between the self-sampling of vaginal samples and the standard collection of endocervical samples for the identification of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Candida spp. carried out by health personnel in women from an urban-rural area of Peru, a prospective and cross-sectional study was carried out in 206 women of childbearing age, we identified some sexually transmitted infections such as Chlamydia trachomatis or Trichomonas vaginalis in 9/206 (4.4%). We obtained a high degree of agreement in the identification of Candida spp. (k = 0.97), Chlamydia trachomatis (k=0.92) and Trichomonas vaginalis by microscopy (k=1.00), and a considerable agreement for the identification of Trichomonas vaginalis by culture (k=0.66). The self-sampling technique can be used to identify some sexually transmitted infections in urban-rural populations.

Con el objetivo de evaluar la concordancia entre la autotoma de muestras vaginales y la toma estándar de muestras endocervicales para la identificación de Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis y Candida spp. realizadas por el personal de salud en mujeres de un área urbano-rural del Perú, se realizó un estudio prospectivo y transversal en 206 mujeres en edad fértil, identificamos algunas infecciones de transmisión sexual como Chlamydia trachomatis o Trichomonas vaginalis en 9 mujeres (4,4%). Obtuvimos una concordancia casi perfecta en la identificación de Candida spp. (k=0,97), Chlamydia trachomatis (k=0,92) y Trichomonas vaginalis por microscopía (k=1,00), y considerable para la identificación de Trichomonas vaginalis por cultivo (k=0,66). La técnica de la autotoma de muestras vaginales podría ser usada para la identificación de algunas infecciones de transmisión sexual en población urbano-rural.

Novel chimeric E2CD154 subunit vaccine is safe and confers long lasting protection against classical swine fever virus.

E2CD154 is a vaccine candidate against classical swine fever (CSF) based on a chimeric protein composed of the E2 glycoprotein fused to porcine CD154 antigen, and formulated in the oil adjuvant Montanide™ ISA 50 V2. This vaccine confers early protection in pigs and prevents vertical transmission in pregnant sows. The objectives of this study were to assess the safety of this immunogen in piglets, to compare several doses of antigen in the formulation, and to study the duration of the immunity provided by this vaccine for up to 9 months. Three trials were conducted by immunizing pigs with a two-dose regime of the vaccine. Challenge experiments were carried out with the highly pathogenic Margarita strain. No local or systemic adverse effects were documented, and neither macroscopic nor microscopic pathological findings were observed in the vaccinated animals. The three antigen doses explored were safe and induced CSF protective neutralizing antibodies. The dose of 50 µg was selected for further development because it provided the best clinical and virological protection. Finally, this protective immunity was sustained for at least 9 months. This study demonstrates that E2CD154 vaccine is safe; defines a vaccine dose of 50 µg antigen, and evidences the capacity of this vaccine to confer long term protection from CSFV infection for up to 9 months post- vaccination. These findings complement previous data on the evaluation of this vaccine candidate, and suggest that E2CD154 is a promising alternative to modified live vaccines in CSF endemic areas.

Porvac® Subunit Vaccine E2-CD154 Induces Remarkable Rapid Protection against Classical Swine Fever Virus.

Live attenuated C-strain classical swine fever vaccines provide early onset protection. These vaccines confer effective protection against the disease at 5-7 days post-vaccination. It was previously reported that intramuscular administration of the Porvac® vaccine protects against highly virulent classical swine fever virus (CSFV) "Margarita" strain as early as seven days post-vaccination. In order to identify how rapidly protection against CSFV is conferred after a single dose of the Porvac® subunit vaccine E2-CD154, 15 swine, vaccinated with a single dose of Porvac®, were challenged intranasally at five, three, and one day post-vaccination with 2 × 103 LD50 of the highly pathogenic Cuban "Margarita" strain of the classical swine fever virus. Another five animals were the negative control of the experiment. The results provided clinical and virological data confirming protection at five days post-vaccination. Classical swine fever (CSF)-specific IFNγ T cell responses were detected in vaccinated animals but not detected in unvaccinated control animals. These results provided the first data that a subunit protein vaccine demonstrates clinical and viral protection at five days post-vaccination, as modified live vaccines.

Concordancia entre autotoma y colección estándar de muestras endocervicales para identificar infecciones de trasmisión sexual en un área urbano-rural del Perú / Concordance between self-sampling and standar endocervical sample collection to identify sexual transmission infections in an urban-rural area of Peru

RESUMEN Con el objetivo de evaluar la concordancia entre la autotoma de muestras vaginales y la toma estándar de muestras endocervicales para la identificación de Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis y Candida spp. realizadas por el personal de salud en mujeres de un área urbano-rural del Perú, se realizó un estudio prospectivo y transversal en 206 mujeres en edad fértil, identificamos algunas infecciones de transmisión sexual como Chlamydia trachomatis o Trichomonas vaginalis en 9 mujeres (4,4%). Obtuvimos una concordancia casi perfecta en la identificación de Candida spp. (k=0,97), Chlamydia trachomatis (k=0,92) y Trichomonas vaginalis por microscopía (k=1,00), y considerable para la identificación de Trichomonas vaginalis por cultivo (k=0,66). La técnica de la autotoma de muestras vaginales podría ser usada para la identificación de algunas infecciones de transmisión sexual en población urbano-rural.

ABSTRACT With the objective of evaluating the concordance between the self-sampling of vaginal samples and the standard collection of endocervical samples for the identification of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Candida spp. carried out by health personnel in women from an urban-rural area of Peru, a prospective and cross-sectional study was carried out in 206 women of childbearing age, we identified some sexually transmitted infections such as Chlamydia trachomatis or Trichomonas vaginalis in 9/206 (4.4%). We obtained a high degree of agreement in the identification of Candida spp. (k = 0.97), Chlamydia trachomatis (k=0.92) and Trichomonas vaginalis by microscopy (k=1.00), and a considerable agreement for the identification of Trichomonas vaginalis by culture (k=0.66). The self-sampling technique can be used to identify some sexually transmitted infections in urban-rural populations.

Concordancia entre autotoma y colección estándar de muestras endocervicales para identificar infecciones de trasmisión sexual en un área urbano-rural del Perú / Concordance between self-sampling and standar endocervical sample collection to identify sexual transmission infections in an urban-rural area of Peru

RESUMEN Con el objetivo de evaluar la concordancia entre la autotoma de muestras vaginales y la toma estándar de muestras endocervicales para la identificación de Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis y Candida spp. realizadas por el personal de salud en mujeres de un área urbano-rural del Perú, se realizó un estudio prospectivo y transversal en 206 mujeres en edad fértil, identificamos algunas infecciones de transmisión sexual como Chlamydia trachomatis o Trichomonas vaginalis en 9 mujeres (4,4%). Obtuvimos una concordancia casi perfecta en la identificación de Candida spp. (k=0,97), Chlamydia trachomatis (k=0,92) y Trichomonas vaginalis por microscopía (k=1,00), y considerable para la identificación de Trichomonas vaginalis por cultivo (k=0,66). La técnica de la autotoma de muestras vaginales podría ser usada para la identificación de algunas infecciones de transmisión sexual en población urbano-rural.

ABSTRACT With the objective of evaluating the concordance between the self-sampling of vaginal samples and the standard collection of endocervical samples for the identification of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Candida spp. carried out by health personnel in women from an urban-rural area of Peru, a prospective and cross-sectional study was carried out in 206 women of childbearing age, we identified some sexually transmitted infections such as Chlamydia trachomatis or Trichomonas vaginalis in 9/206 (4.4%). We obtained a high degree of agreement in the identification of Candida spp. (k = 0.97), Chlamydia trachomatis (k=0.92) and Trichomonas vaginalis by microscopy (k=1.00), and a considerable agreement for the identification of Trichomonas vaginalis by culture (k=0.66). The self-sampling technique can be used to identify some sexually transmitted infections in urban-rural populations.

Immunogenicity of E2CD154 Subunit Vaccine Candidate against Classical Swine Fever in Piglets with Different Levels of Maternally Derived Antibodies.

E2CD154 is a novel subunit vaccine candidate against classical swine fever virus (CSFV). It contains the E2 envelope protein from CSFV fused to the porcine CD154 molecule formulated in the oil adjuvant MontanideTM ISA50 V2. Previous works evidenced the safety and immunogenicity of this candidate. Here, two other important parameters related to vaccine efficacy were assessed. First, the existence of high maternally derived antibody (MDA) titers in piglets born to sows vaccinated with E2CD154 was demonstrated. These MDA titers remained above 1:200 during the first seven weeks of life. To assess whether the titers interfere with active vaccination, 79 piglets from sows immunized with either E2CD154 or a modified live vaccine were vaccinated with E2CD154 following a 0-21-day biphasic schedule. Animals immunized at either 15, 21, or 33 days of age responded to vaccination by eliciting protective neutralizing antibody (NAb) titers higher than 1:600, with a geometric mean of 1:4335, one week after the booster. Those protective levels of NAb were sustained up to six months of age. No vaccination-related adverse effects were described. As a conclusion, E2CD154 is able to induce protective NAb in piglets with different MDA levels and at different days of age.

An entropy-maximization approach to automated training set generation for interatomic potentials.

Machine learning-based interatomic potentials are currently garnering a lot of attention as they strive to achieve the accuracy of electronic structure methods at the computational cost of empirical potentials. Given their generic functional forms, the transferability of these potentials is highly dependent on the quality of the training set, the generation of which can be highly labor-intensive. Good training sets should at once contain a very diverse set of configurations while avoiding redundancies that incur cost without providing benefits. We formalize these requirements in a local entropy-maximization framework and propose an automated sampling scheme to sample from this objective function. We show that this approach generates much more diverse training sets than unbiased sampling and is competitive with hand-crafted training sets.

Parallel algorithms for hyperdynamics and local hyperdynamics.

Hyperdynamics (HD) is a method for accelerating the timescale of standard molecular dynamics (MD). It can be used for simulations of systems with an energy potential landscape that is a collection of basins, separated by barriers, where transitions between basins are infrequent. HD enables the system to escape from a basin more quickly while enabling a statistically accurate renormalization of the simulation time, thus effectively boosting the timescale of the simulation. In the work of Kim et al. [J. Chem. Phys. 139, 144110 (2013)], a local version of HD was formulated, which exploits the intrinsic locality characteristic typical of most systems to mitigate the poor scaling properties of standard HD as the system size is increased. Here, we discuss how both HD and local HD can be formulated to run efficiently in parallel. We have implemented these ideas in the LAMMPS MD code, which means HD can be used with any interatomic potential LAMMPS supports. Together, these parallel methods allow simulations of any size to achieve the time acceleration offered by HD (which can be orders of magnitude), at a cost of 2-4× that of standard MD. As examples, we performed two simulations of a million-atom system to model the diffusion and clustering of Pt adatoms on a large patch of the Pt(100) surface for 80 µs and 160 µs.