Computing the Differences between Asn-X and Gln-X Deamidation and Their Impact on Pharmaceutical and Physiological Proteins: A Theoretical Investigation Using Model Dipeptides.

Protein deamidation is a degradation mechanism that significantly impacts both pharmaceutical and physiological proteins. Deamidation impacts two amino acids, Asn and Gln, where the net neutral residues are converted into their acidic forms. While there are multiple similarities between the reaction mechanisms of the two residues, the impact of Gln deamidation has been noted to be most significant on physiological proteins while Asn deamidation has been linked to both pharmaceutical and physiological proteins. For this purpose, we sought to analyze the thermochemical and kinetic properties of the different reactions of Gln deamidation relative to Asn deamidation. In this study, we mapped the deamidation of Gln-X dipeptides into Glu-X dipeptides using density functional theory (DFT). Full network mapping facilitated the prediction of reaction selectivity between the two primary pathways, as well as between the two products of Gln-X deamidation as a function of solvent dielectric. To achieve this analysis, we studied a total of 77 dipeptide reactions per solvent dielectric (308 total reactions). Modeled at a neutral pH and using quantum chemical and statistical thermodynamic methods, we computed the following values: enthalpy of reaction (ΔHRXN), entropy (ΔSRXN), Gibbs free energy of reaction (ΔGRXN), activation energy (EA), and the Arrhenius preexponential factor (log(A)) for each dipeptide. Additionally, using chemical reaction principles, we generated a database of computed rate coefficients for all possible N-terminus Gln-X deamidation reactions at a neutral pH, predicted the most likely deamidation reaction mechanism for each dipeptide reaction, analyzed our results against our prior study on Asn-X deamidation, and matched our results against qualitative trends previously noted by experimental literature.

Rising incidence of acute total hip arthroplasty for primary and adjunctive treatment of acetabular fracture in older and middle-aged adults.

BACKGROUND: Acute total hip arthroplasty (THA) may be an alternative or an adjuvant to internal fixation for surgical treatment of acetabular fractures. We investigate recent trends in the operative management of acetabular fractures. We hypothesize that the incidence of acute THA for acetabular fractures has increased over time. METHODS: 4569 middle-aged (45-64 years) and older adults (≥ 65 years) who received acute operative management of an acetabular fracture within 3 weeks of admission between 2010 and 2020 were identified from the United States Nationwide Inpatient Sample database. Treatment was classified as open reduction internal fixation (ORIF), THA, or combined ORIF and THA (ORIF + THA). Patients were stratified by age ≥ 65 years old. Associations between demographic factors and the incidence of each procedure over the study period were modeled using linear regression. RESULTS: The relative incidence of treatments was 80.9% ORIF, 12.1% THA, and 7.0% ORIF + THA. Among patients aged 45-64 years old, THA increased 4.8% [R2 = 0.62; ß1 = 0.6% (95% Confidence Interval (CI) 0.2-0.9%)] and ORIF + THA increased 2.6% [R2 = 0.73; ß1 = 0.3% (95% CI 0.2-0.4%)], while the use of ORIF decreased 7.4% [R2 = 0.75; ß1 = -0.9% (95% CI -1.2 to -0.5%)]. Among patients ≥ 65 years old, THA increased 16.5% [R2 = 0.87; ß1 = 1.7% (95% CI 1.2-2.2%)] and ORIF + THA increased 5.0% [R2 = 0.38, ß1 = 0.6% (95% CI 0.0-1.3%)], while ORIF decreased 21.5% [R2 = 0.75; ß1 = -2.4% (95% CI -3.45 to -1.3%)]. CONCLUSION: The treatment of acetabular fractures with acute THA has increased in the last decade, particularly among older adults.

Fentanyl Assay Derived from Intermolecular Interaction-Enabled Small Molecule Recognition (iMSR) with Differential Impedance Analysis for Point-of-Care Testing.

Rapid and effective differentiation and quantification of a small molecule drug, such as fentanyl, in bodily fluids are major challenges for diagnosis and personal medication. However, the current toxicology methods used to measure drug concentration and metabolites require laboratory-based testing, which is not an efficient or cost-effective way to treat patients in a timely manner. Here, we show an assay for monitoring fentanyl levels by combining the intermolecular interaction-enabled small molecule recognition (iMSR) with differential impedance analysis of conjugated polymers. The differential interactions with the designed anchor interface were transduced through the perturbance of the electric status of the flexible conducting polymer. This assay showed excellent fentanyl selectivity against common interferences, as well as in variable body fluids through either testing strips or skin patches. Directly using the patient blood, the sensor provided 1%-5% of the average deviation compared to the "gold" standard method LC-MS results in the medically relevant fentanyl range of 20-90 nM. The superior sensing properties, in conjunction with mechanical flexibility and compatibility, enabled point-of-care detection and provided a promising avenue for applications beyond the scope of biomarker detection.

Electronic structure of the ground and excited states of neutral and charged silicon hydrides, SiHx0/+/-, x = 1-4.

The ground and excited electronic states of the titled species are investigated with multi-reference configuration interaction and diffuse basis sets. We found that in addition to the valence orbitals, the inclusion of the 4s, 4p, and especially 3d orbitals (although with minimal population) of silicon in the active space of the reference complete active space self-consistent field wavefunction are necessary for the proper convergence of the calculations. We also demonstrate that the aug-cc-pVTZ basis set provides quite accurate results compared to both larger basis sets and basis set limit results at a lower computational cost. The excited states involve excitations within the 3s and 3p orbitals of silicon (especially for the mono- and di-hydrides), followed by excitations from the Si-H bonding orbitals to either silicon valence or Rydberg (4s, 4p) orbitals. The number of electronic states per energy unit decrease as we add hydrogen atoms, and the first excited state of SiH4 is at 9.0 eV and leads to SiH3 + H. All species have stable ground state structures with all hydrogen atoms bound to silicon, except for SiH4+ and SiH4-. The former dissociates to SiH2+ + H2, while the latter loses an electron or can dissociate forming H2 as well.

Competitive Hydrogen Migration in Silicon Nitride Nanoclusters: Reaction Kinetics Generalized from Supervised Machine Learning.

The rate coefficients for 52 hydrogen shift reactions for silicon nitrides containing up to 6 atoms of silicon and nitrogen have been calculated using the G3//B3LYP composite method and statistical thermodynamics. The overall reaction of substituted acyclic and cyclic silylenes to their respective silene and imine species by a 1,2-hydrogen shift reaction was sorted by three different types of H shift reactions using overall reaction thermodynamics: (1) endothermic H shift between N and Si:, (2) endothermic H shift between Si and Si:, and (3) exothermic H shift between Si and Si:. Endothermic H shift reactions between Si atoms have one dominant activation barrier where the exothermic H shift reaction between Si atoms has two barriers and a stable intermediate. The rate-determining step was determined to be from the intermediate to the substituted silene, and then kinetic parameters for the overall reaction were calculated for the two-step pathway. The single event pre-exponential factors, Ã, and activation energies, Ea, for the three different classes of hydrogen shift reactions of silicon nitrides were computed. The hydrogen shift reaction was explored for acyclic and cyclic monofunctional silicon nitrides, and the type of hydrogen shift reaction gives the most significant influence on the kinetic parameters. Using a supervised machine learning approach, the models for predicting the energy barrier of three different hydrogen shift reactions were generalized and suggested based on selected descriptors.

The SLIM Study: Economic, Energy, and Waste Savings Through Lowering of Instrumentation Mass in Total Hip Arthroplasty.

BACKGROUND: Nearly 700,000 total hip arthroplasties (THAs) are annually performed in North America, costing the healthcare system >$15 billion and creating over 5 million tons of waste. This study aims to (1) assess satisfaction of current THA setup; (2) determine economic cost, energy cost, and waste cost of current setup and apply lean methodology to improve efficiency; and (3) design and test "Savings through Lowering of Instrumentation Mass (SLIM) setup" based on lean principles and its ability to be safely implemented into practice. METHODS: A Needs Assessment Survey was performed. After review and surgeon input, the "SLIM" set was designed, significantly reducing redundancy. Eighty patients were randomized to either Standard or SLIM setup. Operating room time, blood loss, perioperative adverse events and complications, cost/case, instrument weight (kg/case), total waste (kg/case), case setup time, and number of times and number of extra trays required were compared between groups. RESULTS: The SLIM setup was associated with the following savings: Cost = -$408.19/case; Energy = -7.16 kWh/case; Waste = -1.61 kg/case; Trays = -6 (758 kg/case). No differences in operating room time, blood loss, and complication rate were detected (P > .05) between groups. Setup time was significantly shorter with SLIM (P < .05) and extra instrumentation was opened in <5% of cases. CONCLUSION: A more "minimalist approach" to THA can be safely implemented. The SLIM setup is efficient and has been openly accepted by our allied staff. Such setup can lead to 1,610 kg reduction in waste, 7,160 kWh, and $408,190 in savings per 1,000 THAs performed.

Isolating key reaction energetics and thermodynamic properties during hardwood model lignin pyrolysis.

Computational studies on the pyrolysis of lignin using electronic structure methods have been largely limited to dimeric or trimeric models. In the current work we have modeled a lignin oligomer consisting of 10 syringyl units linked through 9 ß-O-4' bonds. A lignin model of this size is potentially more representative of the polymer in angiosperms; therefore, we used this representative model to examine the behavior of hardwood lignin during the initial steps of pyrolysis. Using this oligomer, the present work aims to determine if and how the reaction enthalpies of bond cleavage vary with positions within the chain. To accomplish this, we utilized a composite method using molecular mechanics based conformational sampling and quantum mechanically based density functional theory (DFT) calculations. Our key results show marked differences in bond dissociation enthalpies (BDE) with the position. In addition, we calculated standard thermodynamic properties, including enthalpy of formation, heat capacity, entropy, and Gibbs free energy for a wide range of temperatures from 25 K to 1000 K. The prediction of these thermodynamic properties and the reaction enthalpies will benefit further computational studies and cross-validation with pyrolysis experiments. Overall, the results demonstrate the utility of a better understanding of lignin pyrolysis for its effective valorization.

Data-Driven Investigation of Monosilane and Ammonia Co-Pyrolysis to Silicon-Nitride-Based Ceramic Nanomaterials.

With its high strength, high thermal stability, low density, and high electrical resistance, silicon-nitride-based ceramics have been widely used as gate insulating layers, oxidation masks, and passivation layers. Employing SiN nanomaterials in anode applications also improves rate performances and cycling stability of the lithium-ion batteries. However, a fundamental understanding of the SiN synthetic process remains elusive. SiN gas-phase synthesis can be tailored with a comprehensive understanding of the underlying thermodynamics. In comparison to the characterization data available for solid-state SiN materials, high-level theoretical studies on gas-phase materials possessing Si-N bonds and comprehensive investigation of the SiN chemistry, particularly for nanoclusters, are very uncommon. Thus, we performed a theoretical study of Si and SiN alloy acyclic hydrides and polycyclic clusters to predict electronic structures and thermochemistry using quantum chemical calculation and statistical thermodynamics. Electronic properties by way of highest and lowest occupied molecular orbital energy gap and natural bonding orbitals analysis were calculated to explore the influence of elemental composition and geometry on the stability. Our studies provide characteristic data of SiN species for a data-driven approach to map the design space for discovery of novel silicon-nitride-based ceramic materials for advanced electronic and coating applications.

Tuning Hydrogenated Silicon, Germanium, and SiGe Nanocluster Properties Using Theoretical Calculations and a Machine Learning Approach.

There are limited studies available that predict the properties of hydrogenated silicon-germanium (SiGe) clusters. For this purpose, we conducted a computational study of 46 hydrogenated SiGe clusters (Si xGe yH z, 1 < X + Y ≤ 6) to predict the structural, thermochemical, and electronic properties. The optimized geometries of the Si xGe yH z clusters were investigated using quantum chemical calculations and statistical thermodynamics. The clusters contained 6 to 9 fused Si-Si, Ge-Ge, or Si-Ge bonds, i.e., bonds participating in more than one 3- to 4-membered rings, and different degrees of hydrogenation, i.e., the ratio of hydrogen to Si/Ge atoms varied depending on cluster size and degree of multifunctionality. Our studies have established trends in standard enthalpy of formation, standard entropy, and constant pressure heat capacity as a function of cluster composition and structure. A novel bond additivity correction model for SiGe chemistry was regressed from experimental data on seven acyclic Si/Ge/SiGe species to improve the accuracy of the standard enthalpy of formation predictions. Electronic properties were investigated by analysis of the HOMO-LUMO energy gap to study the effect of elemental composition on the electronic stability of Si xGe yH z clusters. These properties will be discussed in the context of tailored nanomaterials design and generalized using a machine learning approach.

Patient-specific anatomical and functional parameters provide new insights into the pathomechanism of cam FAI.

BACKGROUND: Femoroacetabular impingement (FAI) represents a constellation of anatomical and clinical features, but definitive diagnosis is often difficult. The high prevalence of cam deformity of the femoral head in the asymptomatic population as well as clinical factors leading to the onset of symptoms raises questions as to what other factors increase the risk of cartilage damage and hip pain. QUESTIONS/PURPOSES: The purpose was to identify any differences in anatomical parameters and squat kinematics among symptomatic, asymptomatic, and control individuals and if these parameters can determine individuals at risk of developing symptoms of cam FAI. METHODS: Forty-three participants (n = 43) were recruited and divided into three groups: symptomatic (12), asymptomatic (17), and control (14). Symptomatic participants presented a cam deformity (identified by an elevated alpha angle on CT images), pain symptoms, clinical signs, and were scheduled for surgery. The other recruited volunteers were blinded and unaware whether they had a cam deformity. After the CT data were assessed for an elevated alpha angle, participants with a cam deformity but who did not demonstrate any clinical signs or symptoms were considered asymptomatic, whereas participants without a cam deformity and without clinical signs or symptoms were considered healthy control subjects. For each participant, anatomical CT parameters (axial alpha angle, radial alpha angle, femoral head-neck offset, femoral neck-shaft angle, medial proximal femoral angle, femoral torsion, acetabular version) were evaluated. Functional squat parameters (maximal squat depth, pelvic range of motion) were determined using a motion capture system. A stepwise discriminant function analysis was used to determine which of the parameters were most suitable to classify each participant with their respective subgroup. RESULTS: The symptomatic group showed elevated alpha angles and lower femoral neck-shaft angles, whereas the asymptomatic group showed elevated alpha angles in comparison with the control group. The best discriminating parameters to determine symptoms were radial alpha angle, femoral neck-shaft angle, and pelvic range of motion (p < 0.001). CONCLUSIONS: In the presence of a cam deformity, indications of a decreased femoral neck-shaft angle and reduced pelvic range of motion can identify those at risk of symptomatic FAI.

Converting structural information into an allosteric-energy-based picture for elongation factor Tu activation by the ribosome.

The crucial process of aminoacyl-tRNA delivery to the ribosome is energized by the GTPase reaction of the elongation factor Tu (EF-Tu). Advances in the elucidation of the structure of the EF-Tu/ribosome complex provide the rare opportunity of gaining a detailed understanding of the activation process of this system. Here, we use quantitative simulation approaches and reproduce the energetics of the GTPase reaction of EF-Tu with and without the ribosome and with several key mutants. Our study provides a novel insight into the activation process. It is found that the critical H84 residue is not likely to behave as a general base but rather contributes to an allosteric effect, which includes a major transition state stabilization by the electrostatic effect of the P loop and other regions of the protein. Our findings have general relevance to GTPase activation, including the processes that control signal transduction.

Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions.

The proposal that enzymatic catalysis is due to conformational fluctuations has been previously promoted by means of indirect considerations. However, recent works have focused on cases where the relevant motions have components toward distinct conformational regions, whose population could be manipulated by mutations. In particular, a recent work has claimed to provide direct experimental evidence for a dynamical contribution to catalysis in dihydrofolate reductase, where blocking a relevant conformational coordinate was related to the suppression of the motion toward the occluded conformation. The present work utilizes computer simulations to elucidate the true molecular basis for the experimentally observed effect. We start by reproducing the trend in the measured change in catalysis upon mutations (which was assumed to arise as a result of a "dynamical knockout" caused by the mutations). This analysis is performed by calculating the change in the corresponding activation barriers without the need to invoke dynamical effects. We then generate the catalytic landscape of the enzyme and demonstrate that motions in the conformational space do not help drive catalysis. We also discuss the role of flexibility and conformational dynamics in catalysis, once again demonstrating that their role is negligible and that the largest contribution to catalysis arises from electrostatic preorganization. Finally, we point out that the changes in the reaction potential surface modify the reorganization free energy (which includes entropic effects), and such changes in the surface also alter the corresponding motion. However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface.

External validation of a model using health administrative data to predict acetabular fracture probability: Brief report.

Analyses using population-based health administrative data can return erroneous results if case identification is inaccurate ("misclassification bias"). An acetabular fracture (AF) prediction model using administrative data decreased misclassification bias compared to identifying AFs using diagnostic codes. This study measured the accuracy of this AF prediction model in another hospital. We calculated AF probability in all hospitalizations in the validation hospital between 2015 and 2020. A random sample of 1000 patients stratified by expected AF probability was selected. Patient imaging studies were reviewed to determine true AF status. The validation population included 1000 people. The AF prediction model was very discriminative (c-statistic 0.90, 95% CI: 0.87-0.92) and very well calibrated (integrated calibration index 0.056, 95% CI: 0.039-0.074). AF probability can be accurately determined using routinely collected health administrative data. This observation supports using the AF prediction model to minimize misclassification bias when studying AF using health administrative data.

Mid to long-term survivorship of hip arthroplasty in patients 40 years and younger.

BACKGROUND: Etiology of hip osteoarthritis (OA) and survival of hip arthroplasty in the young (below 40-years-old) remains poorly described. Furthermore, joint survivorship mid to long-term and PROMs according to the etiology are unclear. The study aims were to 1) identify the indications for arthroplasty in the below 40-years-old cohort; 2) define hip arthroplasty outcomes in the young and 3) test whether patients with sequelae of pediatrics hip disease have inferior outcome compared to other patients. HYPOTHESIS: Our hypothesis was that hip arthroplasty is a viable option for managing hip disease in patients under 40, with excellent survival rates and outcomes. MATERIAL AND METHODS: This is an IRB approved, retrospective, consecutive, multi-surgeon, cohort study from a single academic center. Indication for hip arthroplasty of 346 patients (410 hips) below 40-years-old were studied; 239 underwent THA (58%) and 171 hip resurfacing (42%). Patient, surgical and implant factors were tested for association with implant survivorship and functional outcome for hip arthroplasty performed with a follow-up of more than two years. Pediatric hip sequelae patients were compared for survival and PROMs with the rest of the cohort. RESULTS: The most common etiology of OA was FAI (47%), followed by pediatric hip sequelae (18%). The 10-year survivorship was 97.2% ± 1.2, mean OHS was 45.1 ± 6.3 and mean HHS was 93.4 ± 12.6. The pediatric hip sequelae subgroup demonstrated no differences in 10-year survivorship and better PROMs compared to rest (OHS: 46.6 ± 3.8; HHS: 96.0 ± 8.5). DISCUSSION: The most common aetiologies amongst the young with hip OA is FAI and pediatric hip sequelae. Hip arthroplasty in the young presents excellent 10-year survivorship and PROMs. Excellent survival and PROMs in the young with pediatric hip sequelae provide important information for decision-making in this challenging population. LEVEL OF EVIDENCE: III; retrospective cohort study.

The Relationship of Cup Inclination and Anteversion in the Coronal Plane with Ante-Inclination in the Sagittal Plane: Exposing the Fallacy of Cup Safe Zones.

Background: This study aimed to establish an equation for calculating cup ante-inclination (AI) from radiographic cup inclination and anteversion, to validate this equation in a total hip arthroplasty (THA) cohort, and to test whether achieving previously described radiographic cup inclination and anteversion targets would also satisfy sagittal cup AI targets. Methods: A mathematical equation linking cup AI, radiographic inclination (RI), and anteversion (RA) was determined: tan(AI) = tan(RA)/cos(RI). Supine and standing anteroposterior and lateral radiographs of 440 consecutive THAs were assessed to measure cup RI and RA and spinopelvic parameters, including cup AI, using a validated software tool. Whether orientation within previously defined RI and RA targets was associated with achieving the AI target and satisfying the sagittal component orientation (combined sagittal index, 205° to 245°) was tested. Results: The cups in the THA cohort had a measured mean inclination (and standard deviation) of 43° ± 7°, anteversion of 26° ± 9°, and AI of 34° ± 10°. The calculated cup AI was 34° ± 12°. A strong correlation existed between measured and calculated AI (r = 0.75; p < 0.001), with a mean error of 0° ± 8°. The inclination and anteversion targets were both satisfied in 194 (44.1%) to 330 (75.0%) of the cases, depending on the safe zone targets that were used, and 311 cases (70.7%) satisfied the AI target. Only 125 (28.4%) to 233 (53.0%) of the cases satisfied the AI target as well as the inclination and anteversion targets. Satisfying inclination and anteversion targets was not associated with increased chances of satisfying the AI target. Conclusions: Achieving optimal cup inclination and anteversion does not ensure optimal orientation in the sagittal plane. The equation and nomograms provided can be used to determine and visualize how the 2 planes used for evaluating the cup orientation and the pertinent angles relate, potentially aiding in preoperative planning.

Open Reduction Internal Fixation Versus Distal Femoral Replacement (DFR) for Treatment of OTA/AO 33C Fractures in the Elderly: A Review of Functional Outcomes and Cost Analysis.

OBJECTIVES: To determine the economic cost associated with the treatment of OTA/AO 33C fractures in patients older than 65 years of age using open reduction internal fixation (ORIF) or DFR and to assess the perioperative outcomes of elderly patients treated surgically following OTA/AO 33C fractures. DESIGN: Retrospective cohort over a 10-year period. SETTING: A single level-1 trauma center. PARTICIPANTS AND INTERVENTION: Thirty-nine patients 65 or older with OTA/AO 33C fractures who underwent treatment with ORIF (n = 27) or DFR (n = 12) were included. MAIN OUTCOME MEASUREMENTS: Direct cost associated with surgical treatment along with LOS, functional outcomes, patient-reported outcomes, and all-cause reoperation. RESULTS: Index procedure costs were as follows: DFR: $ 61,259 vs. ORIF: $44,490 (P = 0.056). Five (20%) ORIF patients required revision versus one (8%) in the DFR group. Total cost when including reoperation resulted in DFR being $14,805 more costly, which was not significant. Hospital LOS was similar between groups; however, convalescent LOS was longer in ORIF patients (43.2 vs. 23.1 days, P = 0.02). CONCLUSION: This study demonstrates that there is no significant difference in overall cost between ORIF and DFR when all costs are considered. A larger portion of DFR patients were able to mobilize postoperatively, with subacute length of stay being longer in ORIF patients. A multicenter trial is warranted to determine optimal treatment for this complex problem. LEVEL OF EVIDENCE: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Accuracy of digital templating in uncemented primary total hip arthroplasty: which factors are associated with accuracy of preoperative planning?

BACKGROUND: Preoperative planning is a fundamental step for successful total hip arthroplasty (THA). Studies have highlighted the accuracy of preoperative digital templating for estimating acetabular cup and stem size. Stem design such as single-wedge metadiaphyseal (Type 1 stem) versus mid-short stem (microplasty) and surgical approach (anterior, direct lateral or posterior) have not been well investigated as predictors of THA templating accuracy. METHODS: 204 patients (220 hips) who had undergone elective THA between November 2016 and December 2019 and presented a saved preoperative template were retrospectively reviewed. Templates from 5 different surgeons were involved in the analysis. 3 different approaches were used: direct lateral (DL), posterior (PA), direct anterior (DAA). 2 different stem designs were used: single-wedge metadiaphyseal and single-wedge mid-short (Biomet Taperloc Microplasty), while the acetabular component remained the same. Bivariate and multivariate regression analyses were performed to determine predictors of accuracy. RESULTS: Femoral component size templating accuracy was significantly improved when using the single-wedge mid-short stem (Taperloc Microplasty) design when performing bivariate analysis. Although accuracy of cup sizing was not affected by approach, precision was significantly better in the PA group (p < 0.05). Accuracy of templating was found to be independent of BMI and gender but dependent on presence of calibration marker and stem design (p < 0.05). CONCLUSIONS: When striving for improved templating accuracy, acetabular and femoral component accuracy were best achieved using a calibration marker and a metaphyseal short femoral stem design.

The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors.

Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100 nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity.

Outcome After Open Reduction Internal Fixation of Acetabular Fractures in the Elderly.

OBJECTIVES: (1) Assess outcomes of acetabular open reduction and internal fixation (ORIF) in the elderly, (2) investigate factors influencing outcome, and (3) compare outcomes after low-energy and high-energy mechanisms of injury. DESIGN: Retrospective case series. SETTING: Level 1 trauma center. PATIENTS: Seventy-eight patients older than 60 years (age: 70.1 ± 7.4; 73.1% males). INTERVENTION: ORIF for acetabular fractures. MAIN OUTCOME MEASUREMENTS: Complications, reoperation rates, Oxford Hip Score (OHS), and joint preservation and development of symptomatic osteoarthritis. Cases with osteoarthritis, OHS < 34, and those who required subsequent total hip arthroplasty were considered as poor outcome. RESULTS: At a mean follow-up of 4.3 ± 3.7 years, 11 cases post-ORIF required a total hip arthroplasty. The 7-year joint survival post-ORIF was 80.7 ± 5.7%. Considering poor outcome as failure, the 7-year joint survival was 67.0 ± 8.9%. The grade of reduction was the most significant factor associated with outcome post-ORIF. Female sex (P = 0.03), pre-existing osteoporosis (P = 0.03), low-energy trauma (P = 0.04), and Matta grade (P = 0.002) were associated with poor outcome. Patients with associated both-column fractures were more likely to have nonanatomic reduction (P = 0.008). After low-energy trauma, joint survivorship was 36.6 ± 13.5% at 7 years compared with 75.4 ± 7.4% in the high-energy group when considering poor outcome as an end point (log rank P = 0.006). The cohort's mean OHS was 37.9 ± 9.3 (17-48). CONCLUSIONS: We recommend ORIF whenever an anatomic reduction is feasible. However, achievement and maintenance of anatomic reduction are a challenge in the elderly, specifically in those with low-energy fractures involving both columns, prompting consideration for alternative management strategies. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The role of multifunctional kinetics during early-stage silicon hydride pyrolysis: reactivity of Si2H2 isomers with SiH4 and Si2H6.

Kinetic parameters for the dominant pathways during the addition of the four Si(2)H(2) isomers, i.e., trans-HSiSiH, SiSiH(2), Si(H)SiH, and Si(H(2))Si, to monosilane, SiH(4), and disilane, Si(2)H(6), have been calculated using G3//B3LYP, statistical thermodynamics, conventional and variational transition state theory, and internal rotation corrections. The direct addition products of the multifunctional Si(2)H(2) isomers were monofunctional substituted silylenes, hydrogen-bridged species, and silenes. During addition to monosilane and disilane, the SiSiH(2) isomer was found to be most reactive over the temperature range of 800 to 1200 K. Revised parameters for the Evans-Polanyi correlation and a representative pre-exponential factor for multifunctional silicon hydride addition and elimination reaction families under pyrolysis conditions were regressed from the reactions in this study. This revised kinetic correlation was found to capture the activation energies and rate coefficients better than the current literature methods.