Enhancing postural balance assessment through neural network-based lower-limb muscle strength evaluation with reduced markers.

Aiming to simplify the data acquisition process for balance diagnosis and focused on muscle, a direct factor affecting balance, to assess and judge postural stability. Utilizing a publicly available kinematic dataset, the research retained 3D coordinates and mechanical data for 8 markers on the lower limbs. By integrating this data with the musculoskeletal model in OpenSim, inverse kinematic calculations were performed to derive muscle forces. These forces, alongside the coordinates, were split into an 8:2 training and test set ratio. A neural network was then developed to predict muscle forces using normalized coordinate data from the training set as input, with corresponding muscle force data as training labels. The model's accuracy was confirmed on the test set, achieving coefficients of determination (R2) above 0.99 for 276 muscle forces. Furthermore, the Force Maximum Percentage Difference (FMPD) was introduced as a novel criterion to evaluate and visualize lower limb balance, revealing significant discrepancies between the patient and control groups. This study successfully demonstrates that the neural network model can precisely predict lower limb muscle forces using reduced markers and introduces FMPD as an effective tool for assessing limb balance, providing a robust framework for future diagnostic and rehabilitative applications.

Clinical Nomogram Model for Pre-Operative Prediction of Microvascular Invasion of Hepatocellular Carcinoma before Hepatectomy.

Background and Objectives: Microvascular invasion (MVI) significantly impacts recurrence and survival rates after liver resection in hepatocellular carcinoma (HCC). Pre-operative prediction of MVI is crucial in determining the treatment strategy. This study aims to develop a nomogram model to predict the probability of MVI based on clinical features in HCC patients. Materials and Methods: A total of 489 patients with a pathological diagnosis of HCC were enrolled from our hospital. Those registered from 2012-2015 formed the derivation cohort, and those from 2016-2019 formed the validation cohort for pre-operative prediction of MVI. A nomogram model for prediction was created using a regression model, with risk factors derived from clinical and tumor-related features before surgery. Results: Using the nomogram model to predict the odds ratio of MVI before hepatectomy, the AFP, platelet count, GOT/GPT ratio, albumin-alkaline phosphatase ratio, ALBI score, and GNRI were identified as significant variables for predicting MVI. The Youden index scores for each risk variable were 0.287, 0.276, 0.196, 0.185, 0.115, and 0.112, respectively, for the AFP, platelet count, GOT/GPT ratio, AAR, ALBI, and GNRI. The maximum value of the total nomogram scores was 220. An increase in the number of nomogram points indicated a higher probability of MVI occurrence. The accuracy rates ranged from 55.9% to 64.4%, and precision rates ranged from 54.3% to 68.2%. Overall survival rates were 97.6%, 83.4%, and 73.9% for MVI(-) and 80.0%, 71.8%, and 41.2% for MVI(+) (p < 0.001). The prognostic effects of MVI(+) on tumor-free survival and overall survival were poor in both the derivation and validation cohorts. Conclusions: Our nomogram model, which integrates clinical factors, showed reliable calibration for predicting MVI and provides a useful tool enabling surgeons to estimate the probability of MVI before resection. Consequently, surgical strategies and post-operative care programs can be adapted to improve the prognosis of HCC patients where possible.

Small Molecule NS11021 Promotes BK Channel Activation by Increasing Inner Pore Hydration.

The Ca2+ and voltage-gated big potassium (BK) channels are implicated in various diseases, including heart disease, asthma, epilepsy, and cancer, but remain an elusive drug target. A class of negatively charged activators (NCAs) have been demonstrated to promote the activation of several potassium channels including BK channels by binding to the hydrophobic inner pore, yet the underlying molecular mechanism of action remains poorly understood. In this work, we analyze the binding mode and potential activation mechanism of a specific NCA named NS11021 using atomistic simulations. The results show that NS11021 binding to the pore in deactivated BK channels is nonspecific and dynamic. The binding free energy of -8.3 ± 0.7 kcal/mol (KD = 0.3-3.1 µM) calculated using umbrella sampling agrees quantitatively with the experimental EC50 range of 0.4-2.1 µM. The bound NS11021 remains dynamic and is distal from the filter to significantly impact its conformation. Instead, NS11021 binding significantly enhances the pore hydration due to the charged tetrazol-phenyl group, thereby promoting the opening of the hydrophobic gate. We further show that the free energy barrier to K+ permeation is reduced by ∼3 kcal/mol regardless of the binding pose, which could explain the ∼62-fold increase in the intrinsic opening of BK channels measured experimentally. Taken together, these results support the idea that the molecular mechanism of NS11021 derives from increasing the hydration level of the conformationally closed pore, which does not depend on specific binding and likely explains the ability of NCAs to activate multiple K+ channels.

Polymers for Disrupting Protein-Protein Interactions: Where Are We and Where Should We Be?

Protein-protein interactions (PPIs) are central to the cellular signaling and regulatory networks that underlie many physiological and pathophysiological processes. It is challenging to target PPIs using traditional small molecule or peptide-based approaches due to the frequent lack of well-defined binding pockets at the large and flat PPI interfaces. Synthetic polymers offer an opportunity to circumvent these challenges by providing unparalleled flexibility in tuning their physiochemical properties to achieve the desired binding properties. In this review, we summarize the current state of the field pertaining to polymer-protein interactions in solution, highlighting various polyelectrolyte systems, their tunable parameters, and their characterization. We provide an outlook on how these architectures can be improved by incorporating sequence control, foldability, and machine learning to mimic proteins at every structural level. Advances in these directions will enable the design of more specific protein-binding polymers and provide an effective strategy for targeting dynamic proteins, such as intrinsically disordered proteins.

Predictive model for contralateral inguinal hernia repair within three years of primary repair: a nationwide population-based cohort study.

BACKGROUND: Limited reports have discussed the risk factors for contralateral inguinal hernia (CIH) repair. We generated a risk factor scoring system to predict CIH within 3 years after unilateral inguinal hernia repair. METHODS: We extracted the admission data of patients aged ≥ 18 years who underwent primary unilateral inguinal hernia repair without any other operation from the National Health Insurance Research Database. Patients were randomly divided into 80% and 20% validation cohorts. Multivariate analysis with a logistic regression model was used to generate the scoring system, which was used in the validation group. RESULTS: Overall, 170,492 adult men were included, with a median follow-up of 87 months. The scoring system ranged from 0-5 points, composited with age (< 45 years, 0 points; 45-65 years, 2 points; 65-80 years, 3 points; > 80 years, 2 points) and two comorbidities (cirrhosis and prostate disease: 1 point each). The areas under receiver operating characteristic (ROC) curves were 0.606 and 0.551 for the derivation and validation groups, respectively. The rates and adjusted odds ratios (OR) of CIH repair in the derivation group were 3.0% at 0-2 points, 5.5% (1.854, p < 0.001) at 3, 6.7% (2.279, p < 0.001) at 4, and 6.9% (2.348, p < 0.001) at 5, with similar results in the validation group [2.3% at 0-2 points, 3.8% (1.668, p < 0.001) at 3, 5.4% (2.386, p < 0.001) at 4, and 6.8% (3.033, p < 0.001) at 5]. CONCLUSIONS: The CIH scoring system effectively predicted CIH repair within three years of primary unilateral inguinal hernia repair. Surgeons could perform laparoscopic surgery with CIH scores > 2 points which enables easier contralateral exploration and repair during the same surgery, without additional incisions, to minimize the need for future surgeries. However, further prospective validation of this scoring system is required.

Three-Month Excessive Body Weight Loss < 37.7% as a Predictor of Mid-term Suboptimal Outcomes Postlaparoscopic Sleeve Gastrectomy: Risk Factors and the Impact of Neutrophil-to-Lymphocyte Ratio on Adipocyte Function.

INTRODUCTION: This study aimed to evaluate the impact of achieving < 37.7% excess body-weight loss (EBWL) within 3 months of postlaparoscopic sleeve gastrectomy (LSG) on clinical outcomes and its correlation with adipocyte function. METHODS: Patients (n = 176) who underwent LSG between January 2019 and January 2023 were included. Weight loss and status of health markers were monitored postoperatively. The cohort was stratified based on EBWL < 37.7% at 3 months or not. Variables including neutrophil-to-lymphocyte ratio (NLR), insulin resistance, and comorbidities were analyzed. Omental visceral and subcutaneous adipose tissue samples were used to analyze the differences in adipocyte function by western blot. RESULTS: Patients with EBWL < 37.7% at 3 months post-LSG (suboptimal group) comprised less likelihood of achieving ≥ 50% EBWL than those who achieved ≥ 37.7% EBWL (optimal group) at 6 months (42.55% vs. 95.52% in optimal group, p < 0.001), 12 months (85.11% vs. 99.25% in optimal group, p < 0.001) and 24 months (77.14% vs. 94.74% in optimal group, p = 0.009) post-LSG. High BMI (OR = 1.222, 95% CI 1.138-1.312, p < 0.001), NLR ≥ 2.36 (OR = 2.915, 95% CI 1.257-6.670, p = 0.013), and female sex (OR = 3.243, 95% CI 1.306-8.051, p = 0.011) significantly predicted EBWL < 37.7% at 3 months post-LSG. Patients with NLR ≥ 2.36 had significantly lower adipose triglyceride lipase in omental fat (p = 0.025). CONCLUSION: EBWL < 37.7% at 3 months post-LSG is a strong predictor of subsequent suboptimal weight loss. High BMI, NLR ≥ 2.36, and female sex are risk factors in predicting EBWL < 37.7% at 3 months post-LSG. These findings may offer a reference to apply adjuvant weight loss medications to patients who are predisposed to suboptimal outcomes.

Structural basis for hyperpolarization-dependent opening of human HCN1 channel.

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.

Impact of Recurrent Weight Gain Thresholds on Comorbid Conditions Progression Following Laparoscopic Sleeve Gastrectomy.

INTRODUCTION: Defining recurrent weight gain after metabolic bariatric surgery poses a significant challenge. Our study aimed to standardize recurrent weight gain measurements in patients undergoing laparoscopic sleeve gastrectomy (LSG) and ascertain its association with comorbidity progression. METHODS: We conducted a retrospective data analysis on 122 patients who underwent LSG, tracking their progress over 2-7 years. Data on weight, blood pressure measurements, and laboratory tests were collected, focusing on the postoperative period to identify nadir weight, total weight loss, and recurrent weight gain. RESULTS: Significant weight loss and comorbidity remission were noted, with diabetes, hypertension, and dyslipidemia showing substantial remission rates of 85.71%, 68.24%, and 85.37%, respectively. The median recurrent weight gain was 6.30 kg within 12 months of the nadir. Progression proportion of diabetes, hypertension, and dyslipidemia were 8.20%, 44.26%, and 40.98%, respectively. Hypertension progression was strongly associated with a recurrent weight gain ≥ 10 kg and ≥ 20% of maximum weight loss. Dyslipidemia progression was significantly correlated with recurrent weight gain ≥ 10 kg and ≥ 20% of maximum weight loss. Diabetes progression was significantly correlated with recurrent weight gain ≥ 10% of pre-surgery body weight and ≥ 25% of maximum weight loss. A ≥ 10% weight gain of maximum weight loss did not significantly impact the progression of these conditions. CONCLUSION: Recurrent weight gain ≥ 20% of maximum weight loss can be treated as a specific threshold indicating comorbidity progression post-LSG. Standardizing the measurement of recurrent weight gain can help healthcare providers to implement targeted management strategies to optimize long-term health outcomes.

Tuning single-molecule ClyA nanopore tweezers for real-time tracking of the conformational dynamics of West Nile viral NS2B/NS3 protease.

The flaviviral NS2B/NS3 protease is a conserved enzyme required for flavivirus replication. Its highly dynamic conformation poses major challenges but also offers opportunities for antiviral inhibition. Here, we established a nanopore tweezers-based platform to monitor NS2B/NS3 conformational dynamics in real-time. Molecular simulations coupled with electrophysiology revealed that the protease could be captured in the middle of the ClyA nanopore lumen, stabilized mainly by dynamic electrostatic interactions. We designed a new Salmonella typhi ClyA nanopore with enhanced nanopore/protease interaction that can resolve the open and closed states at the single-molecule level for the first time. We demonstrated that the tailored ClyA could track the conformational transitions of the West Nile NS2B/NS3 protease and unravel the conformational energy landscape of various protease constructs through population and kinetic analysis. The new ClyA-protease platform paves a way to high-throughput screening strategies for discovering new allosteric inhibitors that target the NS2B and NS3 interface.

A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation.

Ca2+ signaling plays a key role in physiological processes such as memory formation and cardiac function. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is the primary kinase that responds to Ca2+ inputs in these cells. There are four CaMKII paralogs in mammals which are alternatively spliced in the variable linker region to create upwards of 70 different variants. In this study, we systematically studied different linker regions and determined that the position of charged residues within the linker region modulates the Ca2+/CaM sensitivity of the holoenzyme. We present an X-ray crystal structure of full-length CaMKIIδ that shows a domain-swapped conformation of the subunits within the dodecameric holoenzyme. In this structure, the kinase domain of one subunit is docked onto the hub domain of a different subunit, providing an additional interface within the holoenzyme. Mutations at the equatorial and lateral interfaces revealed that the kinase-hub interaction dissociates as the hub-hub interfaces are disturbed, which led alterations in the stoichiometry of CaMKII holoenzyme and Ca2+/CaM sensitivity. Molecular dynamics simulations of linker-containing domain-swapped and non-domain-swapped CaMKIIs reveal that the domain-swapped configuration facilitates an interaction between the calmodulin binding domain and the variable linker region, such that dynamic electrostatic forces between charges on these segments can modulate the equilibrium between the compact and extended conformational states of the holoenzyme. Small angle X-ray scattering data confirms that a negatively charged linker CaMKII holoenzyme adopts a more compact conformation compared to a positively charged linker. These data support a model where patches of charged linker residues interact with the calmodulin binding domain to allosterically regulate sensitivity to Ca2+/CaM. Our findings provide a new framework for understanding CaMKII structure and allosteric regulation by the variable linker region in Ca2+-sensitive cells.

Assessing risk of recurrent small bowel obstruction after non-operative management in patients with history of intra-abdominal surgery: a population-based comprehensive analysis in Taiwan.

BACKGROUND: Despite a significant 30% ten-year readmission rate for SBO patients, investigations into recurrent risk factors after non-operative management are scarce. The study aims to generate a risk factor scoring system, the 'Small Bowel Obstruction Recurrence Score' (SBORS), predicting 6-month recurrence of small bowel obstruction (SBO) after successful non-surgical management in patients who have history of intra-abdominal surgery. METHODS: We analyzed data from patients aged ≥ 18 with a history of intra-abdominal surgery and diagnosed with SBO (ICD-9 code: 560, 568) and were successful treated non-surgically between 2004 and 2008. Participants were divided into model-derivation (80%) and validation (20%) group. RESULTS: We analyzed 23,901 patients and developed the SBORS based on factors including the length of hospital stay > 4 days, previous operations > once, hemiplegia, extra-abdominal and intra-abdominal malignancy, esophagogastric surgery and intestino-colonic surgery. Scores > 2 indicated higher rates and risks of recurrence within 6 months (12.96% vs. 7.27%, OR 1.898, p < 0.001 in model-derivation group, 12.60% vs. 7.05%, OR 1.901, p < 0.001 in validation group) with a significantly increased risk of mortality and operative events for recurrent episodes. The SBORS model demonstrated good calibration and acceptable discrimination, with an area under curve values of 0.607 and 0.599 for the score generation and validation group, respectively. CONCLUSIONS: We established the effective 'SBORS' to predict 6-month SBO recurrence risk in patients who have history of intra-abdominal surgery and have been successfully managed non-surgically for the initial obstruction event. Those with scores > 2 face higher recurrence rates and operative risks after successful non-surgical management.

Backbone interactions and secondary structures in phase separation of disordered proteins.

Intrinsically disordered proteins (IDPs) are one of the major drivers behind the formation and characteristics of biomolecular condensates. Due to their inherent flexibility, the backbones of IDPs are significantly exposed, rendering them highly influential and susceptible to biomolecular phase separation. In densely packed condensates, exposed backbones have a heightened capacity to interact with neighboring protein chains, which might lead to strong coupling between the secondary structures and phase separation and further modulate the subsequent transitions of the condensates, such as aging and fibrillization. In this mini-review, we provide an overview of backbone-mediated interactions and secondary structures within biomolecular condensates to underscore the importance of protein backbones in phase separation. We further focus on recent advances in experimental techniques and molecular dynamics simulation methods for probing and exploring the roles of backbone interactions and secondary structures in biomolecular phase separation involving IDPs.

Toward Accurate Simulation of Coupling between Protein Secondary Structure and Phase Separation.

Intrinsically disordered proteins (IDPs) frequently mediate phase separation that underlies the formation of a biomolecular condensate. Together with theory and experiment, efficient coarse-grained (CG) simulations have been instrumental in understanding the sequence-specific phase separation of IDPs. However, the widely used Cα-only models are limited in capturing the peptide nature of IDPs, particularly backbone-mediated interactions and effects of secondary structures, in phase separation. Here, we describe a hybrid resolution (HyRes) protein model toward a more accurate description of the backbone and transient secondary structures in phase separation. With an atomistic backbone and coarse-grained side chains, HyRes can semiquantitatively capture the residue helical propensity and overall chain dimension of monomeric IDPs. Using GY-23 as a model system, we show that HyRes is efficient enough for the direct simulation of spontaneous phase separation and, at the same time, appears accurate enough to resolve the effects of single His to Lys mutations. HyRes simulations also successfully predict increased ß-structure formation in the condensate, consistent with available experimental CD data. We further utilize HyRes to study the phase separation of TPD-43, where several disease-related mutants in the conserved region (CR) have been shown to affect residual helicities and modulate the phase separation propensity as measured by the saturation concentration. The simulations successfully recapitulate the effect of these mutants on the helicity and phase separation propensity of TDP-43 CR. Analyses reveal that the balance between backbone and side chain-mediated interactions, but not helicity itself, actually determines phase separation propensity. These results support that HyRes represents an effective protein model for molecular simulation of IDP phase separation and will help to elucidate the coupling between transient secondary structures and phase separation.

Biomechanical behavior of deep anterior lamellar keratoplasty: a finite element analysis.

Deep Anterior Lamellar Keratoplasty (DALK) is a surgical procedure used to restore sight and manage corneal diseases by replacing cloudy corneal tissue with allogeneic normal corneal tissue or artificial corneal material. However, the limited availability and mechanical defects of artificial corneal materials pose challenges in DALK. To predicting postoperative mechanical behavior of Deep Anterior Lamellar Keratoplasty (DALK), a three-dimensional finite element model of the postoperative DALK cornea with suture holes was developed. The postoperative corneal displacement and von Mises (VM) stress changes were also simulated under varying depths of cut (DOC: 0.16-0.26 µm), intraocular pressure (IOP: 12, 15, 18 mmHg), and central corneal thickness (CCT: 420-620 µm). The model indicated that higher IOP and CCT were associated with improved postoperative corneal stability. The postoperative corneal displacement increased from the edge to the center, while the maximum VM stress value occurs at the corneal suture hole. Corneal displacement and VM stress decrease with increasing CCT and decreasing IOP. DOC has a slight effect on corneal displacement and VM stress, with an overall positive relationship. The model has potential application in the preoperative assessment of risk in keratoplasty.

Hydrophobic gating in bundle-crossing ion channels: a case study of TRPV4.

Transmembrane ion channels frequently regulate ion permeation by forming bundle crossing of the pore-lining helices when deactivated. The resulting physical constriction is believed to serve as the de facto gate that imposes the major free energy barrier to ion permeation. Intriguingly, many ion channels also contain highly hydrophobic inner pores enclosed by bundle crossing, which can undergo spontaneous dewetting and give rise to a "vapor barrier" to block ion flow even in the absence of physical constriction. Using atomistic simulations, we show that hydrophobic gating and bundle-crossing mechanisms co-exist and complement one and another in the human TRPV4 channel. In particular, a single hydrophilic mutation in the lower pore can increase pore hydration and reduce the ion permeation free energy barrier by about half without affecting the bundle crossing. We believe that hydrophobic gating may play a key role in other bundle-crossing ion channels with hydrophobic inner pores.

Accurate Simulation of Coupling between Protein Secondary Structure and Liquid-Liquid Phase Separation.

Intrinsically disordered proteins (IDPs) frequently mediate liquid-liquid phase separation (LLPS) that underlies the formation of membraneless organelles. Together with theory and experiment, efficient coarse-grained (CG) simulations have been instrumental in understanding sequence-specific phase separation of IDPs. However, the widely-used Cα-only models are severely limited in capturing the peptide nature of IDPs, including backbone-mediated interactions and effects of secondary structures, in LLPS. Here, we describe a hybrid resolution (HyRes) protein model for accurate description of the backbone and transient secondary structures in LLPS. With an atomistic backbone and coarse-grained side chains, HyRes accurately predicts the residue helical propensity and chain dimension of monomeric IDPs. Using GY-23 as a model system, we show that HyRes is efficient enough for direct simulation of spontaneous phase separation, and at the same time accurate enough to resolve the effects of single mutations. HyRes simulations also successfully predict increased beta-sheet formation in the condensate, consistent with available experimental data. We further utilize HyRes to study the phase separation of TPD-43, where several disease-related mutants in the conserved region (CR) have been shown to affect residual helicities and modulate LLPS propensity. The simulations successfully recapitulate the effect of these mutants on the helicity and LLPS propensity of TDP-43 CR. Analyses reveal that the balance between backbone and sidechain-mediated interactions, but not helicity itself, actually determines LLPS propensity. We believe that the HyRes model represents an important advance in the molecular simulation of LLPS and will help elucidate the coupling between IDP transient secondary structures and phase separation.

Incorporating physics to overcome data scarcity in predictive modeling of protein function: A case study of BK channels.

Machine learning has played transformative roles in numerous chemical and biophysical problems such as protein folding where large amount of data exists. Nonetheless, many important problems remain challenging for data-driven machine learning approaches due to the limitation of data scarcity. One approach to overcome data scarcity is to incorporate physical principles such as through molecular modeling and simulation. Here, we focus on the big potassium (BK) channels that play important roles in cardiovascular and neural systems. Many mutants of BK channel are associated with various neurological and cardiovascular diseases, but the molecular effects are unknown. The voltage gating properties of BK channels have been characterized for 473 site-specific mutations experimentally over the last three decades; yet, these functional data by themselves remain far too sparse to derive a predictive model of BK channel voltage gating. Using physics-based modeling, we quantify the energetic effects of all single mutations on both open and closed states of the channel. Together with dynamic properties derived from atomistic simulations, these physical descriptors allow the training of random forest models that could reproduce unseen experimentally measured shifts in gating voltage, ∆V1/2, with a RMSE ~ 32 mV and correlation coefficient of R ~ 0.7. Importantly, the model appears capable of uncovering nontrivial physical principles underlying the gating of the channel, including a central role of hydrophobic gating. The model was further evaluated using four novel mutations of L235 and V236 on the S5 helix, mutations of which are predicted to have opposing effects on V1/2 and suggest a key role of S5 in mediating voltage sensor-pore coupling. The measured ∆V1/2 agree quantitatively with prediction for all four mutations, with a high correlation of R = 0.92 and RMSE = 18 mV. Therefore, the model can capture nontrivial voltage gating properties in regions where few mutations are known. The success of predictive modeling of BK voltage gating demonstrates the potential of combining physics and statistical learning for overcoming data scarcity in nontrivial protein function prediction.

Efficacy and safety of an extended-release sebacoyl dinalbuphine ester for laparoscopic cholecystectomy: A randomized controlled trial.

BACKGROUND: A long-acting κreceptor agonist parenteral analgesic may theoretically improve acute pain and reduce incidence of chronic postsurgical pain (CPSP) after laparoscopic cholecystectomy with minimal drug-related side effects of the traditional µreceptor opioids. METHODS: Eighty adult patients undergoing elective laparoscopic cholecystectomy were randomly assigned to receive single intramuscular injection of an extended-release sebacoyl dinalbuphine ester (SDE, Naldebain 150 mg; n = 40) or placebo (n = 40) after anesthesia induction. Standard multimodal analgesia (MMA) was administered for postoperative pain control. The primary endpoint was pain intensity within 7 days after surgery. The secondary endpoints were incidence CPSP at 3 months and adverse reactions up to 7 days after surgery. RESULTS: The highest visual analogue scale (VAS) and area under the curve of VAS 0 to 48 hours after operation were not different between the two groups and a similar proportion of patients requested rescue parenteral analgesics. Average pain intensities were also not different at 72 hours and 7 days after surgery. Incidence of CPSP was 22.5% and 13.1% in patients who received placebo and SDE treatment, respectively (P = .379). Significantly higher incidence of drug-related adverse events, including dizziness, nausea and injection site reactions, were recorded in the SDE group. CONCLUSION: A single dose of extended-release analgesic SDE given intraoperatively did not provide sufficient add-on effect for acute and chronic pain management after laparoscopic cholecystectomies in patients who received standard postoperative MMA. Intramuscular injection of 150 mg SDE in patients with average body mass causes adverse events that could have been overlooked. More clinical studies are warranted to determine the target populations who may benefit from SDE injections for improvement of acute and chronic postsurgical pain management.

Incorporating physics to overcome data scarcity in predictive modeling of protein function: a case study of BK channels.

Machine learning has played transformative roles in numerous chemical and biophysical problems such as protein folding where large amount of data exists. Nonetheless, many important problems remain challenging for data-driven machine learning approaches due to the limitation of data scarcity. One approach to overcome data scarcity is to incorporate physical principles such as through molecular modeling and simulation. Here, we focus on the big potassium (BK) channels that play important roles in cardiovascular and neural systems. Many mutants of BK channel are associated with various neurological and cardiovascular diseases, but the molecular effects are unknown. The voltage gating properties of BK channels have been characterized for 473 site-specific mutations experimentally over the last three decades; yet, these functional data by themselves remain far too sparse to derive a predictive model of BK channel voltage gating. Using physics-based modeling, we quantify the energetic effects of all single mutations on both open and closed states of the channel. Together with dynamic properties derived from atomistic simulations, these physical descriptors allow the training of random forest models that could reproduce unseen experimentally measured shifts in gating voltage, ΔV 1/2 , with a RMSE ∼ 32 mV and correlation coefficient of R ∼ 0.7. Importantly, the model appears capable of uncovering nontrivial physical principles underlying the gating of the channel, including a central role of hydrophobic gating. The model was further evaluated using four novel mutations of L235 and V236 on the S5 helix, mutations of which are predicted to have opposing effects on V 1/2 and suggest a key role of S5 in mediating voltage sensor-pore coupling. The measured ΔV 1/2 agree quantitatively with prediction for all four mutations, with a high correlation of R = 0.92 and RMSE = 18 mV. Therefore, the model can capture nontrivial voltage gating properties in regions where few mutations are known. The success of predictive modeling of BK voltage gating demonstrates the potential of combining physics and statistical learning for overcoming data scarcity in nontrivial protein function prediction. Author Summary: Deep machine learning has brought many exciting breakthroughs in chemistry, physics and biology. These models require large amount of training data and struggle when the data is scarce. The latter is true for predictive modeling of the function of complex proteins such as ion channels, where only hundreds of mutational data may be available. Using the big potassium (BK) channel as a biologically important model system, we demonstrate that a reliable predictive model of its voltage gating property could be derived from only 473 mutational data by incorporating physics-derived features, which include dynamic properties from molecular dynamics simulations and energetic quantities from Rosetta mutation calculations. We show that the final random forest model captures key trends and hotspots in mutational effects of BK voltage gating, such as the important role of pore hydrophobicity. A particularly curious prediction is that mutations of two adjacent residues on the S5 helix would always have opposite effects on the gating voltage, which was confirmed by experimental characterization of four novel mutations. The current work demonstrates the importance and effectiveness of incorporating physics in predictive modeling of protein function with scarce data.

Predicting in-hospital mortality risk for perforated peptic ulcer surgery: the PPUMS scoring system and the benefit of laparoscopic surgery: a population-based study.

BACKGROUND: The major treatment for perforated peptic ulcers (PPU) is surgery. It remains unclear which patient may not get benefit from surgery due to comorbidity. This study aimed to generate a scoring system by predicting mortality for patients with PPU who received non-operative management (NOM) and surgical treatment. METHOD: We extracted the admission data of adult (≥ 18 years) patients with PPU disease from the NHIRD database. We randomly divided patients into 80% model derivation and 20% validation cohorts. Multivariate analysis with a logistic regression model was applied to generate the scoring system, PPUMS. We then apply the scoring system to the validation group. RESULT: The PPUMS score ranged from 0 to 8 points, composite with age (< 45: 0 points, 45-65: 1 point, 65-80: 2 points, > 80: 3 points), and five comorbidities (congestive heart failure, severe liver disease, renal disease, history of malignancy, and obesity: 1 point each). The areas under ROC curve were 0.785 and 0.787 in the derivation and validation groups. The in-hospital mortality rates in the derivation group were 0.6% (0 points), 3.4% (1 point), 9.0% (2 points), 19.0% (3 points), 30.2% (4 points), and 45.9% when PPUMS > 4 point. Patients with PPUMS > 4 had a similar in-hospital mortality risk between the surgery group [laparotomy: odds ratio (OR) = 0.729, p = 0.320, laparoscopy: OR = 0.772, p = 0.697] and the non-surgery group. We identified similar results in the validation group. CONCLUSION: PPUMS scoring system effectively predicts in-hospital mortality for perforated peptic ulcer patients. It factors in age and specific comorbidities is highly predictive and well-calibrated with a reliable AUC of 0.785-0.787. Surgery, no matter laparotomy or laparoscope, significantly reduced mortality for scores < = 4. However, patients with a score > 4 did not show this difference, calling for tailored approaches to treatment based on risk assessment. Further prospective validation is suggested.