Explainable machine learning using perioperative serial laboratory results to predict postoperative mortality in patients with peritonitis-induced sepsis.

Purpose: Sepsis is one of the most common causes of death after surgery. Several conventional scoring systems have been developed to predict the outcome of sepsis; however, their predictive power is insufficient. The present study applies explainable machine-learning algorithms to improve the accuracy of predicting postoperative mortality in patients with sepsis caused by peritonitis. Methods: We performed a retrospective analysis of data from demographic, clinical, and laboratory analyses, including the delta neutrophil index (DNI), WBC and neutrophil counts, and CRP level. Laboratory data were measured before surgery, 12-36 hours after surgery, and 60-84 hours after surgery. The primary study output was the probability of mortality. The areas under the receiver operating characteristic curves (AUCs) of several machine-learning algorithms using the Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS) 3 models were compared. 'SHapley Additive exPlanations' values were used to indicate the direction of the relationship between a variable and mortality. Results: The CatBoost model yielded the highest AUC (0.933) for mortality compared to SAPS3 and SOFA (0.860 and 0.867, respectively). Increased DNI on day 3, septic shock, use of norepinephrine therapy, and increased international normalized ratio on day 3 had the greatest impact on the model's prediction of mortality. Conclusion: Machine-learning algorithms increase the accuracy of predicting postoperative mortality in patients with sepsis caused by peritonitis.

Long-term Clinical Outcomes After TightRope Versus Hook Plate Fixation for Acute Acromioclavicular Joint Dislocation.

Background: There is limited information regarding the long-term efficacy of techniques for surgical fixation after acromioclavicular (AC) joint dislocation. Purpose: To evaluate the efficacy of hook plate (HP) and TightRope (TR) fixation for acute AC joint dislocations by comparing the long-term clinical and radiological patient outcomes. Study Design: Cohort study, Level of evidence, 3. Methods: This study retrospectively analyzed data from 61 patients with acute AC joint dislocation between July 2011 and November 2015. The patients were grouped according to surgical procedure: HP (n = 36) and TR (n = 25). Clinical outcomes at final follow-up were evaluated using the visual analog scale (VAS) for pain; the American Shoulder and Elbow Surgery score; the Korean Shoulder Score; and the University of California, Los Angeles (UCLA) shoulder score. Side-to-side coracoclavicular (CC) distance on radiographs, postoperative complications, and the rate of subacromial erosion in the HP group were also assessed between procedures. Results: The mean follow-up period was 7.0 ± 1.0 years, and there were no significant differences in pain or outcome scores between the HP and TR groups (all P > .05). Forward flexion was better in the TR group (172.6° ± 5.6°) versus the HP group (166.0° ± 10.8°; P = .002). The percentages of patients with a difference in the side-to-side CC distance of <5 mm were 83.3% and 72.0% in the HP and TR groups, respectively (P = .288). Complications were found in 2 patients in the HP group and 1 in the TR group (P ≥ .999). Subacromial erosion was observed in 41.7% of patients after HP fixation, with no difference in VAS pain scores at the final follow-up in patients with versus without subacromial erosion (P = .719). Conclusion: When comparing HP with TR fixation for the treatment of acute AC joint dislocations, there were no significant differences in functional outcome scores, final CC distance, or complications. Slightly better forward flexion was seen after TR fixation. Subacromial erosion occurred in 40% of patients after HP fixation, but this did not affect long-term VAS pain scores. Both surgical techniques are effective treatment options for AC joint dislocation.

A Bibliometric Analysis of the Field of Computer-Assisted Orthopedic Surgery during 2002-2021.

Background: This study aimed to investigate the characteristics of research articles and research trends in computer-assisted orthopedic surgery (CAOS) by conducting bibliometric analyses. Methods: CAOS-related research articles published in international journals from 2002 to 2021 were collected using the PubMed database and analyzed using the bibliometric method. Their publication year, journal name, corresponding author's country name, and the number of citations of all collected articles were noted. Contents of the articles were analyzed to evaluate the time point and anatomical site at which the digital technique was applied. Further, the 20-year period was divided into two halves of 10 years each to analyze the research trends. Results: A total of 639 CAOS-related articles were identified. An average of 32.0 CAOS-related articles were published annually, with an average of 20.6 and 43.3 published in the first half and second half, respectively. Of all articles, 47.6% were published in the top 10 journals, and 81.2% were written in the top 10 countries. The total numbers of citations were 11.7 and 6.3 in the first and second halves, respectively, but the average annual number of citations was higher in the second half than in the first one. Articles on application of digital techniques during surgery were 62.3% and those on pre-surgery application were 36.9%. Further, articles in the knee (39.0%), spine (28.5%), and hip and pelvis (21.5%) fields accounted for 89.0% of the total publications. But the increase in publications in the said period was highest in the fields of the hand and wrist (+1,300.0%), ankle (+466.7%), and shoulder (+366.7%). Conclusions: Over the last 20 years, the publication of CAOS-related research articles in international journals has grown steadily. Although the knee, spine, hip, and pelvis fields account for most CAOS-related research, research in new fields is also increasing. This study analyzed the types of articles and trends in CAOS-related research and provided useful information for future research in the field of CAOS.

Decreasing Incidence of Gastric Cancer with Increasing Time after Helicobacter pylori Treatment: A Nationwide Population-Based Cohort Study.

Background: Treatment of Helicobacter pylori (HP) has been shown to reduce the risk of gastric cancer (GC) development. However, previous studies have focused on patients at high risk of GC. This study aimed to assess the effect of HP treatment on the incidence of GC in the general population. Materials and Methods: Medical records were obtained from the Common Data Model-converted sample Cohort of the National Health Insurance Service of Korea (NHIS-CDM). The target cohort included those who had been prescribed HP treatment and the comparator cohort included those who had not. The association between HP treatment and the risk of GC development was assessed using the Cox proportional hazard model. The incidences of GC according to the period after HP treatment in different age groups were analyzed using proportional trend tests. Results: After large-scale 1:4 propensity score matching, 2735 and 5328 individuals were included in the target and comparator cohorts, respectively. During the median follow-up of 6.5 years, the GC incidence was lower in the HP treatment cohort than in the comparator cohort, but this was statistically insignificant (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.50−1.13; p-value = 0.19). This trend was also observed among the older age (≥65 years, HR: 0.87; 95% CI: 0.44−1.68; p-value = 0.69) and male cohorts (HR: 0.82; 95% CI: 0.51−1.27; p-value = 0.38). Among 58,684 individuals who were treated for HP from the whole NHIS-CDM cohort, the incidence of GC consistently decreased over time and showed a marked decrease with increasing age (p for trend < 0.05). Conclusions: In all age groups of the general population, HP treatment could be recommended to reduce the risk of GC.

Incidence and Survival Outcomes of Colorectal Cancer in Long-Term Metformin Users with Diabetes: A Population-Based Cohort Study Using a Common Data Model.

BACKGROUND AND AIMS: Previous studies have reported that metformin use in patients with diabetes mellitus may reduce the risk of colorectal cancer (CRC) incidence and prognosis; however, the evidence is not definite. This population-based cohort study aimed to investigate whether metformin reduces the risk of CRC incidence and prognosis in patients with diabetes mellitus using a common data model of the Korean National Health Insurance Service database from 2002 to 2013. METHODS: Patients who used metformin for at least 6 months were defined as metformin users. The primary outcome was CRC incidence, and the secondary outcomes were the all-cause and CRC-specific mortality. Cox proportional hazard model was performed and large-scaled propensity score matching was used to control for potential confounding factors. RESULTS: During the follow-up period of 81,738 person-years, the incidence rates (per 1000 person-years) of CRC were 5.18 and 8.12 in metformin users and non-users, respectively (p = 0.001). In the propensity score matched cohort, the risk of CRC incidence in metformin users was significantly lower than in non-users (hazard ratio (HR), 0.58; 95% CI (confidence interval), 0.47-0.71). In the sensitivity analysis, the lag period extending to 1 year showed similar results (HR: 0.63, 95% CI: 0.51-0.79). The all-cause mortality was significantly lower in metformin users than in non-users (HR: 0.71, 95% CI: 0.64-0.78); CRC-related mortality was also lower among metformin users. However, there was no significant difference (HR: 0.55, 95% CI: 0.26-1.08). CONCLUSIONS: Metformin use was associated with a reduced risk of CRC incidence and improved overall survival.

Aspirin, metformin, and statin use on the risk of gastric cancer: A nationwide population-based cohort study in Korea with systematic review and meta-analysis.

BACKGROUND/AIMS: Although several chemopreventive drugs against gastric cancer have been proposed, their effects have not been fully evaluated. We examined the impacts of aspirin, metformin, and statin use on gastric cancer development in a population-based cohort in Korea. METHODS: We analyzed the association between potential chemopreventive drugs-aspirin, metformin, and statin-and gastric cancer through the Observational Medical Outcomes Partnership Common Data Model-based Korean nationwide cohort. Use of aspirin, metformin, and statin was defined by ≥365 days of prescriptions for each drug in the general population. To summarize the current evidence, we further performed a systematic review and meta-analysis of the impact of aspirin, metformin, and statin on gastric cancer development. RESULTS: After propensity score matching, 31,839, 6764, and 10,251 subjects were observed for medians of 4.7, 4.2, and 4.2 years for aspirin, metformin, and statin analysis, respectively. Use of aspirin or statin was associated with lower risks of gastric cancer compared to their non-use, respectively (hazard ratio [HR] [95% confidence interval [CI]]: aspirin, 0.72 [0.60-0.85], p < 0.01; statin, 0.67 [0.49-0.92], p = 0.01). However, no association was observed between metformin use and gastric cancer development (HR [95% CI]: 0.85 [0.59-1.23], p = 0.40). A subgroup of subjects with diabetes mellitus showed a lower risk of gastric cancer development with statin use. The meta-analysis showed the highest effect size of gastric cancer development for statin, followed by aspirin and metformin. CONCLUSIONS: Statin and aspirin use were associated with significantly reduced risks of gastric cancer development, while the use of metformin was not associated with the gastric cancer risk. The protective effect of statin against gastric cancer was also significant in patients with diabetes mellitus.

Effect of the stellate ganglion block on symptoms of ulcerative colitis: A case report.

RATIONALE: Chronic ulcerative colitis is an autoimmune disease in which epithelial injury continuously occurs in the colonic mucosa. While mesalazine (5-aminosalicylic acid) is used to treat ulcerative colitis, it can also cause liver failure, headaches, and abdominal pain; therefore, an alternative treatment is required. The purpose of this study was to evaluate the effectiveness of 80 stellate ganglion blocks in reducing pain and other symptoms in a patient with chronic ulcerative colitis. PATIENT CONCERNS: A 54-year-old female patient with a history of ulcerative colitis was concerned with worsening symptoms, such as abdominal discomfort and bloody-mucous stools, over the past 3 years. DIAGNOSES: Oozing mucosal bleeding and a small amount of exudate were observed on colonoscopy; a diagnosis of ulcerative colitis was made upon histologic examination. INTERVENTIONS AND OUTCOMES: A total of 80 stellate ganglion blocks were administered, after which the patient's symptom and pain level was decreased from 6 to 4 points on the numeric rating scale (11-point, 0 = no pain, 10 = worst pain imaginable). Improved clinical signs were observed on colonoscopy at a follow-up assessment. LESSONS: The stellate ganglion block may be effective for the reduction of pain and other symptoms in patients with chronic ulcerative colitis.

Multimodal nerve injection provides noninferior analgesic efficacy compared with interscalene nerve block after arthroscopic rotator cuff repair.

PURPOSE: This randomized noninferiority trial aimed to evaluate whether combined suprascapular, axillary nerve, and the articular branch of lateral pectoral nerve block (3NB) is noninferior to interscalene nerve block (ISB) for pain control after arthroscopic rotator cuff repair (ASRCR). MATERIALS AND METHODS: Eighty-five patients undergoing ASRCR were randomized to either 3NB (n = 43) or ISB (n = 42) group. We used 5 and 15 ml of 0.2% ropivacaine for each nerve in the 3NB and ISB groups, respectively. The primary outcome was the visual analog scale (VAS) pain score at 4 h postoperatively measured assessed on an 11-point scale (ranging from 0 = no pain to 10 = worst pain) that was analyzed using noninferiority testing. The secondary outcome was VAS pain scores in the recovery room and at 8, 12, 24, 36, 48, and 72 h postoperatively. Rebound pain, IV-PCA usage during 48 h, dyspnea, muscle weakness, and satisfaction were evaluated. RESULTS: Regarding the primary outcome, the mean difference in VAS pain scores between the 3NB (2.5 ± 1.6) and ISB (2.2 ± 2.3) groups at 4 h postoperatively was 0.3, with a 95% confidence interval (CI) of -0.56 to 1.11. The upper limit of 95% CI is lower than the noninferiority margin of 1.3 (p < 0.001). At all other time points, except in the recovery room, 3NB showed noninferior to ISB. Rebound pain, IV-PCA usage during the second 24 h, and muscle weakness were lower in the 3NB group (all p < 0.005). The satisfaction was similar in both groups (p = 0.815). CONCLUSION: Combined 3NB is noninferior to ISB in terms of pain control after ASRCR; and is associated with low levels of rebound pain, IV-PCA usage, and muscle weakness. LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

Association between proton pump inhibitor use and gastric cancer: a population-based cohort study using two different types of nationwide databases in Korea.

OBJECTIVE: The association between proton pump inhibitor (PPI) use and gastric cancer related to Helicobacter pylori eradication has not been fully investigated in geographical regions with high risk of gastric cancer. We aimed to evaluate the association between PPIs and gastric cancer in Korea. DESIGN: This study analysed the original and common data model versions of the Korean National Health Insurance Service database from 2002 to 2013. We compared the incidence rates of gastric cancer after 1-year drug exposure, between new users of PPIs and other drugs excluding PPIs, by Cox proportional hazards model. We also analysed the incidence of gastric cancer among PPI users after H. pylori eradication. RESULTS: The analysis included 11 741 patients in matched PPI and non-PPI cohorts after large-scale propensity score matching. During a median follow-up of 4.3 years, PPI use was associated with a 2.37-fold increased incidence of gastric cancer (PPI≥30 days vs non-PPI; 118/51 813 person-years vs 40/49 729 person-years; HR 2.37, 95% CI 1.56 to 3.68, p=0.001). The incidence rates of gastric cancer showed an increasing trend parallel to the duration of PPI use. In H. pylori-eradicated subjects, the incidence of gastric cancer was significantly associated with PPI use over 180 days compared with the non-PPI group (PPI≥180 days vs non-PPI; 30/12 470 person-years vs 9/7814 person-years; HR 2.22, 95% CI 1.05 to 4.67, p=0.036). CONCLUSION: PPI use was associated with gastric cancer, regardless of H. pylori eradication status. Long-term PPIs should be used with caution in high-risk regions for gastric cancer.

Gemcitabine-induced hemolytic uremic syndrome in pancreatic cancer: a case report and review of the literature.

Hemolytic uremic syndrome (HUS) is a rare thrombotic complication characterized by a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS may be caused by several different conditions, including infection, malignancy, and chemotherapeutic agents, such as mitomycin, cisplatin, and most recently, gemcitabine. The outcome of gemcitabine-induced HUS is poor, and the disease has a high mortality rate. This study reports a case of gemcitabine-induced HUS in a patient with pancreatic cancer in Korea.

Discovery of a potent tubulin polymerization inhibitor: synthesis and evaluation of water-soluble prodrugs of benzophenone analog.

Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3·HCl (l-valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3·HCl intravenously, with rapid clearance of 3·HCl indicating the effective cleavage of prodrug. Compound 3·HCl (CKD-516) has now been progressed to phase 1 clinical trial.

Identification of CKD-516: a potent tubulin polymerization inhibitor with marked antitumor activity against murine and human solid tumors.

Tubulin polymerization inhibitors had emerged as one of promising anticancer therapeutics because of their dual mechanism of action, i.e. apoptosis by cell-cycle arrest and VDA, vascular disrupting agent. VDAs are believed to be more efficient, less toxic, and several of them are currently undergoing clinical trials. To identify novel tubulin inhibitors that possess potent cytotoxicity and strong inhibition of tubulin polymerization as well as potent in vivo antitumor efficacy, we have utilized benzophenone scaffold. Complete SAR analysis of newly synthesized analogues that were prepared by incorporation of small heterocycles (C2, C4, and C5 position) into B-ring along with the evaluation of their in vitro cytotoxicity, tubulin polymerization inhibition, and in vivo antitumor activity allowed us to identify 22 (S516). Compound 22 was found to have potent cytotoxicity against several cancer cells including P-gp overexpressing MDR positive cell line (HCT15). It also induced cell cycle arrest at G(2)/M phase, which is associated with strong inhibition of tubulin polymerization. Its in vivo efficacy was improved by preparing its (l)-valine prodrug, 65 (CKD-516), which together with greatly improved aqueous solubility has shown marked antitumor efficacy against both murine tumors (CT26 and 3LL) and human xenogratfs (HCT116 and HCT15) in mice.

Structural chemoproteomics and drug discovery.

Our laboratories have developed several technologies to accelerate drug discovery process on the basis of structural chemoproteomics. They include SPS technology for the efficient determination of protein structures, SCP technology for the rapid lead generation and SDF technology for the productive lead optimization. Using these technologies, we could determine many 3D structures of target proteins bound with biologically active chemicals including the structure of phosphodiesterase 5/Viagra complex and obtain highly potent compounds in animal models of obesity, diabetes, cancer and inflammation. In this paper, we will discuss concepts and applications of structural chemoproteomics for drug discovery.

Phage-display selection of a human single-chain fv antibody highly specific for melanoma and breast cancer cells using a chemoenzymatically synthesized G(M3)-carbohydrate antigen.

Overexpression of the cell-surface glycosphingolipid G(M3) is associated with a number of different cancers, including those of the skin, colon, breast, and lung. Antibodies against the G(M3) epitope have potential application as therapeutic agents in the treatment of these cancers. We describe the chemoenzymatic synthesis of two G(M3)-derived reagents and their use in the panning of a phage-displayed human single-chain Fv (scFv) antibody library derived from the blood of cancer patients. Three scFv-phage clones, GM3A6, GM3A8, and GM3A15, were selected for recombinant expression and were characterized using BIAcore and flow cytometry. BIAcore measurements using the purified, soluble scFvs yielded dissociation constants (K(d)) ranging from 4.2 x 10(-7) to 2.1 x 10(-5) M. Flow cytometry was used to evaluate the ability of each scFv to discriminate between normal human cells (human dermal fibroblast, HDFa), melanoma cells (HMV-1, M21, and C-8161), and breast cancer cells (BCM-1, BCM-2, and BMS). GM3A6 displayed cross-reactivity with normal cells, as well as tumor cells, and GM3A15 possessed little or no binding activity toward any of the cell lines tested. However, GM3A8 bound to five of the six tumor cell lines and showed no measurable reactivity against the HDFa cells. Hence, we have demonstrated that a synthetic G(M3) panning reagent can be used to isolate a fully human scFv that is highly specific for native G(M3) on the surface of tumor cells. The result is a significant step toward effective immunotherapies for the treatment of cancer.

A parallel approach to the discovery of carrier delivery vehicles to enhance antigen immunogenicity.

As part of an ongoing effort to generate human and murine monoclonal antibodies against poorly immunogenic tumor-associated antigens we have merged the rapidly expanding disciplines of parallel polymer synthesis and controlled-release technology with immunology to produce a rapid and generic approach to improve the immunogenicity of carrier-bound antigens. The process involves three stages: An array of cross-linked hydrogel materials containing a carrier protein (at various concentrations) is prepared in parallel in one step. The array is then screened in mice to determine the most effective hydrogel at enhancing the immunogenicity of the encapsulated versus nonencapsulated carrier. Finally, the most efficient hydrogel is prepared containing the critical carrier-antigen conjugate and is used for immunization protocols. The strategy was successful for the BSA-glycoconjugate of the tumor-associated antigen GM3 analogue 4. When encapsulated within the hydrogel array member most efficient at elevating BSA immunogenicity, the BSA-4 glycoconjugate was significantly more immunogenic that when administered as a free antigen.