The Impact of Withdrawing or Withholding of Life-Sustaining Treatment: A Nationwide Case-Control Study Based on Medical Cost Analysis.

This study measured the impact of the Decisions on Life-Sustaining Treatment Act by analyzing medical cost data from the National Health Insurance Service-National Sample Cohort. After identifying the patients who died in 2018 and 2019, the case and control groups were set using the presence of codes for managing the implementation of life-sustaining treatment with propensity score matching. Regarding medical costs, the case group had higher medical costs for all periods before death. The subdivided items of medical costs with significant differences were as follows: consultation, admission, injection, laboratory tests, imaging and radiation therapy, nursing hospital bundled payment, and special equipment. This study is the first analysis carried out to measure the impact of the Decision on Life-Sustaining Treatment Act through a cost analysis and to refute the common expectation that patients who decided to withhold or withdraw life-sustaining treatment would go through fewer unnecessary tests or treatments.

Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload. An ADC platform that enables DAR optimization could improve the success rate of clinical candidates. Here we report a systematic exploration of DAR across a wide range, by combining THIOMAB protein engineering technology with Dolasynthen, an auristatin-based platform with monomeric and trimeric variants. This approach enabled the generation of homogeneous, site-specific ADCs spanning a discrete range of DARs 2, 4, 6, 12, and 18 by conjugation of trastuzumab IgG1 THIOMAB constructs with 1, 2, or 3 engineered cysteines to monomeric or trimeric Dolasynthen. All ADCs had physicochemical properties that translated to excellent in vivo pharmacology. Following a single dose of ADCs in a HER2 xenograft model with moderate antigen expression, our data demonstrated comparable pharmacokinetics for the conjugates across all DARs and dose-dependent efficacy of all test articles. These results demonstrate that the Dolasynthen platform enables the generation of ADCs with a broad range of DAR values and with comparable physiochemical, pharmacologic, and pharmacokinetics profiles; thus, the Dolasynthen platform enables the empirical determination of the optimal DAR for a clinical candidate for a given target.

Changes in Protein Dynamics in Escherichia coli SufS Reveal a Possible Conserved Regulatory Mechanism in Type II Cysteine Desulfurase Systems.

In the Suf Fe-S cluster assembly pathway, the activity of the cysteine desulfurase, SufS, is regulated by interactions with the accessory sulfotransferase protein, SufE. SufE has been shown to stimulate SufS activity, likely by inducing conformational changes in the SufS active site that promote the desulfurase step and by acting as an efficient persulfide acceptor in the transpersulfuration step. Previous results point toward an additional level of regulation through a "half-sites" mechanism that affects the stoichiometry and affinity for SufE as the dimeric SufS shifts between desulfurase and transpersulfuration activities. Investigation of the covalent persulfide intermediate of SufS by backbone amide hydrogen-deuterium exchange mass spectrometry identified two active site peptides (residues 225-236 and 356-366) and two peptides at the dimer interface of SufS (residues 88-100 and 243-255) that exhibit changes in deuterium uptake upon formation of the intermediate. Residues in these peptides are organized to form a conduit between the two active sites upon persulfide formation and include key cross-monomer interactions, suggesting they may play a role in the half-sites regulation. Three evolutionarily conserved residues at the dimer interface (R92, E96, and E250) were investigated by alanine scanning mutagenesis. Two of the substituted enzymes (E96A and E250A SufS) resulted in 6-fold increases in the value of KSufE, confirming a functional role. Re-examination of the dimer interface in reported crystal structures of SufS and the SufS homologue CsdA identified previously unnoticed residue mobility at the dimer interface. The identification of conformational changes at the dimer interface by hydrogen-deuterium exchange confirmed by mutagenesis and structural reports provides a physical mechanism for active site communication in the half-sites regulation of SufS activity. Given the conservation of the interface interactions, this mechanism may be broadly applicable to type II cysteine desulfurase systems.

Medical students' clinical performance of dealing with patients in the context of domestic violence.

PURPOSE: The aim of this study was to inquire about the clinical performance and determine the performance pattern of medical students in standardized patient (SP) based examinations of domestic violence (DV). METHODS: The clinical performance sores in DV station with SP of third-year (n=111, in 2014) and 4th-year (n=143, in 2016) medical students of five universities in the Busan-Gyeongnam Clinical Skills Examination Consortium were subjected in this study. The scenarios and checklists of DV cases were developed by the case development committee of the consortium. The students' performance was compared with other stations encountered in SP. The items of the checklists were categorized to determine the performance pattern of students investigating DV into six domains: disclosure strategy (D), DV related history taking (H), checking the perpetrator's psychosocial state (P), checking the victim's condition (V), negotiating and persuading the interviewee (N), and providing information about DV (I). RESULTS: Medical students showed poorer performance in DV stations than in the other stations with SP in the same examination. Most students did confirm the perpetrator and commented on confidentiality but ignored the perpetrator's state and patient's physical and psychological condition. The students performed well in the domains of D, H, and I but performed poorly in domains P, V, and N. CONCLUSION: Medical students showed poor clinical performance in the DV station. They performed an 'event oriented interview' rather than 'patient centered' communication. An integrated educational program of DV should be set to improve students' clinical performance.

Authenticity, acceptability, and feasibility of a hybrid gynecology station for the Papanicolaou test as part of a clinical skills examination in Korea.

PURPOSE: The objective of this study was to evaluate the authenticity, acceptability, and feasibility of a hybrid station that combined a standardized patient encounter and a simulated Papanicolaou test. METHODS: We introduced a hybrid station in the routine clinical skills examination (CSE) for 335 third-year medical students at 4 universities in Korea from December 1 to December 3, 2014. After the tests, we conducted an anonymous survey on the authenticity, acceptability, and feasibility of the hybrid station. RESULTS: A total of 334 medical students and 17 professors completed the survey. A majority of the students (71.6%) and professors (82.4%) agreed that the hybrid station was more authentic than the standard CSE. Over 60 percent of the students and professors responded that the station was acceptable for assessing the students' competence. Most of the students (75.2%) and professors (82.4%) assessed the required tasks as being feasible after reading the instructions. CONCLUSION: Our results showed that the hybrid CSE station was a highly authentic, acceptable, and feasible way to assess medical students' performance.

A pilot study on the evaluation of medical student documentation: assessment of SOAP notes.

PURPOSE: The purpose of this study was evaluation of the current status of medical students' documentation of patient medical records. METHODS: We checked the completeness, appropriateness, and accuracy of 95 Subjective-Objective-Assessment-Plan (SOAP) notes documented by third-year medical students who participated in clinical skill tests on December 1, 2014. Students were required to complete the SOAP note within 15 minutes of an standard patient (SP)-encounter with a SP complaining rhinorrhea and warring about meningitis. RESULTS: Of the 95 SOAP notes reviewed, 36.8% were not signed. Only 27.4% documented the patient's symptoms under the Objective component, although all students completed the Subjective notes appropriately. A possible diagnosis was assessed by 94.7% students. Plans were described in 94.7% of the SOAP notes. Over half the students planned workups (56.7%) for diagnosis and treatment (52.6%). Accurate documentation of the symptoms, physical findings, diagnoses, and plans were provided in 78.9%, 9.5%, 62.1%, and 38.0% notes, respectively. CONCLUSION: Our results showed that third-year medical students' SOAP notes were not complete, appropriate, or accurate. The most significant problems with completeness were the omission of students' signatures, and inappropriate documentation of the physical examinations conducted. An education and assessment program for complete and accurate medical recording has to be developed.

Assessing clinical reasoning abilities of medical students using clinical performance examination.

PURPOSE: The purpose of this study is to investigate the reliability and validity of new clinical performance examination (CPX) for assessing clinical reasoning skills and evaluating clinical reasoning ability of the students. METHODS: Third-year medical school students (n=313) in Busan-Gyeongnam consortium in 2014 were included in the study. One of 12 stations was developed to assess clinical reasoning abilities. The scenario and checklists of the station were revised by six experts. Chief complaint of the case was rhinorrhea, accompanied by fever, headache, and vomiting. Checklists focused on identifying of the main problem and systematic approach to the problem. Students interviewed the patient and recorded subjective and objective findings, assessments, plans (SOAP) note for 15 minutes. Two professors assessed students simultaneously. We performed statistical analysis on their scores and survey. RESULTS: The Cronbach α of subject station was 0.878 and Cohen κ coefficient between graders was 0.785. Students agreed on CPX as an adequate tool to evaluate students' performance, but some graders argued that the CPX failed to secure its validity due to their lack of understanding the case. One hundred eight students (34.5%) identified essential problem early and only 58 (18.5%) performed systematic history taking and physical examination. One hundred seventy-three of them (55.3%) communicated correct diagnosis with the patient. Most of them had trouble in writing SOAP notes. CONCLUSION: To gain reliability and validity, interrater agreement should be secured. Students' clinical reasoning skills were not enough. Students need to be trained on problem identification, reasoning skills and accurate record-keeping.

SufE D74R Substitution Alters Active Site Loop Dynamics To Further Enhance SufE Interaction with the SufS Cysteine Desulfurase.

Many essential metalloproteins require iron-sulfur (Fe-S) cluster cofactors for their function. In vivo persulfide formation from l-cysteine is a key step in the biogenesis of Fe-S clusters in most organisms. In Escherichia coli, the SufS cysteine desulfurase mobilizes persulfide from l-cysteine via a PLP-dependent ping-pong reaction. SufS requires the SufE partner protein to transfer the persulfide to the SufB Fe-S cluster scaffold. Without SufE, the SufS enzyme fails to efficiently turn over and remains locked in the persulfide-bound state. Coordinated protein-protein interactions mediate sulfur transfer from SufS to SufE. Multiple studies have suggested that SufE must undergo a conformational change to extend its active site Cys loop during sulfur transfer from SufS. To test this putative model, we mutated SufE Asp74 to Arg (D74R) to increase the dynamics of the SufE Cys51 loop. Amide hydrogen/deuterium exchange mass spectrometry (HDX-MS) analysis of SufE D74R revealed an increase in solvent accessibility and dynamics in the loop containing the active site Cys51 used to accept persulfide from SufS. Our results indicate that the mutant protein has a stronger binding affinity for SufS than that of wild-type SufE. In addition, SufE D74R can still enhance SufS desulfurase activity and did not show saturation at higher SufE D74R concentrations, unlike wild-type SufE. These results show that dynamic changes may shift SufE to a sulfur-acceptor state that interacts more strongly with SufS.

A phase II study of irinotecan with biweekly, low dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFIRI) as first line therapy for patients with recurrent or metastatic gastric cancer.

BACKGROUND: To determine the activity and toxicities of a low-dose leucovorin plus 5-fluorouracil (5-FU) regimen, combined with irinotecan and administered every 2 weeks (modified FOLFIRI), as a first-line therapy for patients with advanced gastric cancer. METHOD: Patients were treated with cycles of 150 mg/m irinotecan on day 1 plus 50 mg of LV, followed by a 400 mg/m 5-FU bolus and a 22-hour continuous infusion of 600 mg/m 5-FU on days 1 and 2. RESULTS: The median patient age was 55 years (range, 29-75 years), and 77% (34/44) of the patients had a performance status (Eastern Cooperative Oncology Group) of 0 or 1. Of the 44 patients evaluated for their tumor response, 3 patients (6.8%) and 14 patients (31.8%) achieved a complete and partial response, respectively, with an overall response rate of 38.6% (95% confidence interval, 23.7%-53.6%). 13 patients (29.6%) evidenced a stable disease, and 14 patients (31.8%) progressed during the course of the treatment. The median time to progression and overall survival time were 4.9 months (range, 0.9-22.8 months) and 10.3 months (range, 1.2-29.0 months) from the start of the chemotherapy, respectively. A total of 293 cycles were assessed for toxicity. The major hematologic toxicities included grade 1 to 2 anemia (27.6%), neutropenia (48.8%), and grade 3 to 4 neutropenia (12.6%). There were 7 cycles of neutropenic fever. Nonhematological toxicities were observed grade 3 vomiting (6.8%), grade 3 diarrhea (4.5%), and grade 3 mucositis (2.3%). We noted no treatment-related deaths. CONCLUSIONS: The modified FOLFIRI regimen-lowering of irinotecan and LV doses-is a safe and feasible regimen as a first-line therapy for patients with recurrent or metastatic gastric cancer.

Clinical significances of preoperative serum interleukin-6 and C-reactive protein level in operable gastric cancer.

BACKGROUND: The interleukin-6 (IL-6) pathway is one of the mechanisms that link inflammation and angiogenesis to malignancy. Because the C-reactive protein (CRP) is a representative marker for inflammation, CRP has recently been associated with the progression of disease in many cancer types. The principal objective of this study was to determine the preoperative serum levels of IL-6 and CRP in gastric carcinoma, and to correlate them with disease status and prognosis. METHODS: A total of 115 patients who underwent gastrectomy were enrolled in this study. Serum levels of IL-6 were assessed via Enzyme-Linked Immuno-Sorbent Assay (ELISA), and CRP was measured via immunoturbidimetry. Histological findings included tumor size, depth of tumor invasion, lymph node (LN) metastasis, and TNM stage (6th AJCC Stage Groupings: The staging systems; Primary tumor, regional LN, metastasis). RESULTS: Increases in cancer invasion and staging are generally associated with increases in preoperative serum IL-6 levels. IL-6 and CRP levels were correlated with invasion depth (P < 0.001, P = 0.001), LN metastasis (P < 0.001, P = 0.024) and TNM stage (P < 0.001, P < 0.001). The presence of peritoneal seeding metastasis is associated with IL-6 levels (P = 0.012). When we established the cutoff value for IL-6 level (6.77 pg/dL) by ROC curve, we noted significant differences in time to progression (TTP; P < 0.001) and overall survival (OS; P = 0.010). However, CRP evidenced no significance with regard to patients' TTP and OS levels. Serum IL-6 levels were correlated positively with CRP levels (r2 = 0.049, P = 0.018). CONCLUSION: Preoperative serum IL-6 and CRP levels might be markers of tumor invasion, LN metastasis, and TNM stage. Preoperative high IL-6 levels were proposed as a poor prognostic factor for disease recurrence and overall survival in patients with gastric cancers.