Development of the Korean Standardized Antimicrobial Administration Ratio as a Tool for Benchmarking Antimicrobial Use in Each Hospital

BackgroundThe Korea National Antimicrobial Use Analysis System (KONAS), a benchmarking system for antimicrobial use in hospitals, provides Korean Standardized Antimicrobial Administration Ratio (K-SAAR) for benchmarking. This article describes K-SAAR predictive models to enhance the understanding of K-SAAR, an important benchmarking strategy for antimicrobial usage in KONAS.MethodsWe obtained medical insurance claims data for all hospitalized patients aged ≥ 28 days in all secondary and tertiary care hospitals in South Korea (n = 347) from January 2019 to December 2019 from the Health Insurance Review & Assessment Service. Modeling was performed to derive a prediction value for antimicrobial use in each institution, which corresponded to the denominator value for calculating K-SAAR. The prediction values of antimicrobial use were modeled separately for each category, for all inpatients and adult patients (aged ≥ 15 years), using stepwise negative binomial regression.ResultsThe final models for each antimicrobial category were adjusted for different significant risk factors. In the K-SAAR models of all aged patients as well as adult patients, most antimicrobial categories included the number of hospital beds and the number of operations as significant factors, while some antimicrobial categories included mean age for inpatients, hospital type, and the number of patients transferred from other hospitals as significant factors.ConclusionWe developed a model to predict antimicrobial use rates in Korean hospitals, and the model was used as the denominator of the K-SAAR.     

Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment

Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or dietary supplement, its molecular target(s) is debatable. Here, we showed that EPA and its metabolites strongly and reversibly inhibit vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and release of adenosine triphosphate (ATP) in purinergic chemical transmission. In vitro analysis showed that EPA inhibits human VNUT-mediated ATP uptake at a half-maximal inhibitory concentration (IC₅₀) of 67 nM, acting as an allosteric modulator through competition with Cl⁻. EPA impaired vesicular ATP release from neurons without affecting the vesicular release of other neurotransmitters. In vivo, VNUT^−/− mice showed a delay in the onset of neuropathic pain and resistance to both neuropathic and inflammatory pain. EPA potently attenuated neuropathic and inflammatory pain in wild-type mice but not in VNUT^−/− mice without affecting the basal nociception. The analgesic effect of EPA was canceled by the intrathecal injection of purinoceptor agonists and was stronger than that of existing drugs used for neuropathic pain treatment, with few side effects. Neuropathic pain impaired insulin sensitivity in previous studies, which was improved by EPA in the wild-type mice but not in the VNUT^−/− mice. Our results showed that VNUT is a molecular target of EPA that attenuates neuropathic and inflammatory pain and insulin resistance. EPA may represent a unique nutrient-based treatment and prevention strategy for neurological, immunological, and metabolic diseases by targeting purinergic chemical transmission.

Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are essential nutrients that contain multiple double bonds. PUFAs can be classified into ω-3 and ω-6 depending on the position of the bonds. As humans cannot produce PUFAs, they must be acquired from the diet to maintain homeostasis. Omega-3 PUFAs, such as eicosapentaenoic acid (EPA), are abundantly present in fish and linseed oil and exhibit antiinflammatory, neuroprotective, and cardiovascular-protective activities via the competitive inhibition of cyclooxygenase (COX)-2 in eicosanoid production (1–3). Danish and Greenland Inuit epidemiological studies have reported that EPA reduces the risk of death after myocardial infarction (4, 5), and other studies have reported its influence on analgesia, neuroinflammatory disease (Parkinson’s disease, Alzheimer’s disease, and depression) improvement, platelet aggregation inhibition, decrease in blood triglyceride and glucose levels, and improved insulin resistance (1, 6–11). Omega-3 fatty acid supplementation in COVID-19 patients showed a beneficial effect in managing the cytokine storm (12). Conversely, omega-6 fatty acids, such as arachidonic acid, produce inflammatory eicosanoids and play central roles in the initial stage of inflammatory responses (13). Although arachidonic acid has also been reported to produce antiinflammatory metabolites, omega-6 PUFA-derived linoleate diols have a harmful effect and are biomarkers for severe COVID-19 infection (14). An omega-6 PUFA-enriched Western-style diet, which abundantly contains linoleate, causes neuropathy and chronic pain, but an omega-3 PUFA-enriched diet attenuates these pathological conditions (15).All therapeutic effects of EPA cannot be explained by COX-2 inhibition alone (16). Typically, COX-2 inhibitors (nonsteroidal antiinflammatory druga [NSAIDs]) are effective for inflammatory pain but ineffective for neuropathic pain (16). However, EPA significantly attenuates both inflammatory and neuropathic pain, which strongly suggests another important molecular target of EPA related to neuropathy (7, 8). Although chronic pain is coincidentally caused by inflammation and neuropathy, there is no therapeutic drug with few side effects to attenuate both inflammatory and neuropathic pain (17–20). In this situation, EPA may affect the key signaling molecule(s) in neurological, metabolic, and immunological functions.Purinergic chemical transmission is involved in neurological, metabolic, and immunological disruptions and functions, including neuropathic and inflammatory pain, depression, inflammation, increase in blood triglyceride and glucose levels, insulin resistance, and blood coagulation (21, 22). The released adenosine triphosphate (ATP) and degraded adenosine diphosphate (ADP) or adenosine binds to many types of purinoceptors that are intricately involved in biological and pathological processes. In pain perception, ATP and ADP bind to P2X and P2Y receptors and thereby exacerbate neuropathic and inflammatory pain (23). Adenosine binds to P1 receptors and thereby attenuates neuropathic and inflammatory pain (24). However, a vesicular nucleotide transporter (VNUT/SLC17A9) is localized in the secretory vesicles of neuronal, endocrine, and immune cells. It plays an essential role in vesicular ATP storage in a Δψ- and Cl^–-dependent manner in the purinergic chemical transmission, which leads to vesicular ATP release (25, 26). Thus, VNUT is a key molecule in the initiation of purinergic signaling for neurological, metabolic, and immunological disruptions and functions. Interestingly, the observed effects of the VNUT inhibitor and phenotypes of VNUT^−/− mice were consistent with the above-mentioned therapeutic effects of EPA (27–31). Therefore, we hypothesized that VNUT serves as a molecular target of EPA to attenuate neuropathic and inflammatory pain.Here, we demonstrated that a low concentration of EPA and its metabolites, but not docosahexaenoic acid (DHA), are potent and selective physiological inhibitors of vesicular ATP release via the blockade of purinergic chemical transmission, which improved neuropathic and inflammatory pain and insulin resistance. Furthermore, EPA is more effective for neuropathic and inflammatory pain and has fewer side effects than existing drugs.     

Usefulness of <Superscript>11</Superscript>C-methionine PET in the evaluation of brain lesions that are hypo- or isometabolic on <Superscript>18</Superscript>F-FDG PET

The fact that some brain tumors show hypo- or isometabolism on fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) has caused problems in the detection of primary or recurrent tumors and in the differentiation from benign lesions. We investigated the usefulness of carbon-11 methionine PET in characterizing brain lesions under these conditions. 11C-methionine PET was performed in 45 patients with brain lesions (in 34 for initial diagnosis and in 11 for detection of recurrence) that showed hypo- or isometabolism compared with normal brain tissue on FDG PET. Ten minutes after the injection of 555-740 MBq of 11C-methionine, attenuation-corrected brain images were obtained with a dedicated PET scanner. The brain lesions comprised 24 gliomas, five metastatic brain tumors, four meningiomas, two other brain tumors and ten benign lesions (including three cases of cysticercosis, two cases of radiation necrosis, one tuberculous granuloma, one hemangioma, one benign cyst, and one organizing infarction). Proliferative activity was measured using the Ki-67 immunostaining method in glioma tissues. Thirty-one of 35 brain tumors (89% sensitivity) showed increased 11C-methionine uptake despite iso- or hypometabolism on FDG PET. By contrast, all ten benign lesions showed decreased or normal 11C-methionine uptake (100% specificity). Twenty-two of 24 gliomas (92%) showed increased 11C-methionine uptake, the extent and degree of which exceeded 18F-FDG uptake, and the 11C-methionine uptake correlated with the proliferation index (r=0.67). The mean (+/-SD) uptake ratios of glioma to normal brain on FDG and 11C-methionine PET were 0.92+/-0.34 and 2.54+/-1.25, respectively. All metastatic tumors except one showed intense 11C-methionine uptake in the entire tumor or in the peripheral margin of the tumor. In meningiomas, 11C-methionine uptake showed a variable increase. In conclusion, brain lesions that show hypo- or isometabolism on FDG PET can be detected and differentiated with high sensitivity and good contrast using 11C-methionine PET. 11C-methionine PET can provide additional information when used in combination with FDG PET in the evaluation of these patients.     

Three-Point Bending Properties of Hybrid Multi-Materials Using Adhesive Bonding Dependent on Strength Difference between Steel and Aluminum

The mechanical behaviors of two multi-materials, DP590 (steel sheet)–A356 (cast aluminum alloy) and SS330 (steel sheet)–A5052 (aluminum sheet), were studied. A structural adhesive was used for the joining of steel and aluminum at adhesion strengths of 10, 22, and 30 MPa. To demonstrate that the three-point bending properties depend on the difference in strength between steel and aluminum and adhesion strength, optical microscopy (OM), scanning electron microscopy (SEM), and finite-element analysis (FEA) were performed. According to the results of the bending tests on both multi-materials under the same stacking conditions, the flexural stress increased with the improvement in the adhesion strength until interface separation or aluminum fracture. At the same adhesion strength, the DP590 (lower)–A356 (upper) and SS330 (upper)–A5052 (lower) configurations exhibited a tendency to decrease in the sudden stress drop due to aluminum fracture and interface separation. The bending results were analyzed through the FEA and the stress distribution as a function of the stacking and adhesion strength was confirmed.     

Olfactory Stimulation with Volatile Aroma Compounds of Basil (Ocimum basilicum L.) Essential Oil and Linalool Ameliorates White Fat Accumulation and Dyslipidemia in Chronically Stressed Rats

We explored the physiological effects of inhaling basil essential oil (BEO) and/or linalool and identified odor-active aroma compounds in BEO using gas chromatography/mass spectrometry (GC–MS) and GC–olfactometry (GC–O). Linalool was identified as the major volatile compound in BEO. Three groups of rats were administered BEO and linalool via inhalation, while rats in the control group were not. Inhalation of BEO for 20 min only reduced the total weight gain (190.67 ± 2.52 g) and increased the forced swimming time (47.33 ± 14.84 s) compared with the control group (219.67 ± 2.08 g, 8.33 ± 5.13 s). Inhalation of BEO for 5 min (392 ± 21 beats/min) only reduced the pulse compared with the control group (420 ± 19 beats/min). Inhalation of linalool only reduced the weight of white adipose tissue (5.75 ± 0.61 g). The levels of stress-related hormones were not significantly different among the groups. The total cholesterol and triglyceride levels decreased after inhalation of BEO for 20 min (by more than −10% and −15%, respectively). Low-density lipoprotein cholesterol levels were lowered (by more than −10%) by the inhalation of BEO and linalool, regardless of the inhalation time. In particular, BEO inhalation for 20 min was associated with the lowest level of low-density lipoprotein cholesterol (53.94 ± 2.72 mg/dL). High-density lipoprotein cholesterol levels increased after inhalation of BEO (by more than +15%). The atherogenic index and cardiac risk factors were suppressed by BEO inhalation. Animals exposed to BEO and linalool had no significant differences in hepatotoxicity. These data suggest that the inhalation of BEO and linalool may ameliorate cardiovascular and lipid dysfunctions. These effects should be explored further for clinical applications.     

Effect of a Boarding Restriction Protocol on Emergency Department Crowding

PurposeAccess block due to the lack of hospital beds causes crowding of emergency departments (ED). We initiated the “boarding restriction protocol” that limits the time of stay in the ED for patients awaiting hospitalization to 24 hours from arrival. The purpose of this study was to determine the effect of the boarding restriction protocol on ED crowding.Materials and MethodsThe primary outcome was ED occupancy rate, which was calculated as the ratio of the number of occupying patients to the total number of ED beds. Time factors, such as length of stay (LOS), treatment time, and boarding time, were investigated.ResultsThe mean of the ED occupancy rate decreased from 1.532±0.432 prior to implementation of the protocol to 1.273±0.353 after (p<0.001). According to time series analysis, the absolute effect caused by the protocol was -0.189 (-0.277 to -0.110) (p=0.001). The proportion of patients with LOS exceeding 24 hours decreased from 7.6% to 4.0% (p<0.001). Among admitted patients, ED LOS decreased from 770.7 (421.4–1587.1) minutes to 630.2 (398.0–1156.8) minutes (p<0.001); treatment time increased from 319.6 (198.5–482.8) minutes to 344.7 (213.4–519.5) minutes (p<0.001); and boarding time decreased from 298.9 (109.5–1149.0) minutes to 204.1 (98.7–545.7) minutes (p<0.001). In pre-protocol period, boarding patients accumulated in the ED during the weekdays and resolved on Friday, but this pattern was alleviated in post-period.ConclusionThe boarding restriction protocol was effective in alleviating ED crowding by reducing the accumulation of boarding patients in the ED during the weekdays.     

Platelet Function and Genotype after DES Implantation in East Asian Patients: Rationale and Characteristics of the PTRG-DES Consortium

PurposePlatelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Materials and MethodsSearching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.ResultsNine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (^*2 or ^*3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively.ConclusionThe PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04734028","term_id":"NCT04734028"}}NCT04734028.     

Developing an Institutional Protocol Guideline for Laparoscopy-Assisted Distal Gastrectomy

Background  The technical difficulty of lymph node dissection in laparoscopy-assisted distal gastrectomy (LADG) remains a barrier for extending the indication for this modality and limits its widespread clinical practice. The aim of this study was to evaluate our institutional guidelines for LADG, limiting the indications for this modality to only clinical stage T1N0 or T1N1 gastric cancer. Methods  From January 2002 to October 2006, a total of 294 cases of LADG and 664 cases of open distal gastrectomy (ODG) for clinical T1N0 or T1N1 gastric cancer were performed at the National Cancer Center, Korea. The two groups’ clinicopathologic characteristics, surgical outcome, morbidity, and survival were compared. Results  The mean operating time for the LADG group was significantly longer than that for the ODG group (265.8 ± 56.3 vs. 171.4 ± 43.1 minutes, P < .001). The mean number of retrieved lymph nodes in the LADG group was higher than that of the ODG group (39.5 ± 14.7 vs. 37.2 ± 12.9, P = .017). The postoperative hospital stay was shorter in the LADG group (8.0 ± 3.3 vs. 10.5 ± 4.1 days, P < .001). The complications rate was lower for the LADG group than that for the ODG group (6.8% vs. 11.3%, P = .032). The overall survival rate was not significantly different between the two groups (P = .880). Conclusions  Before considering expanding the indications for LADG, developing a carefully thought-out guideline and conducting an audit are mandatory.     

The Influence of Face Shields on the Quality of Colonoscopy in the Era of the COVID-19 Pandemic

Background/AimsThe worldwide coronavirus disease 2019 pandemic has led endoscopists to use personal protective equipment (PPE) for infection prevention. This study aimed to investigate whether wearing a face shield as PPE affects the quality of colonoscopy.MethodsWe reviewed the medical records and colonoscopy findings of patients who underwent colonoscopies at Asan Medical Center, Korea from March 10 to May 31, 2020. The colonoscopies in this study were performed by five gastroenterology fellows and four expert endoscopists. We compared colonoscopy quality indicators, such as withdrawal time, adenoma detection rate (ADR), mean number of adenomas per colonoscopy (APC), polypectomy time, and polypectomy adverse events, both before and after face shields were added as PPE on April 13, 2020.ResultsOf the 1,344 colonoscopies analyzed, 715 and 629 were performed before and after the introduction of face shields, respectively. The median withdrawal time was similar between the face shield and no-face shield groups (8.72 minutes vs 8.68 minutes, p=0.816), as was the ADR (41.5% vs 39.8%, p=0.605) and APC (0.72 vs 0.77, p=0.510). Polypectomy-associated quality indicators, such as polypectomy time and polypectomy adverse events were also not different between the groups. Quality indicators were not different between the face shield and no-face shield groups of gastroenterology fellows, or of expert endoscopists.ConclusionsColonoscopy performance was not unfavorably affected by the use of a face shield. PPE, including face shields, can be recommended without a concern about colonoscopy quality deterioration.     

Analytical methods and formulation factors to enhance protein stability in solution

Development of stable protein formulations needs intimate knowledge of the proteins?? physicochemical properties. More specifically, understanding the mechanisms of protein degradation is important in designing and evaluating protein formulations. This review describes briefly the different types of interactions of the major protein degradation pathways. The analytical methods to detect protein degradation are included, along with generalized strategies to suppress protein instability with relevant excipients. With an appreciation of the current practices for stable formulations, the development process will be facilitated in a more efficient way.