Usefulness of the d-dimer to albumin ratio for risk assessment in patients with acute variceal bleeding at the emergency department: retrospective observational study.

BACKGROUND: Acute variceal bleeding (AVB) is a severe complication of portal hypertension that is caused by rupture of the esophageal or gastric varix. Scoring system for risk stratification of AVB is difficult to use because various variables must be entered, and it is difficult to apply early in the emergency department (ED). We compared and analyzed the usefulness of the D-dimer to albumin ratio (DAR) for risk stratification of AVB. METHODS: In this retrospective observational study, medical records of patients with AVB Between January 2019 and December 2020 were assessed. The primary endpoint was to evaluate whether DAR was a predictor of clinical outcomes for AVB. Receiver operating characteristic (ROC) curves were constructed using cut-off values determined by the Youden Index. Univariate and multivariate logistic regression analyses were performed to assess the factors contributing to the development of outcomes. RESULTS: Overall, 67 patients required intensive care. The cut-off value of DAR for patients requiring intensive care was 400. A DAR > 400 (adjusted HR: 5.636 [95% CI: 2.216-14.332]) independently predicted the need for ICU admission in these patients. Overall, 13 patients required long-term hospitalization. The cut-off value of DAR for patients requiring long-term hospitalization was 403. A DAR > 403 (adjusted HR: 9.899 [95% CI: 2.012-48.694]) independently predicted the need for long-term hospitalization. Overall, 95 patients required transfusion. The cut-off value of DAR for patients requiring transfusion was 121. A DAR > 121 (adjusted HR: 4.680 [95% CI: 1.703-12.862]) independently predicted the need for transfusion. Overall, 11 patients died during study period. The cut-off value of DAR for mortality was 450. A DAR > 450 (adjusted HR: 26.261 [95% CI: 3.054-225.827]) independently predicted mortality. CONCLUSIONS: The DAR can be used for outcome assessment in patients with AVB with various scoring systems, but its explanatory power is not high.

Effect of Hyperbaric Oxygen Therapy Initiation Time in Acute Carbon Monoxide Poisoning.

OBJECTIVES: Hyperbaric oxygen therapy (HBO2) is recommended for symptomatic patients within 24-hour postcarbon monoxide poisoning. Previous studies have reported significantly better outcomes with treatment administered within 6 hours after carbon monoxide poisoning. Thus, we aimed to compare the neurocognitive outcomes according to HBO2 delay intervals. DESIGN: Retrospective analysis of data from our prospectively collected carbon monoxide poisoning registry. SETTING: A single academic medical center in Wonju, Republic of Korea. PATIENTS: We analyzed the data of 706 patients older than 16 years treated with HBO2 with propensity score matching. Based on carbon monoxide exposure-to-HBO2 delay intervals, we classified patients into the early (control, less than or equal to 6 hr) and late (case, 6-24 hr) groups. The late group was further divided into Case-1 (6-12 hr) and Case-2 (12-24 hr) groups. We also compared mild (nonintubated) and severe (intubated) groups. INTERVENTIONS: HBO2. MEASUREMENTS AND MAIN RESULTS: After propensity score matching, Global Deterioration Scale scores at 6 months postcarbon monoxide exposure showed significantly fewer poor outcome patients in the early than in the late group (p = 0.027). The early group had significantly fewer patients with poor outcomes than the Case-2 group (p = 0.035) at 1 month and than the Case-1 (p = 0.033) and Case-2 (p = 0.004) groups at 6 months. There were significantly more patients with poor prognoses at 6 months as treatment interval increased (p = 0.008). In the mild cohort, the early group had significantly fewer patients with poor 6-month outcomes than the late group (p = 0.033). CONCLUSIONS: Patients who received HBO2 within 6 hours of carbon monoxide exposure had a better 6-month neurocognitive prognosis than those treated within 6-24 hours. An increase in the interval to treatment led to an increase in poor outcomes.

Changes in Diagnosis of Poisoning in Patients in the Emergency Room Using Systematic Toxicological Analysis with the National Forensic Service.

BACKGROUND: It is difficult to diagnose patients with poisoning and determine the causative agent in the emergency room. Usually, the diagnosis of such patients is based on their medical history and physical examination findings. We aimed to confirm clinical diagnoses using systematic toxicological analysis (STA) and investigate changes in the diagnosis of poisoning. METHODS: The Intoxication Analysis Service was launched in June 2017 at our hospital with the National Forensic Service to diagnose intoxication and identify toxic substances by conducting STA. Data were collected and compared between two time periods: before and after the initiation of the project, i.e., from June 2014 to May 2017 and from June 2017 to May 2020. RESULTS: A total of 492 and 588 patients were enrolled before and after the service, respectively. Among the 588 after-service patients, 446 underwent STA. Among the 492 before-service patients, 69.9% were diagnosed clinically, whereas the causative agent could not be identified in 35 patients. After starting the service, a diagnosis was confirmed in 84.4% of patients by performing a hospital-available toxicological analysis or STA. Among patients diagnosed with poisoning by toxins identified based on history taking, only 83.6% matched the STA results, whereas 8.4% did not report any toxin, including known substances. The substance that the emergency physician suspected after a physical examination was accurate in 49.3% of cases, and 12% of cases were not actually poisoned. In 13.4% of patients who visited the emergency room owing to poisoning of unknown cause, poisoning could be excluded after STA. Poisoning was determined to be the cause of altered mental status in 31.5% of patients for whom the cause could not be determined in the emergency room. CONCLUSION: A diagnosis may change depending on the STA results of intoxicated patients. Therefore, appropriate STA can increase the accuracy of diagnosis and help in making treatment decisions.

Seizure during hyperbaric oxygen therapy: experience at a single academic hospital in Korea.

Background: Hyperbaric oxygen (HBO2) therapy is a safe and well-tolerated treatment modality. Seizures, one of the most severe central nervous system side effects of HBO2 therapy, can occur. Episodes of seizures during HBO2 therapy have not yet been reported in countries such as Korea, where hyperbaric medicine is still in the developmental stage. Methods: The registry data of all patients treated with HBO2 therapy in a tertiary academic hospital in Korea were prospectively collected, and patients who developed seizures during HBO2 therapy between October 2016 and December 2019 were evaluated. In addition, we reviewed previous studies on occurrence of seizures during HBO2 therapy. Results: During the study period, a total of 10,425 treatments were provided to 1,308 patients. The most frequently treated indication was carbon monoxide (CO) poisoning ABSTRACT (n=547, 41.8%). During the HBO2 therapy sessions (total: 10,425), five seizure episodes occurred (patients with CO poisoning: n=4; patients with arterial gas embolism [AGE]: n=1). The frequency of seizures in patients with CO poisoning (0.148%) and AGE (3.448%) was significantly higher than that in patients with all indications (0.048%) (p=0.001). None of the patients had lasting effects due to the seizures. Conclusion: Our study revealed a similar frequency rate in terms of all indications and CO poisoning, and a slightly higher rate in AGE. Seizures were observed in patients with CO poisoning and AGE. Therefore, if clinicians plan to operate a hyperbaric center in a country like Korea, where there are several patients with acute CO poisoning, they should be prepared to handle seizures that may occur during HBO2 therapy.

Effects of Adjunctive Therapeutic Hypothermia Combined With Hyperbaric Oxygen Therapy in Acute Severe Carbon Monoxide Poisoning.

OBJECTIVE: To determine the effects of adjunctive therapeutic hypothermia, by comparing hyperbaric oxygen therapy versus hyperbaric oxygen therapy combined with therapeutic hypothermia in acute severe carbon monoxide poisoning. DESIGN: Retrospective analysis of data from our prospectively collected carbon monoxide poisoning registry. SETTING: A single academic medical center in Wonju, Republic of Korea. PATIENTS: Patients with acute severe carbon monoxide poisoning older than 18 years. Acute severe carbon monoxide poisoning was defined as mental status showing response to painful stimulus or unresponsive at the emergency department, and a continuation of this depressed mental status even after the first hyperbaric oxygen therapy. Patients were classified into the no-therapeutic hypothermia and therapeutic hypothermia groups. Hyperbaric oxygen therapy was performed up to twice within 24 hours after emergency department arrival, whereas therapeutic hypothermia was performed at a body temperature goal of 33°C for 24 hours using an endovascular cooling device after the first hyperbaric oxygen therapy. INTERVENTIONS: Hyperbaric oxygen therapy versus hyperbaric oxygen therapy combined with therapeutic hypothermia. MEASUREMENTS AND MAIN RESULTS: We investigated the difference in the Global Deterioration Scale score at 1 and 6 months after carbon monoxide exposure, between the no-therapeutic hypothermia and therapeutic hypothermia groups. Global Deterioration Scale scores were classified as follows: 1-3 points (favorable neurocognitive outcome) and 4-7 points (poor neurocognitive outcome). During the study period, 37 patients were treated for acute severe carbon monoxide poisoning, with 16 and 21 patients in the no-therapeutic hypothermia and therapeutic hypothermia groups, respectively. The therapeutic hypothermia group demonstrated significantly higher number of patients with favorable outcomes (p = 0.008) at 6 months after carbon monoxide exposure and better improvement of the 6-month Global Deterioration Scale score than the 1-month score (p = 0.006). CONCLUSIONS: Our data suggest that in acute severe carbon monoxide poisoning, patients who were treated using therapeutic hypothermia combined with hyperbaric oxygen therapy had significantly more favorable neurocognitive outcomes at 6 months after carbon monoxide exposure than those treated with hyperbaric oxygen therapy alone.

The effect of adjunctive hyperbaric oxygen therapy in patients with central retinal artery occlusion.

Purpose: Central retinal artery occlusion (CRAO) is an ophthalmic emergency with poor prognosis, despite diligent conventional treatment. According to the clinical recommendations of the Undersea and Hyperbaric Medical Society, hyperbaric oxygen (HBO2) is a potentially beneficial treatment; however, the benefit of adjunctive HBO2 in patients with CRAO in Korea remains unclear. The present study aimed to evaluate the effect of adjunctive HBO2 in patients with CRAO. Methods: This registry-based observational study included adult patients who presented to the emergency department or ophthalmology outpatient department within 24 hours of the onset of CRAO symptoms. Data of patients from October 2016 to February 2019 were analyzed. The patients were categorized into two groups according to the use of adjunctive HBO2: no HBO2 and HBO2. Result: During the study period, 34 consecutive patients were enrolled, of which 19 were included in the study. In the total cohort, 10 patients (52.6%) were treated with adjunctive HBO2. There were no statistically significant differences in terms of age, sex, comorbidities, duration from symptoms onset to hospital visit, presence of the cilioretinal artery, and use of anterior chamber paracentesis between the two groups. The HBO2 group showed significantly higher change in best-corrected visual acuity than the no HBO2 group (p=0.043). Conclusion: Patients with CRAO in the HBO2 group showed significantly greater visual improvement than those in the no-HBO2 group. Clinicians should consider adjunctive HBO2 in the treatment approach in patients with CRAO who visit the hospital within 24 hours of symptoms onset.

Methods for preventing middle ear barotrauma in computer-controlled pressurization of monoplace hyperbaric chambers.

Middle ear barotrauma (MEB), one of the side effects of hyperbaric oxygen (HBO2) therapy, sometimes cannot be directly diagnosed during the therapy itself. Instead, its incidence and degree are judged based on subjective statements made by patients when in conversation with medical staff regarding how they feel. To prevent MEB in practice, it is proposed that the tympanic membrane evaluation system and automatic control chamber developed in a previous study be applied as part of a prevention algorithm [16]. The proposed algorithm, which determines and equalizes the unbalanced pressure of a subject based on their tympanic admittance, was evaluated in conjunction with conventional HBO2 therapy in an experiment involving 100 subjects. Among the 50 subjects in the control group who received HBO2 therapy 16 subjects experienced MEB. In contrast, the experimental group of 50 subjects were treated with a hyperbaric chamber protocol incorporating the automatic control system and proposed algorithm. At the conclusion of the treatment, no subjects exhibited middle ear barotrauma. In the case of the control group, while the target pressure was achieved, middle ear barotrauma still occurred. However, in the case of the experimental group, the pressure inside the chamber was adjusted as per the algorithm, which allowed the target pressure for every subject to be achieved without experiencing MEB. When a particular subject was unable to perform any pressure equalization method such as swallowing or the Valsalva maneuver, the chamber was not pressurized based on the tympanic admittance and thus no MEB occurred.

Operation of a hyperbaric oxygen therapy center in Korea: Report of our experience from a setting in its nascent stages.

Purpose: Hyperbaric medicine is nascent in Korea when compared to other developed countries, such as the United States and Japan. Our facility has been managed by physicians with certifications from the Undersea and Hyperbaric Medical Society (UHMS) and National Oceanic and Atmospheric Administration in diving and clinical diseases since October 2016. This study was conducted to share similar issues that are encountered during the establishment of a program in a new area through our experiences in the operation of a hyperbaric oxygen (HBO2) therapy center. Methods: In this retrospective observational study we collected data on HBO2 patients treated at our center between October 2016 and June 2018 after HBO2 was conducted by HBO2-certified physicians. We then compared demographic data of patients with data from January 2011 to September 2015 - before HBO2 operations were conducted by HBO2-certified physicians. Result: A total of 692 patients received 5,130 treatments. Twelve indicated diseases were treated using HBO2 therapy. Fifty-six critically ill patients with intubation received HBO2. Although two patients experienced seizure due to oxygen toxicity during the study period, certified physicians and inside attendant took immediate corrective action. Conclusion: After the establishment of the HBO2 center operated by physicians with certification, more patients, including critically ill patients, received HBO2 safely for various diseases. In order to improve the practice of hyperbaric medicine in Korea, the Korean Academy of Undersea and Hyperbaric Medicine (KAUHM), an advanced and well-organized academic society, should communicate often with HBO2 centers, with the aim to set Korean education programs at UHMS course levels and increase reimbursement for HBO2 therapy.

Life-threatening pulmonary embolism that occurred immediately after acute carbon monoxide poisoning in the emergency department.

The risk of thromboembolism is higher in those with carbon monoxide (CO) poisoning than in the general population. Pulmonary embolisms (PE) usually develop during admission for acute CO poisoning. We report the first case of a life-threatening PE that occurred immediately after acute CO poisoning and was treated with a thrombolytic agent. A 38-year-old woman presented at the emergency department with a stuporous mental status immediately after acute CO poisoning. She was started on hyperbaric oxygen therapy (HBOT), which maintained her hemodynamic stability. After completing the first HBOT session, profound shock occurred. The results of focused cardiac ultrasound performed by an emergency physician were completely different from those of the ultrasound conducted before HBOT; hyperdynamic left ventricle systolic function and right ventricle enlargement with dysfunction were detected. We administered a thrombolytic agent as she was suspected with acute PE based on ultrasound findings; computed tomography could not be performed because of impending arrest. She recovered after the treatment. We should consider that PE is also an important differential cause in patients with hypotension. In these patients, bedside ultrasound performed by emergency physicians can act as the only diagnostic examination.

Mechanical Improvement of Gas Monitoring System in Monoplace Hyperbaric Chamber to Advance the Safety and Efficacy.

Introduction: A Monoplace hyperbaric chamber delivers oxygen to the patient's tissues through breathing. Gas monitoring inside the chamber is important because oxygen (O2) is consumed, and carbon dioxide (CO2) is increased because treatment is performed in a closed volume. This study aimed to advance the safety and efficacy of the monoplace hyperbaric chamber (MHC) through mechanical improvement in a gas monitoring system (GMS). Methods: First, as the oxygen supply method was changed to the direction of the patient's face, it was compared the values of O2, CO2, humidity, and temperature were measured in the MHC and the GMS when operating at 2.0 atmosphere absolute (ATA) and 3.0 ATA. Second, to evaluate the effects of variables across measuring time, it was analyzed in a 3-way repeated measure ANOVA (10 min.×20 min.×30 min.). Lastly, the values before and after the optimization of the MHC were compared by applying a cooler to prevent temperature rise inside the MHC. Results: In 2.0 ATA, the average humidity was higher in the MHC than in the GMS (p<0.001). Also, the average temperature was lower in the MHC than in the GMS (p<0.001). In 3.0 ATA, the average CO2 and humidity were higher in the MHC than in the GMS, respectively (p<0.001, p=0.004). The 3-way repeated measures ANOVA revealed a significant difference in most main and interacted factors (p<0.05). O2 and temperature, comparing before and after MHC optimization, revealed a significant difference (p<0.05). Conclusion: Few studies have verified safety and effectiveness by evaluating the pressure, oxygen concentration, etc. of a monoplace hyperbaric chamber. Further research is expected to verify the effectiveness of providing comfort to patients receiving hyperbaric oxygen treatment and increase the treatment effect.

Improvement of NASH and liver fibrosis through modulation of the gut-liver axis by a novel intestinal FXR agonist.

Farnesoid X receptor (FXR) plays a pivotal role in the regulation of bile acid homeostasis and is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Although FXR agonists effectively alleviate pathological features of NASH, adverse effects such as disturbance of cholesterol homeostasis and occurrence of pruritus remain to be addressed. Here, we identified a novel FXR agonist, ID119031166 (ID166), and explored the pharmacological benefits of ID166 in the treatment of NASH. ID166, a potent and selective non-bile acid FXR agonist, exhibits preferential distribution in the intestine and shows no agonist activity against potential itch receptors including Mas-related G protein-coupled receptor X4 (MRGPRX4). Interestingly, ID166 significantly attenuated total nonalcoholic fatty liver disease (NAFLD) activity and liver fibrosis in a free choice diet-induced NASH hamster model. In addition, ID166 drastically modulated the relative abundance of five gut microbes and reduced the increase in plasma total bile acid levels to normal levels in NASH hamsters. Moreover, long-term treatment with ID166 significantly improved key histological features of NASH and liver fibrosis in a diet-induced NASH mouse model. In the NASH mouse livers, RNA-seq analysis revealed that ID166 reduced the gene expression changes associated with both NASH and liver fibrosis. Notably, ID166 exhibited no substantial effects on scratching behavior and serum IL-31 levels in mice. Our findings suggest that ID166, a novel FXR agonist with improved pharmacological properties, provides a preclinical basis to optimize clinical benefits for NASH drug development.

Initial experience of a surgical fellow in laparoscopic colorectal cancer surgery under training protocol and supervision: comparison of short-term results for 70 early cases (under supervision) and 73 late cases (without supervision).

PURPOSE: Laparoscopic colorectal surgery is a technically challenging procedure for beginners, such as surgical fellows. The purpose of this study was to assess the safety, feasibility, and short-term surgical outcomes of laparoscopic colorectal cancer surgery by a single surgical fellow. METHODS: The study analyzed the data from 143 consecutive patients who underwent laparoscopic colorectal resection by a single surgical fellow between August 2009 and October 2010. The patients were divided into two groups: the early group-the first 70 patients (under supervision of experienced surgeon), and the late group-the last 73 patients (without supervision). The short-term surgical results were compared between two groups. RESULTS: The operations were 24 right colon resections, two transverse colectomies, six left colectomies, 36 anterior resections, 57 low anterior resections, 12 intersphincteric resections, two abdominoperineal resections, three Hartmann's operations, and 1 total colectomy. The mean operating time, mean amounts of blood loss, and conversion rate were similar between the two groups. The morbidity rate, anastomosis leak rate, and mortality rate within 30 days of surgery did not differ significantly. The mean number of lymph nodes was larger in the late group (23.8 vs. 31.7, P = 0.017). In terms of low anterior resection, the mean number of endo-linear staplers used was smaller in the late group (2.46 ± 0.81 vs. 1.97 ± 0.83, P = 0.028). The anastomosis leakage rate in rectal cancer surgery was not significantly different between the two groups. CONCLUSIONS: This study demonstrates that laparoscopic colorectal resections can be independently performed safely after a period of supervision and training by an experienced surgeon.

A Refractory Livedoid Vasculopathy Accompanied by Methylene Tetrahydrofolate Reductase Gene Polymorphism Successfully Treated with Hyperbaric Oxygen Therapy.

Livedoid vasculopathy (LV) is a chronic coagulation disorder characterized by recurrent, painful ulcers on the lower extremities. Methylene tetrahydrofolate reductase (MTHFR) gene polymorphism is associated with coagulopathy. Therapeutic options usually include anti-inflammatory or immunosuppressive agents. However, the condition is still highly challenging to manage and no consensus over the first-line treatment for LV exists. Furthermore, when LV is accompanied with MTHFR gene polymorphism, clinical presentations could be more severe and resistant to treatment. We report a case of refractory LV accompanied by MTHFR gene polymorphism, which was successfully treated with hyperbaric oxygen therapy (HBOT). A 63-year-old female patient presented with multiple painful ulcers, atrophie blanches, and retiform purpura on both lower legs and feet. Histopathologic findings were compatible with LV. LV was diagnosed based on these clinicopathological findings. Following the diagnosis, we treated the patient with pentoxifylline, aspirin, systemic corticosteroid, antihistamine, and antibiotics. In spite of six-month treatment, the skin lesions did not improve; hence, HBOT was performed. It was performed at 2.0 absolute atmosphere for 120 minutes each time, three times a week. After 4 sessions, the ulcers began to heal and after 13 sessions, the skin lesions almost healed. During the eight-month follow-up period, the skin ulcers did not recur and the symptoms remained stable. Additionally, it was confirmed that she had MTHFR gene polymorphism after a genetic test. In conclusion, we wish to provide evidence regarding the effectiveness of HBOT and suggest that HBOT might be a considerable treatment option in refractory LV.

Reappraisal of the Lymphatic Drainage System of the Distal Rectum: Functional Lymphatic Flow into the Presacral Space and Its Clinical Implication in Rectal Cancer Treatment.

Understanding the source and route of pelvic metastasis is essential to developing an optimal strategy for controlling local and systemic diseases of rectal cancer. This study aims to delineate the distribution of lymphatic channels and flow from the distal rectum. In fresh-frozen cadaveric hemipelvis specimens, the ligamentous attachment of the distal rectum to the pelvic floor muscles and the presacral fascia were evaluated. Using indocyanine green (ICG) fluorescence imaging, we simultaneously evaluated the gross anatomy of the lymphatic communication of the distal rectum. We also investigated the lymphatic flow in the pelvic cavity intraoperatively in rectal cancer patients who underwent radical rectal resection with total mesorectal excision (TME). In fresh cadavers, multiple small perforating lymphovascular branches exist in the retrorectal space, posteriorly connecting the mesorectum to the presacral fascia. The lymphatic flow from the distal rectum drains directly into the presacral space through the branches. In patients who underwent TME for rectal cancer, intraoperative ICG fluorescence signals were seen in the pelvic sidewalls and the presacral space. This anatomical study demonstrated that the lymphatic flow from the distal rectum runs directly to the pelvic lateral sidewalls and the presacral space, suggesting a possible route of metastasis in distal rectal cancer.

Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety.

PARP inhibitors have been approved by the FDA for use in the treatment of patients with ovarian, breast, pancreatic, and prostate cancers. PARP inhibitors show diverse suppressive effects on PARP family members and PARP-DNA trapping potency. These properties are associated with distinct safety/efficacy profiles. Here, we report the nonclinical characteristics of venadaparib (also known as IDX-1197 or NOV140101), a novel potent PARP inhibitor. The physiochemical properties of venadaparib were analyzed. Furthermore, the efficacy of venadaparib against PARP enzymes, PAR formation, and PARP trapping activities, and growth inhibition of cell lines with BRCA mutations were evaluated. Ex vivo and in vivo models were also established to study pharmacokinetics/pharmacodynamics, efficacy, and toxicity. Venadaparib specifically inhibits PARP-1 and -2 enzymes. Oral administration of venadaparib HCl at doses above 12.5 mg/kg significantly reduced tumor growth in the OV_065 patient-derived xenograft model. Intratumoral PARP inhibition remained at over 90% until 24 hours after dosing. Venadaparib had wider safety margins than olaparib. Notably, venadaparib showed favorable physicochemical properties and superior anticancer effects in homologous recombination-deficient in vitro and in vivo models with improved safety profiles. Our results suggest the possibility of venadaparib as a next-generation PARP inhibitor. On the basis of these findings, phase Ib/IIa studies on the efficacy and safety of venadaparib have been initiated.

Beta-Meta: a meta-analysis application considering heterogeneity among genome-wide association studies.

Many packages for a meta-analysis of genome-wide association studies (GWAS) have beendeveloped to discover genetic variants. Although variations across studies must be considered, there are not many currently-accessible packages that estimate between-study heterogeneity. Thus, we propose a python based application called Beta-Meta which can easilyprocess a meta-analysis by automatically selecting between a fixed effects and a randomeffects model based on heterogeneity. Beta-Meta implements flexible input data manipulation to allow multiple meta-analyses of different genotype-phenotype associations in asingle process. It provides a step-by-step meta-analysis of GWAS for each association inthe following order: heterogeneity test, two different calculations of an effect size and ap-value based on heterogeneity, and the Benjamini-Hochberg p-value adjustment. Thesemethods enable users to validate the results of individual studies with greater statisticalpower and better estimation precision. We elaborate on these and illustrate them with examples from several studies of infertility-related disorders.

Derivation and Validation of a Score for Predicting Poor Neurocognitive Outcomes in Acute Carbon Monoxide Poisoning.

Importance: Preventing neurocognitive sequelae is a major goal of treating acute carbon monoxide (co) poisoning. There is a lack of reliable score systems exist for assessing the probability of these sequelae. Objective: To develop and validate a novel clinical scoring system for predicting poor neurocognitive outcomes after acute co poisoning. Design, Setting, and Participants: This prognostic study included derivation and validation cohorts based on consecutive patient data prospectively collected at university hospitals from January 2006 to July 2021 in Wonju, Republic of Korea, and from August 2016 to June 2020 in Incheon, Republic of Korea. Participants included individuals aged 16 years or older admitted with co poisoning. Data were analyzed from October 2021 to January 2022. Exposures: Clinical and laboratory variables. Main Outcomes and Measures: The outcome of interest was neurocognitive sequelae at 4 weeks after co poisoning. Logistic regression models were used to identify predictors of poor neurocognitive outcomes in the derivation cohort. Outcomes were assessed using the Global Deterioration Scale [GDS] at 1-month after co exposure and classified as good (1-3 points) or poor (4-7 points). Results: A total of 1282 patients (median [IQR] age, 47.0 [35.0-59.0] years; 810 [63.2%] men) were assessed, including 1016 patients in the derivation cohort and 266 patients in the validation cohort. The derivation cohort included 126 patients (12.4%) with poor GDS scores. Among 879 patients in the derivation cohort with 1-year follow-up data, 757 (86.1%) had unchanged GDS scores, 102 (11.6%) had improved GDS scores, and 20 (2.3%) had worsened GDS scores. In the final prediction model, age older than 50 years (1 point), Glasgow Coma Scale score of 12 or less (1 point), shock (1 point), serum creatine kinase level greater than 320 U/L at emergency department presentation (1 point), and no use of hyperbaric oxygen therapy (1 point) remained factors significantly associated with worse outcome; therefore, this scoring system was called COGAS (creatine kinase, hyperbaric oxygen therapy, Glasgow Coma Scale, age, shock). Area under the receiver operating characteristic curve for COGAS score was 0.862 (95% CI, 0.828-0.895) for the derivation cohort and 0.870 (95% CI, 0.779-0.961) for the validation cohort. Conclusions and Relevance: These findings suggest that assessing the COGAS score during the early phase of co poisoning may help identify patients at risk of poor neurocognitive sequelae.

Discovery of Novel Dual Adenosine A2A and A1 Receptor Antagonists with 1H-Pyrazolo[3,4-d]pyrimidin-6-amine Core Scaffold as Anti-Parkinson's Disease Agents.

New compounds with 1H-pyrazolo [3,4-d]pyrimidin-6-amine core scaffolds were synthesized and characterized in vitro to determine their affinity for human A2A and A1 receptors. Among the tested compounds, a few compounds displayed nanomolar binding affinities for both receptors. One particular compound, 11o, showed high binding activities (hA2A Ki = 13.3 nM; hA1 Ki = 55 nM) and full antagonism (hA2A IC50 = 136 nM; hA1 IC50 = 98.8 nM) toward both receptors. Further tests showed that 11o has low hepatic clearance and good pharmacokinetic properties in mice, along with high bioavailability and a high brain plasma ratio. In addition, 11o was associated with very low cardiovascular risk and mutagenic potential, and was well-tolerated in rats and dogs. When tested in an MPTP-induced mouse model of Parkinson's disease, 11o tended to improve behavior. Moreover, 11o dose-dependently reversed haloperidol-induced catalepsy in female rats, with graded ED50 of between 3 and 10 mg/kg. Taken together, these results suggest that this potent dual A2A/A1 receptor antagonist, 11o, is a good candidate for the treatment of Parkinson's disease with an excellent metabolic and safety profile.

International Normalized Ratio-to-Albumin Ratio as a Novel Marker of Upper Gastrointestinal Bleeding Severity.

Introduction: Upper gastrointestinal bleeding (UGIB) is a potentially life-threatening gastrointestinal emergency, and effective management depends on early risk stratification. The Glasgow-Blatchford and Rockall scores are commonly used prognostic measures for UGIB, although these scoring systems are relatively difficult to apply in early emergency settings. AIMS65 with five items, albumin, international normalized ratio, mental status, systolic blood pressure, and age (>65 years), showed efficacy in predicting long-term hospitalization and mortality. This study aimed to investigate the usefulness of the prothrombin time-international normalized ratio-to-albumin ratio (PTAR) in the emergency room for early UGIB risk stratification. Methods: We retrospectively examined patients who visited a tertiary academic hospital's emergency department (ED) with UGIB as the chief presentation between January 2019 and December 2020. The cutoff values and diagnostic accuracies of the PTAR, Glasgow-Blatchford score, AIMS65 score, pre-endoscopy, and complete Rockall score were analyzed, and the performance of the PTAR was compared with that of other risk stratification methods. In total, 519 patients were enrolled: 163 patients were admitted in the intensive care unit (ICU) and 35 died during admission. Multiple logistic regression analyses confirmed the association of the PTAR with ICU admission and mortality. The adjusted odd ratio (aOR) of the PTAR for ICU admission care was 8.376 (2.722-25.774), and the aOR of the PTAR for mortality was 27.846 (8.701-89.116). Conclusions: The PTAR measured in the ED is an independent factor related to ICU admission and mortality in patients with UGIB. Using ED blood laboratory results, which are reported relatively quickly and are easy to acquire and calculate, the PTAR can be used as a risk stratification marker in the early emergency setting.