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Isomerization of aspartic acid (Asp) in therapeutic proteins could lead to safety and efficacy concerns. Thus, accurate quantitation of various Asp isomerization along with kinetic understanding of the variant formations is needed to ensure optimal process development and sufficient product quality control. In this study, we first observed Asp-succinimide conversion in complementarity-determining regions (CDRs) Asp-Gly motif of a recombinant mAb through ion exchange chromatography, intact protein analysis by mass spectrometry, and LC-MS/MS. Then, we developed a specific peptide mapping method, with optimized sample digestion conditions, to accurately quantitate Asp-succinimide-isoAsp variants at peptide level without method-induced isomerization. Various kinetics of Asp-succinimide-isoAsp isomerization pathways were elucidated using 18O labeling followed by LC-MS analysis. Molecular modeling and molecular dynamic simulation provide additional insight on the kinetics of Asp-succinimide formation and stability of succinimide intermediate. Findings of this work shed light on the molecular construct and the kinetics of the formation of isoAsp and succinimide in peptides and proteins, which facilitates analytical method development, protein engineering, and late phase development for commercialization of therapeutic proteins.

For chronic obstructive pulmonary disease (COPD), the role of physical activity in reducing COPD mortality and heart loading and in extending life expectancy remains unclear. Participants in comprehensive medical screening were recruited with spirometry on everyone. We analyzed physical activity volume calculated from intensity, duration and frequency of self-reported exercise history. Deaths were identified from the National Death File. The impacts of physical activity on mortality, heart rate and life expectancy were analyzed. Among the cohort of 483,603 adults, 32,535 had spirometry-determined COPD, indicating an adjusted national prevalence of 11.4% (male) and 9.8% (female). On the average, COPD increased all-cause mortality with a hazard ratio of 1.44 and loss of 6.0 years in life expectancy. Almost two thirds (65%) of the causes of deaths were extra-pulmonary, such as cardiovascular disease, diabetes, cancer and kidney diseases. In addition, COPD was associated with increases in heart rate proportionate to its severity, which led to higher mortality. Participants with COPD who were fully active physically could reduce mortality and have improved heart rates as compared with those without physical activity. In addition, their life expectancy could be extended close to those of the no COPD but inactive cohort. Fully active physical activity can help patients with COPD overcome most of the mortality risks, decrease heart rate, and achieve a life expectancy close to that of patients without COPD. The effectiveness of physical activity on COPD is facilitated by its systemic nature beyond lung disease.

Cardiopulmonary resuscitation (CPR) training and its quality are critical in improving the survival rate of cardiac arrest. This randomized controlled study investigated the efficacy of a newly developed CPR training program for the public in a Taiwanese setting. A total of 832 adults were randomized to either a traditional or blended (18-minute e-learning plus 30-minute hands-on) compression-only CPR training program. The primary outcome was compression depth. Secondary outcomes included CPR knowledge test, practical test, quality of CPR performance, and skill retention. The mean compression depth was 5.21 cm and 5.24 cm in the blended and traditional groups, respectively. The mean difference in compression depth between groups was −0.04 (95% confidence interval −0.13 to infinity), demonstrating that the blended CPR training program was non-inferior to the traditional CPR training program in compression depth after initial training. Secondary outcome results were comparable between groups. Although the mean compression depth and rate were guideline-compliant, only half of the compressions were delivered with adequate depth and rate in both groups. CPR knowledge and skill retained similarly in both groups at 6 and 12 months after training. The blended CPR training program was non-inferior to the traditional CPR training program. However, there is still room for improvement in optimizing initial skill performance as well as skill retention. Clinical Trial Registration: NCT03586752; www.clinicaltrial.gov

(1) Background: The association of sugar-sweetened beverages (SSBs) with cardiovascular disease (CVD) mortality in younger adults (age 20–39) is rarely mentioned in the literature. Younger adults are less vulnerable to CVDs, but they tend to consume more SSBs. This prospective study aimed to assess the association between CVD mortality and SSBs in younger adults between 1994 and 2017. (2) Methods: The cohort enrolled 288,747 participants consisting of 139,413 men and 148,355 women, with a mean age 30.6 ± 4.8 years, from a health surveillance program. SSBs referred to any drink with real sugar added, such as fructose corn syrup or sucrose. One serving of SSB contains about 150 Kcal of sugar in 12 oz of drink. Cox models were used to estimate the mortality risk. (3) Results: There were 391 deaths from CVDs in the younger adults, and the positive association with CVD mortality started when SSB intake was ≥2 servings/day (HR: 1.59, 95% CI: 1.16–2.17). With mortalities from diabetes and kidney disease added to CVDs, the so-called expanded CVD mortality risk was 1.49 (95% CI: 1.11–2.01). By excluding CVD risk factors (hypertension, diabetes, and smoking), the CVD mortality risk increased to 2.48 (95% CI: 1.33–4.62). The dose–response relationship persisted (p < 0.05 for trend) in every model above. (4) Conclusions: Higher intake of SSBs (≥2 servings/day) was associated with increased CVD mortality in younger adults. The younger adults (age 20–39) with SSB intake ≥2 servings/day had a 50% increase in CVD mortality in our study, and the mortality risk increased up to 2.5 times for those without CVD risk factors. The dose–response relationship between the quantity of SSB intake and the mortality risk of CVD in younger adults discourages SSB intake for the prevention of CVD mortality.

We investigated the effects of combination therapy albendazole and doxycycline in Angiostrongylus cantonensis-infected mice during early and late treatment. C57BL/6 and BALB/c mice were divided into five groups: (i) uninfected, (ii) infected with A. cantonensis, (iii) infected + 10 mg/kg albendazole, (iv) infected + 25 mg/kg doxycycline, and (v) infected + 10 mg/kg albendazole + 25 mg/kg doxycycline. We administered drugs in both early treatments started at 7-day post infections (dpi) and late treatments (14 dpi) to A. cantonensis-infected C57BL/6 and BALB/c mice. To assess the impact of these treatments, we employed the Morris water maze test to evaluate spatial learning and memory abilities, and the rotarod test to measure motor coordination and balance in C57BL/6 mice. Additionally, we monitored the expression of the cytokine IL-33 and GFAP in the brain of these mice using Western blot analysis. In this study, A. cantonensis infection was observed to cause extensive cerebral angiostrongyliasis in C57BL/6 mice. This condition significantly affected their spatial learning and memory abilities, as assessed by the Morris water maze test, as well as their motor coordination, which was evaluated using the rotarod test. Early treatment with albendazole led to favorable recovery outcomes. Both C57BL/6 and BALB/c mice express IL-33 and GFAP after co-therapy. The differences of levels and patterns of IL-33 and GFAP expression in mice may be influenced by the balance between pro-inflammatory and anti-inflammatory signals within the immune system. Combination therapy with anthelmintics and antibiotics in the early stage of A. cantonensis infection, in C57BL/6 and BALB/c mice resulted in the death of parasites in the brain and reduced the subsequent neural function damage and slowed brain damage and neurobehavior impairment. This study suggests a more effective and novel treatment, and drug delivery method for brain lesions that can decrease the neurological damage of angiostrongyliasis patients.

This study assesses the performance of National Early Warning Score (NEWS), Quick Sepsis-related Organ Failure Assessment (qSOFA), Modified Early Warning Score (MEWS), Rapid Emergency Medicine Score (REMS), and Rapid Acute Physiology Score (RAPS) in predicting emphysematous pyelonephritis (EPN) patients’ need for intensive care unit (ICU) admission. A retrospective analysis was conducted at four training and research hospitals’ emergency departments (EDs) on all EPN adult patients from January 2007 to August 2017. Data extracted were used to calculate raw scores for five physiologic scoring systems. Mann-Whitney U tests and χ 2 tests were done for numerical and categorical variables respectively to examine differences between characteristics of ICU and non-ICU patient populations. Predictability of ICU admission was evaluated with AUROC analysis. ICU patients had lower GCS scores, SpO2, platelet counts, and estimated glomerular filtration rate; and higher bands, blood urea nitrogen, creatinine, and incidences of septic shock and nephrectomy. NEWS performed best, with 73.85% accuracy at optimal cut-off of 3. In this multicentre ED EPN series, we recommend using NEWS in early identification of critical EPN patients and advance planning for ICU admission. This would reduce delays in ICU transfer and ultimately improve patient outcomes.

Aortoesophageal fistula (AEF) is an extremely rare cardiovascular etiology of hematemesis and upper gastrointestinal bleeding. As such, its recognition and diagnosis are challenging and may be delayed when such patients present to the emergency department (ED). Without timely surgical intervention, AEF is almost always fatal. Awareness of AEF as a possible diagnosis and consequently early identification of these patients presenting to the ED are therefore crucial in optimizing clinical outcomes. We report a 45-year-old male presenting to the ED with the classical triad of an AEF (Chiari's triad)—midthoracic pain or dysphagia, a sentinel episode of minor hematemesis, then massive hematemesis with risk of exsanguination. The case report highlights the importance of considering the differential diagnosis of AEF when evaluating patients presenting to the ED with hematemesis, especially if they have predisposing risk factors such as prior aortic or esophageal surgeries, aortic aneurysms, or thoracic malignancies. Patients suspected of having AEF should be prioritized for early computed tomography angiography to expedite diagnosis and treatment.

This study aims to evaluate the performance of Rapid Emergency Medicine Score (REMS), Rapid Acute Physiology Score (RAPS), and Modified Early Warning Score (MEWS) in ascertaining the severity of illness and predicting the mortality of adult hepatic portal venous gas (HPVG) patients presenting to the emergency department (ED). This will assist emergency physicians (EPs) in risk stratification. Data for 66 adult HPVG patients who visited the EDs of 2 research hospitals between October 1999 and April 2016 were analyzed. REMS, RAPS, and MEWS were calculated based on data in the ED, and probability of death was calculated for each patient based on these scores. The ability of REMS, RAPS, and MEWS to predict group mortality was assessed by using receiver operating characteristic (ROC) curve analysis and calibration analysis. The sensitivity, specificity, and accuracy for each scoring system were 92.1%, 89.3%, and 90.9% for REMS, 86.8%, 82.1%, and 84.8% for RAPS, and 78.9%, 89.3%, and 83.3% for MEWS respectively. In the ROC curve analysis, the areas under the curve for REMS, RAPS, and MEWS were 0.929, 0.877, and 0.856 respectively. Our study is the largest series performed in a population of adult HPVG patients in the ED. The results from this study demonstrate that REMS is superior in predicting the mortality of these patients compared to RAPS and MEWS. We therefore recommend that REMS be used for outcome prediction and risk stratification of adult HPVG in the ED.

Modest drinking has been repeatedly discussed in scientific papers as protective against certain diseases, such as cardiovascular diseases, but in most cases, alcohol worsens health conditions, especially when consumed at high risk levels. The complexity of the risk relationship between alcohol and health conditions has confused clinicians as to whether it should be recommended. The study aims to balance the risks and benefits of modest drinking. This retrospective cohort study of 430,016 adults recruited from a standard health-screening program since 1994, with 11,031 deaths identified as of 2008. Drinking distinguished “modest drinker” (no more than one drink a day) from “regular drinker”. Mortality risks including all-cause mortality and diseases-specific mortality with hazard ratio (HR) were calculated by adjusting for 15 confounders. Life table was used for life expectancy. Risk predictors were subjected to Cox proportional hazards regression analysis to identify significant predictors in multivariate models and life expectancy analysis. Nearly one out of 4 males (23%) was a modest drinker, who gained 0.94 year (95% CI 0.65–1.23 year) in life over non-drinker and had 8% reduction in adjusted all-cause mortality (HR 0.92, 95% CI 0.86–0.97). In contrast, regular drinkers had 43% increase in overall mortality (HR 1.43, CI 1.35–1.52) and shortened life by 6.9 years (95% CI 6.6–7.1 years). As most drinkers also smoked, 59% in modest and 75% in regular, the combined effect shortened life by 2.0 years (95% CI 1.6–2.4 years) in modest drinker and 10.3 years (95% CI 9.8–10.7 years) in regular drinker. Cancer were increased in modest drinkers for oral (HR 2.35, CI 1.38–4.01) and esophageal (HR 3.83, CI 1.90–7.73) cancer. The gain of one year by modest drinkers was erased by a two to fourfold increase in oral and esophageal cancer and that drinking beyond modest amount led to a large loss of life expectancy. Given that drinkers are prone to cross the line of drinking, clinicians should balance the risks and benefits of drinking, as well as the understanding of whether the patient is at risk for addiction.

Purpose: To develop and internally validate a novel prediction score to predict the occurrence of arterial–esophageal fistula (AEF) in esophageal cancer bleeding. Methods: This retrospective cohort study enrolled patients with esophageal cancer bleeding in the emergency department. The primary outcome was the diagnosis of AEF. The patients were randomly divided into a derivation group and a validation group. In the derivation stage, a predictive model was developed using logistic regression analysis. Subsequently, internal validation of the model was conducted in the validation cohort during the validation stage to assess its discrimination ability. Results: A total of 257 patients were enrolled in this study. All participants were randomized to a derivation cohort (n = 155) and a validation cohort (n = 102). AEF occurred in 22 patients (14.2%) in the derivation group and 14 patients (13.7%) in the validation group. A predictive model (HEARTS-Score) comprising five variables (hematemesis, active bleeding, serum creatinine level >1.2 mg/dL, prothrombin time >13 s, and previous stent implantation) was established. The HEARTS-Score demonstrated a high discriminative ability in both the derivation and validation cohorts, with c-statistics of 0.90 (95% CI 0.82–0.98) and 0.82 (95% CI 0.72–0.92), respectively. Conclusions: By employing this novel prediction score, clinicians can make more objective risk assessments, optimizing diagnostic strategies and tailoring treatment approaches.