Multidisciplinary approaches to combat emerging viruses: diagnostics, therapeutic gene and vaccine delivery, and nanotherapeutics.

Emerging viruses, such as filoviruses (Ebola, Marburg), SARS and MERS coronaviruses, and Zika, pose significant threats to global public health, particularly for individuals with co-morbidities. To address these challenges, this review article explores multidisciplinary strategies for combatting emerging viruses. We emphasize the importance of developing accurate diagnostics, innovative therapeutic gene and vaccine delivery systems, and long-acting nanotherapeutics. These approaches are designed to enhance the safety and efficacy of treatments against these deadly pathogens. We discuss the collaborative efforts of virologists, geneticists, formulation scientists, clinicians, immunologists, and medicinal chemists in advancing these therapeutic modalities.

Chemical reagents for the enrichment of modified peptides in MS-based identification.

Chemical reagents with special groups as enrichable handles have empowered the ability to label and enrich modified peptides. Here is an overview of different chemical reagents with affinity tags to isolate labeled peptides and the latest developments of enrichment strategies. Biotin is the most used affinity tag due to its high interaction with avidin. To decrease the unfavorable influence of biotin for its poor efficiency in ionization and fragmentation in downstream MS analysis, cleavable moieties were installed between the reactive groups and biotin to release labeled peptides from the biotin. To minimize the steric hindrance of biotin, a two-step method was developed, for which alkyne- or azide-tagged linkers were firstly used to label peptides and then biotin was installed through click chemistry. Recently, new linkers using a small phosphonic acid as the affinity tag for IMAC or TiO2 enrichment have been developed and successfully used to isolate chemically labeled peptides in XL-MS. A stable P-C instead of P-O bond was introduced to linkers to differentiate labeled and endogenous phosphopeptides. Furthermore, a membrane-permeable phosphonate-containing reagent was reported, which facilitated the study of living systems. Taking a cue from classic chemical reactions, stable metal-complex intermediates, including cobalt and palladium complexes, have been developed as peptide purification systems. Advanced enrichment strategies have also been proposed, such as the two-stage IMAC enrichment method and biotin-based two-step reaction strategy, allowing the reduction of unwanted peptides and improvements for the analysis of specific labeled peptides. Finally, future trends in the area are briefly discussed.

Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.

Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways.

Association between circadian body temperature rhythm during the first 24 hours of ICU stay and 28-day mortality in elderly critically ill patients: A retrospective cohort study.

Disrupted circadian temperature rhythm is commonly observed in elderly patients in the intensive care unit (ICU), but the association between circadian temperature rhythm and mortality in elderly patients is unclear. Adult patients with a relatively complete record of body temperature (BT) during the first 24 hours of ICU stay in the Multi-parameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database were included in this retrospective cohort study. The circadian rhythm of body temperature was blunted as a ratio of the maximum BT between 12:00 and 24:00 divided by the minimum BT between 0:00 and 12:00, and we defined it as BT fluctuation ratio. The associations of BT fluctuation ratio with 28-day mortality were assessed separately using Cox proportional hazards model in elderly patients and non-elderly patients. The overall cohort comprised 12 767 patients. After adjusting for covariates, the analysis showed that the BT fluctuation ratio (%) was significantly associated with mortality at 28 days in total patients (hazard ratio: 1.044; 95% CI 1.001-1.088; P = 0.042), and still significantly in elderly patients (hazard ratio 1.055, 95% CI as 1.004-1.109, p = 0.035), but not significantly in non-elderly patients. The implementation of restricted cubic splines demonstrated a nonlinear correlation between the ratio of BT fluctuation and the hazard ratio of 28-day mortality, indicating that increased diurnal temperature fluctuations are linked to elevated risk of mortality. This study revealed that the augmented amplitude of the circadian rhythm of body temperature in the elderly patients constitutes a risk factor for the rise of 28-day mortality. Additionally, the circadian body temperature rhythm may facilitate the early detection of critically ill elderly patients.

Clinical Effect of Electroacupuncture on Acute Pancreatitis: Efficacies and Mechanisms.

Acute pancreatitis (AP) is a common acute abdomen and the number one cause of acute digestive hospitalizations in the United States. Abdominal pain is the main clinical manifestation of abdominal symptoms, so reducing the abdominal symptoms caused by inflammation is very important to alleviate the pain of patients. Electroacupuncture (EA) as a traditional Chinese medicine (TCM) therapy has significant conditioning effects on various inflammatory diseases including AP. Continuous studies in recent years have shown that EA conditioning has significant effects on reducing inflammation and regulating gastrointestinal symptoms in AP. At the same time, there is sufficient evidence to further elucidate the mechanism of EA. In this review, we will summarize the effect of EA on AP and its mechanism, so as to better serve clinical practice in the treatment of AP in the future.

Potential value of neuroimmunotherapy for COVID-19: efficacies and mechanisms of vagus nerve stimulation, electroacupuncture, and cholinergic drugs.

COVID-19 is an inflammatory disease with multiple organs involved, mainly respiratory symptoms. Although the majority of patients with COVID-19 present with a mild to moderate self-limited course of illness, about 5-10% of patients with inflammatory disorders in severe COVID-19 have life-threatening progression. With the exception of a few drugs that have shown outstanding anti-COVID-19 effects, the efficacy of most drugs remains controversial. An increasing number of animal and clinical studies have shown that neuromodulation has a significant effect on reducing inflammatory markers of COVID-19, thus exerting an effective neuroimmunotherapeutic value. Currently, the main neuroimmunomodulatory measures effective against COVID-19 include vagus nerve stimulation, electroacupuncture, and cholinergic drugs. In this review, we will summarize the research progress of potential value of this neuroimmunotherapy measures for COVID-19 and elaborate its efficacies and mechanisms, in order to provide reliable evidence for clinical intervention.

Electroacupuncture in Regulating Gastrointestinal Symptoms of COVID-19: A Mini-review.

Nearly three years into the COVID-19 pandemic, there is still no effective treatment. In the meantime, more and more evidence indicate that gastrointestinal symptoms are important manifestations of COVID-19. Therefore, the involvement of multiple system symptoms brings a lot of burden and harm to patients. To our knowledge, traditional Chinese medicine (TCM) has a remarkable effect on improving gastrointestinal function. In particular, a considerable number of clinical practices during the pandemic have demonstrated the significant value of electroacupuncture (EA) in regulating the gastrointestinal function of COVID-19. In summary, EA can regulate the gastrointestinal function of COVID-19. As more is learned about EA, its potential value in COVID-19 deserves further consideration. In this review, we will elucidate the potential efficacy and mechanism of EA in the treatment of gastrointestinal symptoms of COVID-19.

Association of demographic and clinical factors with risk of acute pancreatitis: An exposure-wide Mendelian randomization study.

BACKGROUND: The incidence of acute pancreatitis (AP) is increasing over years, which brings enormous economy and health burden. However, the aetiologies of AP and underlying mechanisms are still unclear. Here, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations between all reported possible risk factors and AP using publicly available genome-wide association study summary statistics. METHODS: A series of quality control steps were taken in our analysis to select eligible instrumental single nucleotide polymorphisms which were strongly associated with exposures. To make the conclusions more robust and reliable, we utilized several analytical methods (inverse-variance weighting, MR-PRESSO method, weighted median, MR-Egger regression) that are based on different assumptions of two-sample MR analysis. The MR-Egger intercept test, radial regression and leave-one-out sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on each exposure. A two-step MR method was applied to explore mediators in significant associations. RESULTS: Genetic predisposition to cholelithiasis (effect estimate: 17.30, 95% CI: 12.25-22.36, p = 1.95 E-11), body mass index (0.32, 95% CI: 0.13-0.51, p < 0.001), body fat percentage (0.57, 95% CI: 0.31-0.83, p = 1.31 E-05), trunk fat percentage (0.36, 95% CI: 0.14-0.59, p < 0.005), ever smoked (1.61, 95% CI: 0.45-2.77, p = 0.007), and limbs fat percentage (0.55, 95% CI: 0.41-0.69, p < 0.001) were associated with an increased risk of AP. In addition, whole-body fat-free mass (-0.32, 95% CI: -0.55 to -0.10, p = 0.004) was associated with a decrease risk of AP. CONCLUSION: Genetic predisposition to cholelithiasis, obesity and smoking could be causally associated with an increased risk of AP, and whole body fat-free mass could be associated with a decreased risk of AP.

Viral pancreatitis: research advances and mechanisms.

Acute pancreatitis is caused by trypsinogen activation in acinar cells caused by various injury forms (gallstone, high triglycerides, alcohol, etc.). Viral pancreatitis is a clinically rare disease type, which is easily neglected by clinicians and causes serious adverse consequences. Viral pancreatitis involves the entry of viruses into pancreatic cells, triggering inflammation, immune response activation, and enzymatic autodigestion, leading to tissue damage and potential complications. At present, there are few available reports on viral pancreatitis, most of which are case reports. This review brings attention to clinicians by describing the incidence of viral pancreatitis to enhance clinical understanding and patient care.

New-onset diabetes secondary to acute pancreatitis: An update.

Diabetes is a condition of persistent hyperglycemia caused by the endocrine disorder of the pancreas. Therefore, all pancreatic diseases have the risk of diabetes. In particular, increasing attention has been paid recently to new-onset diabetes secondary to acute pancreatitis (AP). The complications of secondary diabetes have caused a lot of trouble for patients and have garnered increasing attention. At present, the pathophysiological mechanism of new-onset diabetes caused by AP is not clear. This review summarizes the current understanding of new-onset diabetes secondary to AP.

GPIHBP1 autoantibody is an independent risk factor for the recurrence of hypertriglyceridemia-induced acute pancreatitis.

BACKGROUND: GPIHBP1, a glycolipid-anchored protein of capillary endothelial cells, is a crucial partner for lipoprotein lipase (LPL) in plasma triglyceride metabolism. GPIHBP1 autoantibodies block LPL binding to GPIHBP1 and lead to severe hypertriglyceridemia (HTG) and HTG-induced acute pancreatitis (HTG-AP). We sought to define the incidence of GPIHBP1 autoantibodies in patients with HTG-AP. OBJECTIVE: We determined the incidence of GPIHBP1 autoantibody in HTG-AP patients, and compared the clinical features and long-term outcomes between GPIHBP1 autoantibody-positive and negative groups. METHODS: An enzyme-linked immunosorbent assay was used to screen for GPIHBP1 autoantibody in 116 HTG-AP patients hospitalized from Jan 1, 2015 to Aug 31, 2019. All patients were followed up for 24 months. The primary outcome was the recurrence rate of HTG-AP during the two-year follow-up period. The incidence of recurrent episodes was analyzed by the Kaplan-Meier method and multivariable Cox regression was used to identify risk factors. RESULTS: GPIHBP1 autoantibodies were present in 17 of 116 study patients (14.66%). The 2-year recurrence rate of HTG-AP was much higher in the GPIHBP1 autoantibody-positive group (35%, 6 in 17) than in the negative group (4%, 4 in 99). The multivariable Cox regression analysis showed that GPIHBP1 autoantibody was an independent risk factor for HTG-AP recurrence in two years. CONCLUSIONS: The presence of GPIHBP1 autoantibody is common in patients with HTG-AP, and is an independent risk factor for two-year recurrence of HTG-AP.

Dose-response relationship between risk factors and incidence of COVID-19 in 325 hospitalized patients: A multicenter retrospective cohort study.

BACKGROUND: The epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19) patients have been widely reported, but the assessment of dose-response relationships and risk factors for mortality and severe cases and clinical outcomes remain unclear. AIM: To determine the dose-response relationship between risk factors and incidence of COVID-19. METHODS: In this retrospective, multicenter cohort study, we included patients with confirmed COVID-19 infection who had been discharged or had died by February 6, 2020. We used multivariable logistic regression and Cox proportional hazard models to determine the dose-response relationship between risk factors and incidence of COVID-19. RESULTS: It clarified that increasing risk of in-hospital death were associated with older age (HR: 1.04, 95%CI: 1.01-1.09), higher lactate dehydrogenase [HR: 1.04, 95% confidence interval (CI): 1.01-1.10], C-reactive protein (HR: 1.10, 95%CI: 1.01-1.23), and procalcitonin (natural log-transformed HR: 1.88, 95%CI: 1.22-2.88), and D-dimer greater than 1 µg/mL at admission (natural log transformed HR: 1.63, 95%CI: 1.03-2.58) by multivariable regression. D-dimer and procalcitonin were logarithmically correlated with COVID-19 mortality risk, while there was a linear dose-response correlation between age, lactate dehydrogenase, D-dimer and procalcitonin, independent of established risk factors. CONCLUSION: Higher lactate dehydrogenase, D-dimer, and procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality.

A time-incorporated SOFA score-based machine learning model for predicting mortality in critically ill patients: A multicenter, real-world study.

BACKGROUND: Organ dysfunction (OD) assessment is essential in intensive care units (ICUs). However, current OD assessment scores merely describe the number and the severity of each OD, without evaluating the duration of organ injury. The objective of this study is to develop and validate a machine learning model based on the Sequential Organ Failure Assessment (SOFA) score for the prediction of mortality in critically ill patients. MATERIAL AND METHODS: Data from the eICU Collaborative Research Database and Medical Information Mart for Intensive Care (MIMIC) -III were mixed for model development. The MIMIC-IV and Nanjing Jinling Hospital Surgical ICU database were used as external test set A and set B, respectively. The outcome of interest was in-ICU mortality. A modified SOFA model incorporating time-dimension (T-SOFA) was stepwise developed to predict ICU mortality using extreme gradient boosting (XGBoost), support vector machine, random forest and logistic regression algorithms. Time-dimensional features were calculated based on six consecutive SOFA scores collected every 12 h within the first three days of admission. The predictive performance was assessed with the area under the receiver operating characteristic curves (AUROC) and calibration plot. RESULTS: A total of 82,132 patients from the real-world datasets were included in this study, and 7,494 patients (9.12%) died during their ICU stay. The T-SOFA M3 that incorporated the time-dimension features and age, using the XGBoost algorithm, significantly outperformed the original SOFA score in the validation set (AUROC 0.800 95% CI [0.787-0.813] vs. 0.693 95% CI [0.678-0.709], p < 0.01). Good discrimination and calibration were maintained in the test set A and B, with AUROC of 0.803, 95% CI [0.791-0.815] and 0.830, 95% CI [0.789-0.870], respectively. CONCLUSIONS: The time-incorporated T-SOFA model could significantly improve the prediction performance of the original SOFA score and is of potential for identifying high-risk patients in future clinical application.

Nonthyroidal illness syndrome in acute pancreatitis patients: an 8-year cohort study.

BACKGROUND: Nonthyroidal illness syndrome (NTIS) is common in critical illness and is associated with poor prognosis. The aim of this study was to find the prevalence, charateristics, and prognosis of NTIS and its correlation with outcomes in AP patients. METHODS: A retrospective review of AP patients with a diagnosis of NTIS from Jan 2012 to September 2020 was performed. The serum thyroidal hormone (TH) disturbances, as well as the demographic characteristics and clinical outcomes of the study patients, were collected and analyzed. RESULTS: Over the eight years, 183 included AP patients were diagnosed as NTIS, constituting an incidence of 64.7%. Patients with NTIS were admitted with worse condition based on the higher APACHE II score, SOFA score, Balthazar's CT score, CRP and lower albumin than euthyroid patients. Also, these patients had a longer ICU duration (3, 2-10 vs 2, 0-3, days, P = 0.039) and tended to be more likely to develop infected pancreatic necrosis (IPN) (15.3% vs 6.3%, P = 0.087) and gastrointestinal fistula (6% vs 0%, P = 0.082) than euthyroid patients. Free triiodothyronine (FT3) was found the best performance in predicting death compared by other well-recognized biomarkers. CONCLUSION: NTIS is common in AP patients within 7 days after the onset of the disease. NTIS is associated with the worse characteristics at admission and poor outcome during the course. FT3 should be investigate as a potential biomarker in the prediction of death in AP patients.

Predictive value of serum cholinesterase in the mortality of acute pancreatitis: A retrospective cohort study.

BACKGROUND: Severe acute pancreatitis has a high mortality of 20%-40%, but there is a lack of optimal prognostic biomarker for the severity of acute pancreatitis (AP) or mortality. This study is designed to investigate the relationship between serum cholinesterase (ChE) level and poor outcomes of AP. METHODS: A total of 1904 AP patients were screened in the study, and we finally got 692 patients eligible for analysis. Patients were divided into 2 groups based on serum ChE. The primary outcome was mortality, and multivariable logistic regression analysis for mortality was completed. Additionally, we used receiver operating characteristic (ROC) curve analysis to clarify the predictive value of serum ChE for mortality and organ failure. RESULTS: Three hundred and seventy eight patients and 314 patients were included in the ChE-low and ChE-normal group, respectively. Patients in the ChE-low group were older (46.68 ± 12.70 vs. 43.56 ± 12.13 years old, p = .001) and had a lower percentage of man (62.4% vs. 71.0%, p = .017) when compared to the ChE-normal group. Mortality was significantly different in two groups (10.3% vs. 0.0%, p < .001). Moreover, organ failure also differed significantly in two groups (46.6% vs. 8.6%, p < .001). Decreased ChE level was independently associated with mortality in acute pancreatitis (odds ratio: 0.440; 95% confidence interval, 0.231, 0.838, p = .013). The area under the curve of serum ChE was 0.875 and 0.803 for mortality and organ failure, respectively. CONCLUSIONS: Lower level of serum ChE was independently associated with the severity and mortality of AP.

Letter to editor: One case of congenital dorsal penile cutaneous fistula.

Congenital cutaneous fistula in the pubic area in infants and young children is a very rare congenital dysplasia disease, mainly manifested by abnormal punctiform opening near the midline of the area. What we are going to describe is a case of a 2-month-old boy with a congenital dorsal penile cutaneous fistula. At first, the main manifestation was pus at the opening of the fistula. The child recovered well after surgery without obvious complications.