Severe acute respiratory syndrome-associated coronavirus 2 is a major global health issue and is driving the need for new therapeutics.The surface spike protein,which plays a central role in virus infection,is currently the target for vaccines and neutralizing treatments.The emergence of novel variants with multiple mutations in the spike protein may reduce the effectiveness of neutralizing antibodies by altering the binding activity of the protein with angiotensin-converting enzyme 2(ACE2).To understand the impact of spike protein mutations on the binding interactions required for virus infection and the effectiveness of neutralizing monoclonal antibody(mAb)therapies,the binding activities of the original spike protein receptor binding domain(RBD)sequence and the reported spike protein variants were investigated using surface plasmon resonance.In addition,the interactions of the ACE2 receptor,an anti-spike mAb(mAb1),a neutralizing mAb(mAb2),the original spike RBD sequence,and mutants D614G,N501Y,N439K,Y453F,and E484K were assessed.Compared to the original RBD,the Y453F and N501Y mutants displayed a significant increase in ACE2 binding affinity,whereas D614G had a substantial reduction in binding affinity.All mAb-RBD mutant proteins displayed a reduction in binding affinities relative to the original RBD,except for the E484K-mAb1 interaction.The potential neutralizing capability of mAb1 and mAb2 was investigated.Accordingly,mAb1 failed to inhibit the ACE2-RBD interaction while mAb2 inhibited the ACE2-RBD interactions for all RBD mutants,except mutant E484K,which only dis-played partial blocking.

BACKGROUND: This study aimed to determine whether modified shock index (MSI) is associated with mortality that is superior to heart rate, blood pressure, or the shock index (SI) in emergency patients.METHODS: A retrospective database review was performed on 22161 patients who presented to Peking Union Medical College Hospital Emergency Department and received intravenous fluids from January 1 to December 31, 2009. We gathered data of the patients on age, gender, vital signs, levels of consciousness, presenting complaints, and SI and MSI were calculated for all patients.RESULTS: Multivariate regression analysis was performed to determine the correlation between risk factors and outcome. There is a significant correlation between emergency patient mortality rate and patient's vital signs obtained at the triage desk (HR>120 beats/min, systolic BP<90 mmHg, diastolic BP<60 mmHg). MSI is a stronger predictor of emergency patient mortality compared to heart rate and blood pressure alone, whereas SI does not have a significant correlation with emergency patient mortality rate.CONCLUSION: MSI is a clinically significant predictor of mortality in emergency patients. It may be better than using heart rate and blood pressure alone. SI is not significantly correlated with the mortality rate of the emergency patient.

OBJECTIVES: Screening for colorectal cancer is considered cost effective, but is underutilized in the U.S. Information on the efficiency of "tailored interventions" to promote colorectal cancer screening in primary care settings is limited. The paper reports the results of a cost effectiveness analysis that compared a survey-only control group to a Centers for Disease Control (CDC) web-based intervention (screen for life) and to a tailored interactive computer-based intervention. METHODS: A randomized controlled trial of people 50 and over, was conducted to test the interventions. The sample was 1224 partcipants 50-70 years of age, recruited from Kelsey-Seybold Clinic, a large multi-specialty clinic in Houston, Texas. Screening status was obtained by medical chart review after a 12-month follow-up period. An "intention to treat" analysis and micro costing from the patient and provider perspectives were used to estimate the costs and effects. Analysis of statistical uncertainty was conducted using nonparametric bootstrapping. RESULTS: The estimated cost of implementing the web-based intervention was $40 per person and the cost of the tailored intervention was $45 per person. The additional cost per person screened for the web-based intervention compared to no intervention was $2602 and the tailored intervention was no more effective than the web-based strategy. CONCLUSIONS: The tailored intervention was less cost-effective than the web-based intervention for colorectal cancer screening promotion. The web-based intervention was less cost-effective than previous studies of in-reach colorectal cancer screening promotion. Researchers need to continue developing and evaluating the effectiveness and cost-effectiveness of interventions to increase colorectal cancer screening.
Aged ; Colorectal Neoplasms/*diagnosis ; Cost-Benefit Analysis ; Early Detection of Cancer/*economics/*methods ; Female ; Health Promotion/*methods ; Humans ; *Internet ; Male ; Middle Aged ; Primary Health Care/organization & administration ; United States

Monoclonal antibodies (mAbs) have been widely used as therapeutic drugs for treating diseases such as cancers and auto-immune diseases. When using an IgG4 isotype, one of the challenges is the instability of its hinge which is prone to Fab-arm exchange (FAE). The hinge sequence of a wild type IgG4 is -CPSC-, however, a single point mutation S228P from -CPSC- to -CPPC- can effectively diminish FAE, thereby improving hinge stability of the IgG4 molecule. Sintilimab is the fully human anti-PD-1 monoclonal antibody designed and developed for immuno-oncology, in which serine 228 in the hinge was engineered to proline to mitigate FAE. In this study, LC-MS is used to study hinge stability of sintilimab in both in vitro (PBS and human serum) and in vivo (SCID mouse) studies. The studies demonstrate that LC-MS is a fast and simple way to monitor for the occurrence of FAE in vitro and in vivo, and FAE can be eliminated by antibody engineering with a single point mutation.

Background: and Purpose Infarct volume and other imaging markers are increasingly used as surrogate measures for clinical outcome in acute ischemic stroke research, but how improvements in these imaging surrogates translate into better clinical outcomes is currently unclear. We investigated how changes in infarct volume at 24 hours alter the probability of achieving good clinical outcome (modified Rankin Scale [mRS] 0–2). Methods: Data are from endovascular thrombectomy patients from the randomized controlled ESCAPE-NA1 (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischaemic Stroke) trial. Infarct volume at 24 hours was manually segmented on non-contrast computed tomography or diffusion-weighted magnetic resonance imaging. Probabilities of achieving good outcome based on infarct volume were obtained from a multivariable logistic regression model. The probability of good outcome was plotted against infarct volume using linear spline regression. Results: A total of 1,099 patients were included in the analysis (median final infarct volume 24.9 mL [interquartile range: 6.6–92.2]). The relationship between total infarct volume and good outcome probability was nearly linear for infarct volumes between 0 mL and 250 mL. In this range, a 10% increase in the probability of achieving mRS 0–2 required a decrease in infarct volume of approximately 34.0 mL (95% confidence interval: -32.5 to -35.6). At infarct volumes above 250 mL, the probability of achieving mRS 0–2 probability was near zero. The relationships of tissue-specific infarct volumes and parenchymal hemorrhage volume generally showed similar patterns, although variability was high. Conclusion There seems to be a near-linear association between total infarct volume and probability of achieving good outcome for infarcts up to 250 mL, whereas patients with infarct volumes greater than 250 mL are highly unlikely to have a favorable outcome.