Non-organ-specific autoantibodies in Indian patients with chronic liver disease

Background

Autoantibody testing is used to diagnose autoimmune hepatitis (AIH), a cause of chronic liver disease (CLD). However, various autoantibodies are often detectable in patients with CLD due to other causes too. Since data on autoantibody prevalence in Indian patients with CLD are limited, we decided to undertake the current study.

Methods

Patients with CLD with a known cause other than AIH and a separate group of patients with CLD in whom no cause could be identified were studied. Indirect immunofluorescence assays were used to detect anti-nuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA) and anti-liver-kidney microsomal antibodies (anti-LKM). Serum dilutions tested were 1:80 for ANA and 1:40 for other autoantibodies.

Results

Of the 175 patients with CLD of a known cause, 69 (39?%) had one or more autoantibodies, including ANA in 35 (20?%) patients and ASMA in 44 (25?%) patients. None had anti-LKM. The prevalence rates of any autoantibody, ANA and ASMA were similar in patients with CLD due to alcohol (34?%, 20?%, and 24?%, respectively), HCV infection (43?%, 20?%, and 26?%) and HBV infection (40?%, 18?%, and 25?%). The most common ANA pattern observed was speckled (29/35 patients), followed by nucleolar (5/35) and homogeneous (1/35). The ASMA titers did not exceed 1:80. The antibody prevalence rates were similar in patients with liver cirrhosis and chronic hepatitis, and in those with different disease severity. Serum IgG levels were similar in patients with and without detectable autoantibodies. Patients with no known cause of CLD (n?=?50) had similar prevalence rates of autoantibodies, ANA or ASMA.

Conclusion

Autoantibodies were detected in a large proportion of patients with CLD, both cryptogenic and with known cause. Detection of autoantibodies in CLD does not necessarily indicate a diagnosis of AIH, and presence of homogenous pattern of ANA may be more relevant. Indiscriminate testing for autoantibodies in patients with CLD, especially those with a known cause, may not be warranted.     

Rating a Sports Medicine Surgeon’s “Quality” in the Modern Era: an Analysis of Popular Physician Online Rating Websites

Background

Consumer-driven healthcare and an increasing emphasis on quality metrics have encouraged patient engagement in the rating of healthcare. As such, online physician rating websites have become mainstream and may play a potential role in future healthcare policy.

Questions/Purposes

The purpose of this study was to evaluate online patient ratings for US sports medicine surgeons, determine predictors of positive ratings and analyze for inter-website scoring correlation.

Methods

The American Orthopedic Society for Sports Medicine (AOSSM) member directory was sampled. Surgeon demographic and rating data were searched on three online physicians rating websites: HealthGrades.com (HG), RateMDs.com (RM) and Vitals.com (V). Written rating comments were categorized as relating to the following: surgeon competence, surgeon affability and process of care. Bivariate linear regression, Pearson correlation and multivariable analyses were used to determine factors associated with positive ratings.

Results

Two hundred seventy-five sports medicine surgeons were included. Two hundred seventy-one (99%) had ratings on at least one of the three websites. Sports surgeons were rated highly across all three websites (mean >4.0/5); however, there was only a low to moderate degree of correlation among websites. On HG, female surgeons and surgeons in academia were more likely to receive higher overall ratings. Across all three websites, increased number of years in practice inversely correlated with ratings; this relationship neared significance for HG and was significant for RM. A surgeon’s online presence or geographic location was not associated with higher ratings. In multivariable regression analysis for ratings on HG, female sex was the only significant predictor of higher ratings. Two thousand three hundred forty-one written comments were analyzed: perceived surgeon competence and communication influenced the direction of ratings for the top and bottom tier surgeons.

Conclusion

There was a low degree of correlation among online websites for surgeon ratings. Female surgeons and those with fewer years in practice appear to have higher ratings on these websites; comment content analysis suggests that high and low ratings are influenced by perceived surgeon competence and affability.

     

Interaction between sleep and the immune response in Drosophila: a role for the NFkappaB relish

STUDY OBJECTIVES: The regulation of sleep is poorly understood. While some molecules, including those involved in inflammatory/immune responses, have been implicated in the control of sleep, their role in this process remains unclear. The Drosophila model for sleep provides a powerful system to identify and test the role of sleep-relevant molecules. DESIGN: We conducted an unbiased screen for molecular candidates involved in sleep regulation by analyzing genome-wide changes in gene expression associated with sleep deprivation in Drosophila. To further examine a role of immune-related genes identified in the screen, we performed molecular assays, analysis of sleep behavior in relevant mutant and transgenic flies, and quantitative analysis of the immune response following sleep deprivation. RESULTS: A major class of genes that increased expression with sleep deprivation was that involved in the immune response. We found that immune genes were also upregulated during baseline conditions in the cyc01 sleep mutant. Since the expression of an NFkappaB, Relish, a central player in the inflammatory response, was increased with all manipulations that reduced sleep, we focused on this gene. Flies deficient in, but not lacking, Relish expression exhibited reduced levels of nighttime sleep, supporting a role for Relish in the control of sleep. This mutant phenotype was rescued by expression of a Relish transgene in fat bodies, which are the major site of inflammatory responses in Drosophila. Finally, sleep deprivation also affected the immune response, such that flies deprived of sleep for several hours were more resistant to bacterial infection than those flies not deprived of sleep. CONCLUSION: These results demonstrate a conserved interaction between sleep and the immune system. Genetic manipulation of an immune component alters sleep, and likewise, acute sleep deprivation alters the immune response.     

The Properties of Cysteine-Conjugated Antibody-Drug Conjugates Are Impacted by the IgG Subclass

Among the numerous antibody-drug conjugate (ADC) clinical candidates, one of the most prevalent types utilizes the interchain cysteines in antibodies to conjugate auristatin via a maleimide-containing linker. In this class of ADCs, there are a paucity of systematic studies characterizing how IgG subclass influences the biophysical properties and in vivo pharmacokinetics of the ADC molecules. In the current investigation, we studied cysteine-conjugated ADCs using a model system consisting of human IgG1, IgG2, and IgG4 antibodies with the same variable region. Our findings identified some unforeseen differences among the three ADCs. Drug conjugation profiling by LC-MS revealed that 50% of inter heavy-light chain disulfide bonds are disrupted to conjugate drugs in IgG1 antibody while only 10% in IgG2 antibody and 20% in IgG4 antibody. The solution behavior of the ADCs was interrogated in concentrating experiments and diffusion interaction parameter measurements. We found that drug conjugation affected the solution property of the three antibodies differently, with the IgG2-based ADC having the most increased propensity to aggregate. Rat PK studies using a sensitive LC-MS-based bioanalytical method showed that the IgG1-based ADC has poor peripheral linker-payload stability while the IgG2- and IgG4-based ADCs are stable. The conjugate stability of the IgG2-based ADC was further confirmed in a cynomolgus monkey PK study. Overall, the IgG2-based ADC exhibited the best PK/conjugate stability but also the most deterioration in stability among the three ADCs. Our findings provide important information and present multifactorial considerations for the selection of IgG subclass during ADC drug discovery when employing stochastic cysteine conjugation.     

An optimal control model for cloud seeding in a deterministic and stochastic environment

To promote artificial rain in India and other such developing countries, in this article, we have proposed and analyzed a nonlinear mathematical model for cloud seeding by considering that aerosols are introduced proportional to the density of water vapors present in the atmosphere. The model is analyzed using Lyapunov's stability theory of differential equations. To reduce the cost of cloud seeding, an optimal control strategy is designed by incorporating four control parameters. We have shown the existence and uniqueness of solution of this optimal control problem, using Pontryagins Maximum Principle. To minimize the cost in making artificial rain, the optimal control problem provides the strategy for the rate of introduction of aerosols in the atmosphere. To capture the effects of environmental noise on control strategies, the model in deterministic framework is converted into stochastic framework. In this regard, the Hamilton-Jacobi-Bellman equation for stochastic control cost function has been formed. The stochastic analysis implies that the control strategy is effective in reducing the cost and increasing rainfall.