Phenotypes of sickle cell intensive care admissions: an unsupervised machine learning approach in a single-center retrospective cohort

Annals of Hematology - Sickle cell disease (SCD) is associated with multiple known complications and increased mortality. This study aims to further understand the profile of intensive care unit...     

Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.     

Predictors of relapse in patients with major depressive disorder in a 52-week,fixed dose,double blind,randomized trial of selegiline transdermal system (STS)

Objective

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment.

Method

After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse.

Results

For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis.

Conclusions

While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD.     

Effect of zinc treatment on clinical outcomes in patients with liver cirrhosis:A systematic review and meta-analysis

BACKGROUND Zinc is an essential trace element integral to many cellular and immune functions. Zinc deficiency is highly prevalent in patients with cirrhosis and related to disease severity.AIM To evaluate whether zinc supplementation improves clinical outcomes(disease severity and mortality) in patients with cirrhosis.METHODS This prospectively registered systematic review(PROSPERO reference: CRD42018118219) included all studies in Medline, Embase or Cochrane database with inclusion criteria of adult human studies, comparing zinc supplementation of at least 28 d with standard care or placebo in patients with cirrhosis. Mortality and clinical severity score data were extracted. Random effects meta-analyses compared mortality at 6 mo and 2 years. Risk of bias was assessed using the National Institutes of Health quality assessment tool.RESULTS Seven hundred and twelve articles were identified of which four were eligible. Zinc formulations and doses varied(elemental zinc 3.4-214 mg daily) for different intervention periods in patients with differing etiology and severity of cirrhosis. Two studies were considered to be at high risk of bias. There was no significant difference in 6-mo mortality between patients treated with zinc versus controls [risk ratio 0.98(0.90-1.05)]. Changes in severity scores were not reported in any study.CONCLUSION Zinc supplementation is not associated with reduced mortality in patients with cirrhosis. Findings are limited by the small number of eligible studies and significant heterogeneity in intervention and patient population.     

Oxidative stress in alcohol-related liver disease

Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P4502E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these processes may identify novel targets for therapy.     

An Integrated Alcohol Abuse and Medical Treatment Model for Patients with Hepatitis C

Background  

Patients with chronic hepatitis C virus (HCV) infection have high rates of alcohol consumption, which is associated with progression of fibrosis and lower response rates to HCV treatment.     

Certolizumab Pegol Compared to Natalizumab in Patients with Moderate to Severe Crohn’s Disease: Results of a Decision Analysis

Introduction  

A significant proportion of patients with Crohn’s disease (CD) lose response to antibodies directed against tumor necrosis factor α (TNF). Prior TNF-antagonist failure is associated with lower rates of response to subsequent TNF-antagonist therapy. In patients failing two anti-TNF agents, a choice exists between using a third-anti-TNF therapy or natalizumab (NAT), an α-4 integrin inhibitor. A cost-effectiveness analysis comparing these competing strategies has not been performed.