Pneumococcal vaccine targeting strategy for older adults: Customized risk profiling

Background

Current pneumococcal vaccine campaigns take a broad, primarily age-based approach to immunization targeting, overlooking many clinical and administrative considerations necessary in disease prevention and resource planning for specific patient populations. We aim to demonstrate the utility of a population-specific predictive model for hospital-treated pneumonia to direct effective vaccine targeting.

Methods

Data was extracted for 1,053,435 members of an Israeli HMO, age 50 and older, during the study period 2008–2010. We developed and validated a logistic regression model to predict hospital-treated pneumonia using training and test samples, including a set of standard and population-specific risk factors. The model's predictive value was tested for prospectively identifying cases of pneumonia and invasive pneumococcal disease (IPD), and was compared to the existing international paradigm for patient immunization targeting.

Results

In a multivariate regression, age, co-morbidity burden and previous pneumonia events were most strongly positively associated with hospital-treated pneumonia. The model predicting hospital-treated pneumonia yielded a c-statistic of 0.80. Utilizing the predictive model, the top 17% highest-risk within the study validation population were targeted to detect 54% of those members who were subsequently treated for hospitalized pneumonia in the follow up period. The high-risk population identified through this model included 46% of the follow-up year's IPD cases, and 27% of community-treated pneumonia cases. These outcomes were compared with international guidelines for risk for pneumococcal diseases that accurately identified only 35% of hospitalized pneumonia, 41% of IPD cases and 21% of community-treated pneumonia.

Conclusions

We demonstrate that a customized model for vaccine targeting performs better than international guidelines, and therefore, risk modeling may allow for more precise vaccine targeting and resource allocation than current national and international guidelines. Health care managers and policy-makers may consider the strategic potential of utilizing clinical and administrative databases for creating population-specific risk prediction models to inform vaccination campaigns.     

Retrospective gating for mouse cardiac MRI.

Cardiac MR imaging in small animals presents some difficulties due to shorter cardiac cycles and smaller dimensions than in human beings, but prospectively gated techniques have been successfully applied. As with human imaging, there may be certain applications in animal imaging for which retrospective gating is preferable to prospective gating. For example, cardiac imaging in multiple mice simultaneously is one such application. In this work we investigate the use of retrospective gating for cardiac imaging in a mouse. Using a three-dimensional imaging protocol, we show that image quality with retrospective gating is comparable to prospectively gated imaging. We conclude that retrospective gating is applicable for small animal cardiac MRI and show how it can be applied to the problem of cardiac MRI in multiple mice.     

Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

Aims/hypothesis  In type 2 diabetes, glucose toxicity leads to beta cell apoptosis with decreased beta cell mass as a consequence. Thioredoxin-interacting protein (TXNIP) is a critical mediator of glucose-induced beta cell apoptosis. Since hyperglycaemia leads to elevated serum insulin, we hypothesised that insulin is involved in the regulation of TXNIP protein levels in beta cells. Methods  We studied the production of TXNIP in INS-1E beta cells and in islets of Psammomys obesus, an animal model of type 2 diabetes, in response to glucose and different modulators of insulin secretion. Results  TXNIP production was markedly augmented in islets from diabetic P. obesus and in beta cells exposed to high glucose concentration. In contrast, adding insulin to the culture medium or stimulating insulin secretion with different secretagogues suppressed TXNIP. Inhibition of glucose and fatty acid-stimulated insulin secretion with diazoxide increased TXNIP production in beta cells. Nitric oxide (NO), a repressor of TXNIP, enhanced insulin signal transduction, whereas inhibition of NO synthase abolished its activation, suggesting that TXNIP inhibition by NO is mediated by stimulation of insulin signalling. Treatment of beta cells chronically exposed to high glucose with insulin reduced beta cell apoptosis. Txnip knockdown mimicking the effect of insulin prevented glucose-induced beta cell apoptosis. Conclusions/interpretation  Insulin is a potent repressor of TXNIP, operating a negative feedback loop that restrains the stimulation of TXNIP by chronic hyperglycaemia. Repression of TXNIP by insulin is probably an important compensatory mechanism protecting beta cells from oxidative damage and apoptosis in type 2 diabetes. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Automated measurement of proprioception following stroke

Background.?Proprioception provides feedback which is essential for adequate motor control. Despite having detrimental functional implications, the assessment of proprioception deficits in current clinical practice is mostly qualitative and inadequate for diagnosis and longitudinal monitoring of subtle impairments and their effect on motor function.

Purpose.?To evaluate a novel quantitative approach to the assessment of proprioception deficits in stroke patients.

Method.?We designed and implemented an automated protocol where a magnetic motion tracking system and a sensor attached to each of the patient's hands, enables registration of trajectories in 3D coordinates. In this protocol the patient's affected and healthy hands are placed respectively below and above a square board. With vision blocked, the subject's affected hand is passively moved to one of four locations, and then the patient is instructed to actively position the healthy hand directly above his/her perceived location of the affected hand. The positional difference between the two hands is automatically recorded by the system. This procedure is repeated several times and the magnitude and direction of errors are used to quantify the proprioception deficit. The data for this pilot study was collected in a sample of 22 stroke patients and an age-matched group of neurologically intact subjects.

Results.?Stroke patients had significantly higher mean distance error compared with the control group (average values of 7.9 and 5.3 cm, respectively), and showed higher instability (variance) in repeated performance (average values of the standard deviation of errors 3.4 and 1.8 cm, respectively). Significant correlation was found between the mean distance error and the results of semi-quantitative clinical tests of proprioception.

Conclusion.?The system provides a reliable quantitative measure of upper limb proprioception, offering considerable advantage over the traditional means applied in the clinic.     

RNAi targeting µ-calpain increases neuron survival and preserves hippocampal function after global brain ischemia

The calpain family of cysteine proteases has a well-established causal role in neuronal cell death following acute brain injury. However, the relative contribution of calpain isoforms has not been determined in in vivo models. Identification of the calpain isoform responsible for neuronal injury is particularly important given the differential role of calpain isoforms in normal physiology. This study evaluates the role of m-calpain and µ-calpain in an in vivo model of global brain ischemia. Adeno-associated viral vectors expressing short hairpin RNAs targeting the catalytic subunits of µ- or m-calpain were used to knockdown expression of the targeted isoforms in adult rat hippocampal CA1 pyramidal neurons. Knockdown of µ-calpain, but not m-calpain, prevented calpain activity 72 h after 6-min transient forebrain ischemia, increased long-term survival and protected hippocampal electrophysiological function. These findings represent the first in vivo evidence that reducing expression of an individual calpain isoform can decrease post-ischemic neuronal death and preserve hippocampal function.     

Alteration of cellular and humoral immunity by mutant p53 protein and processed mutant peptide in head and neck cancer.

PURPOSE: To determine if serologic recognition of p53 mutations at the protein level depends upon the ability of mutant p53 to express new peptide epitopes that bind to human leukocyte antigen (HLA) class II molecules, we used anti-p53 antibody production as a marker for HLA class II-restricted T-cell involvement in head and neck cancer. EXPERIMENTAL DESIGN: An anti-p53 antibody response was correlated with specific p53 mutations and the patients' HLA class II alleles and haplotypes. HLA binding studies and in vitro stimulation (IVS) of peripheral blood mononuclear cells were done using a mutant versus wild-type HLA-DQ7-binding p53 peptide. RESULTS: Certain HLA-DQ and HLA-DR alleles were frequently present in p53 seropositive patients who produced serum anti-p53 antibodies. Selected mutated p53 peptides fit published allele-specific HLA class II binding motifs for the HLA-DQ7 or HLA-DR1 molecules. Moreover, a mutant p53 peptide bound with a 10-fold greater affinity than the wild-type p53 peptide to HLA-DQ7 molecules. IVS of CD4(+) T cells from seven healthy HLA-DQ7(+) donors using this mutant p53 peptide (p53(220C)) was associated with a partial T helper type 2 phenotype compared with IVS using the wild-type p53(210-223) peptide. CONCLUSIONS: Our results support the hypothesis that mutated p53 neoantigens can bind to specific HLA class II molecules, leading to a break in tolerance. This may lead to skewing of the CD4(+) T lymphocyte response toward a tumor-permissive T helper type 2 profile in head and neck cancer patients, as manifested by seropositivity for p53.     

Interferon system in acute transient synovitis.

The interferon system of 20 children aged 2 to 11 years (mean 5 years), diagnosed as having transient synovitis of the hip by clinical criteria, was studied. The mean blood interferon concentration was significantly higher than that of normal children, and the incidence of an antiviral state of cells (in 78% of patients) was also significantly higher than in the control group. These findings are compatible with the hypothesis that the aetiology of transient synovitis is an acute, possibly unusual, viral infection.