The impact of interventions addressing socioeconomic inequalities in cancer-related outcomes in high-income countries: A systematic review

Background: High cancer mortality is a major source of burden. Population-wide programs have been developed to improve cancer outcomes, and although effective in improving outcomes overall, the socioeconomically disadvantaged population have disproportionately benefited. This systematic review evaluated interventions aimed at addressing inequalities in cancer-related outcomes between low and high socioeconomic groups within high-income countries.Materials and Methods: The Cochrane Register of Controlled Trials, EMBASE, and PubMed searches were completed in October 2018. Data extraction and quality appraisal were guided by established mechanisms. Impact of interventions, using odds ratios, with respective 95% confidence intervals were presented, where available.Results: Sixteen studies reporting on 19 interventions were included. Seven interventions (37%) reduced socioeconomic inequalities in cancer-related outcomes, focusing on participation in cancer screening. Interventions included pre-formulated implementation intentions; GP-endorsed screening invitations; enhanced reminder letters; text message reminders; and implementation of an organised screening program.Conclusions: This systematic review found limited evidence on the efficacy of existing interventions that aimed to reduce inequalities in cancer-related outcomes between people living in low and high socioeconomic areas among high-income countries. Future interventions should consider the specific needs of people living in socioeconomically disadvantaged areas to improve the efficacy of an intervention

Assessing the implementation of interventions addressing socioeconomic inequalities in cancer screening in high-income countries

Background: The context of an intervention may influence its effectiveness and success in meeting the needs of the targeted population. Implementation science frameworks have been developed, but previous literature in this field has been mixed. This paper aimed to assess the implementation success of interventions, identified from a systematic review, that reduced inequalities in cancer screening between people in low and high socioeconomic groups.Design and Methods: The implementation framework by Proctor et al. was utilised to assess the potential success of 6 studies reporting on 7 interventions in the “real-world” environment. A standardised rating system to identify the overall implementation success of each intervention was established.Results: Four interventions (57%) demonstrated high potential to be implemented successfully. Interventions included enhanced reminder letters and GP-endorsed screening invitations, containing evidence on the acceptability, from participants and stakeholders, appropriateness and direct cost of the intervention.  Conclusion: While some interventions reduced socioeconomic inequalities in cancer screening participation, there have been missed opportunities to integrate the experiences of the targeted population into design and evaluation components. This has limited the potential for transferability of outcomes to other settings

Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type?

Hypofunction of N-methyl-D-aspartate glutamate receptors (NMDARs), whether caused by endogenous factors like auto-antibodies or mutations, or by pharmacological or genetic manipulations, produces a wide variety of deficits which overlap with—but do not precisely match—the symptom spectrum of schizophrenia. In order to understand how NMDAR hypofunction leads to different components of the syndrome, it is necessary to take into account which neuronal subtypes are particularly affected by it in terms of detrimental functional alterations. We provide a comprehensive overview detailing findings in rodent models with cell type–specific knockout of NMDARs. Regarding inhibitory cortical cells, an emerging model suggests that NMDAR hypofunction in parvalbumin (PV) positive interneurons is a potential risk factor for this disease. PV interneurons display a selective vulnerability resulting from a combination of genetic, cellular, and environmental factors that produce pathological multi-level positive feedback loops. Central to this are two antioxidant mechanisms—NMDAR activity and perineuronal nets—which are themselves impaired by oxidative stress, amplifying disinhibition. However, NMDAR hypofunction in excitatory pyramidal cells also produces a range of schizophrenia-related deficits, in particular maladaptive learning and memory recall. Furthermore, NMDAR blockade in the thalamus disturbs thalamocortical communication, and NMDAR ablation in dopaminergic neurons may provoke over-generalization in associative learning, which could relate to the positive symptom domain. Therefore, NMDAR hypofunction can produce schizophrenia-related effects through an action on various different circuits and cell types

Gene-Environment Interaction in a Conditional NMDAR-Knockout Model of Schizophrenia

Interactions between genetic and environmental risk factors take center stage in the pathology of schizophrenia. We assessed if the stressor of reduced environmental enrichment applied in adulthood provokes deficits in the positive, negative or cognitive symptom domains of schizophrenia in a mouse line modeling NMDA-receptor (NMDAR) hypofunction in forebrain inhibitory interneurons (Grin1∆Ppp1r2 ). We find that Grin1∆Ppp1r2 mice, when group-housed in highly enriched cages, appear largely normal across a wide range of schizophrenia-related behavioral tests. However, they display various short-term memory deficits when exposed to minimal enrichment. This demonstrates that the interaction between risk genes causing NMDA-receptor hypofunction and environmental risk factors may negatively impact cognition later in life

Sparse, decorrelated odor coding in the mushroom body enhances learned odor discrimination

Sparse coding may be a general strategy of neural systems for augmenting memory capacity. In Drosophila melanogaster, sparse odor coding by the Kenyon cells of the mushroom body is thought to generate a large number of precisely addressable locations for the storage of odor-specific memories. However, it remains untested how sparse coding relates to behavioral performance. Here we demonstrate that sparseness is controlled by a negative feedback circuit between Kenyon cells and the GABAergic anterior paired lateral (APL) neuron. Systematic activation and blockade of each leg of this feedback circuit showed that Kenyon cells activated APL and APL inhibited Kenyon cells. Disrupting the Kenyon cell–APL feedback loop decreased the sparseness of Kenyon cell odor responses, increased inter-odor correlations and prevented flies from learning to discriminate similar, but not dissimilar, odors. These results suggest that feedback inhibition suppresses Kenyon cell activity to maintain sparse, decorrelated odor coding and thus the odor specificity of memories

Different Domains of the RNA Polymerase of Infectious Bursal Disease Virus Contribute to Virulence

BACKGROUND: Infectious bursal disease virus (IBDV) is a pathogen of worldwide significance to the poultry industry. IBDV has a bi-segmented double-stranded RNA genome. Segments A and B encode the capsid, ribonucleoprotein and non-structural proteins, or the virus polymerase (RdRp), respectively. Since the late eighties, very virulent (vv) IBDV strains have emerged in Europe inducing up to 60% mortality. Although some progress has been made in understanding the molecular biology of IBDV, the molecular basis for the pathogenicity of vvIBDV is still not fully understood. METHODOLOGY, PRINCIPAL FINDINGS: Strain 88180 belongs to a lineage of pathogenic IBDV phylogenetically related to vvIBDV. By reverse genetics, we rescued a molecular clone (mc88180), as pathogenic as its parent strain. To study the molecular basis for 88180 pathogenicity, we constructed and characterized in vivo reassortant or mosaic recombinant viruses derived from the 88180 and the attenuated Cu-1 IBDV strains. The reassortant virus rescued from segments A of 88180 (A88) and B of Cu-1 (BCU1) was milder than mc88180 showing that segment B is involved in 88180 pathogenicity. Next, the exchange of different regions of BCU1 with their counterparts in B88 in association with A88 did not fully restore a virulence equivalent to mc88180. This demonstrated that several regions if not the whole B88 are essential for the in vivo pathogenicity of 88180. CONCLUSION, SIGNIFICANCE: The present results show that different domains of the RdRp, are essential for the in vivo pathogenicity of IBDV, independently of the replication efficiency of the mosaic viruses

Sparse, decorrelated odor coding in the mushroom body enhances learned odor discrimination

Sparse coding may be a general strategy of neural systems for augmenting memory capacity. In Drosophila melanogaster, sparse odor coding by the Kenyon cells of the mushroom body is thought to generate a large number of precisely addressable locations for the storage of odor-specific memories. However, it remains untested how sparse coding relates to behavioral performance. Here we demonstrate that sparseness is controlled by a negative feedback circuit between Kenyon cells and the GABAergic anterior paired lateral (APL) neuron. Systematic activation and blockade of each leg of this feedback circuit showed that Kenyon cells activated APL and APL inhibited Kenyon cells. Disrupting the Kenyon cell-APL feedback loop decreased the sparseness of Kenyon cell odor responses, increased inter-odor correlations and prevented flies from learning to discriminate similar, but not dissimilar, odors. These results suggest that feedback inhibition suppresses Kenyon cell activity to maintain sparse, decorrelated odor coding and thus the odor specificity of memories. © 2014 Nature America, Inc. All rights reserved

Gene-environment interaction in a conditional NMDAR-knockout model of schizophrenia

Interactions between genetic and environmental risk factors take center stage in the pathology of schizophrenia. We assessed if the stressor of reduced environmental enrichment applied in adulthood provokes deficits in the positive, negative or cognitive symptom domains of schizophrenia in a mouse line modeling NMDA-receptor (NMDAR) hypofunction in forebrain inhibitory interneurons (Grin1 ΔPpp1r2 ). We find that Grin1 ΔPpp1r2 mice, when group-housed in highly enriched cages, appear largely normal across a wide range of schizophrenia-related behavioral tests. However, they display various short-term memory deficits when exposed to minimal enrichment. This demonstrates that the interaction between risk genes causing NMDA-receptor hypofunction and environmental risk factors may negatively impact cognition later in life