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Background The purpose of this study is to undertake a comprehensive systematic review to describe multilevel factors (barriers and facilitators) that may influence the implementation of low-dose chest computed tomography for lung cancer screening in the United States. Methods Systematic literature searches were performed using 6 online databases and citation indexes for peer-reviewed studies, for articles published from 2013 to 2021. Studies were classified into 3 perspectives, based on the study’s unit of analysis: system, health-care provider, and patient. Barriers and facilitators identified for each study included in our final review were then coded and categorized using the Consolidate Framework for Implementation Research domains. Results At the system level, the 2 most common constructs were external policy and incentives and executing the implementation process. At the provider level, the most common constructs were evidence strength and quality of the intervention characteristics, patient needs and resources, implementation climate, and an individual’s knowledge and beliefs about the intervention. At the patient level, the most common constructs were patient needs and resources, individual’s knowledge and beliefs about the intervention, and engaging in the implementation process. These constructs can act as facilitators or barriers to lung cancer screening implementation. Conclusions Applying the Consolidate Framework for Implementation Research domains and constructs to understand and specify factors facilitating uptake of lung cancer screening as well as cataloging the lessons learned from previous efforts helps inform the development and implementation processes of lung cancer screening programs in the community setting. Registration PROSPERO, CRD42021247677.

The extracellular matrix (ECM) is a dynamic structure composed of a large number of molecules that can be divided into six different categories and are collectively called the matrisome. The ECM plays pivotal roles in physiological and pathological processes in many tissues, including the nervous system. Intriguingly, alterations in ECM molecules/pathways are often associated with painful human conditions and murine experimental pain models. Nevertheless, mechanistic insight into the interplay of normal or defective ECM and pain is largely lacking. To expand the knowledge on ECM composition and synthesis in the peripheral nervous system, we used a transcriptomal approach to investigate the expression and cellular origin of matrisome genes in murine and human dorsal root ganglia (DRG), containing the cell bodies of sensory neurons. Bulk RNA sequencing data showed that over 60% of all matrisome genes were expressed in both murine and human DRG, with proportionally more core matrisome genes (glycoproteins, collagens, and proteoglycans) expressed compared to matrisome-associated genes (ECM-affiliated genes, ECM regulators and secreted factors). Examination of the cellular origin of matrisome expression by single cell RNA sequencing on murine DRG revealed that core matrisome genes, especially collagens, were expressed by vascular leptomeningeal-like (fibroblast) cell types whereas matrisome-associated genes were mainly expressed by neuronal cell types. We analyzed cell-cell communication networks with the CellChat R package and predicted an important role for the Collagen signaling pathway in connecting vascular cell types and nociceptors in murine tissue, which we confirmed by analysis of spatial transcriptomic data from human DRG. RNAscopein situhybridization and immunohistochemistry confirmed expression of collagens in fibroblasts surrounding nociceptors in human DRG. This study supports the idea that the DRG matrisome may contribute to neuronal signaling in both mouse and human. The identification of the cellular distribution of murine and human matrisome genes provides a framework to study the role of the ECM in peripheral nervous tissue and its effects on pain signaling.HighlightsTranscriptomal analyses of mouse and human dorsal root ganglia (DRG) revealed that over 60% of matrisome genes are expressed by murine and human dorsal root ganglia (DRG), with over 85% of the genes with orthologues overlapping between both species.Matrisome-associated genes had the highest expression in both species and included conserved expression of annexins, S100 calcium binding proteins and cathepsins.Collagens and collagen receptors are expressed by distinct cell types in murine and human DRG, suggesting that the collagen signaling pathway could be involved in cell-cell signaling.

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target., eLife digest Despite being unpleasant, pain is critical to survival because it acts as a warning for damage or impending harm. Day-to-day pain like a stubbed toe or a pricked finger is called acute pain. It alerts the body to harm but only lasts a short time and usually goes away on its own. Pain that persists more than three months after the damaged tissue has healed is known as chronic pain, and it is a serious problem that is often difficult to treat. Learning more about the causes of chronic pain is necessary to help develop more effective therapies. Nerve pathways in the spinal cord help process pain and other sensory information from the skin and relay it to the brain. These pathways include sensory fibers that carry pain information from the body to the spinal cord, as well as cells that relay this information to the brain. But not much is known about how the nerves and cells in this region prioritize or refine sensory information before sending it to the brain. Now, Smith et al. have used mice to show that nerve cells in the spinal cord that produce the protein calretinin can act as a pain amplifier, causing it to persist. A technique called optogenetics was used to turn on calretinin nerve cells by exposing them to light. This caused the mice to behave like they were in pain even though they had not been harmed, and the behaviour stopped when they were treated with morphine, a powerful painkiller. Further experiments showed that calretinin nerve cells form a highly interconnected network in the spinal cord. These results show that calretinin nerve cells can ‘jump-start’ the pain pathway within the spinal cord, even when there is no painful stimulation of the skin. Turning on these cells even briefly causes behaviours associated with prolonged pain. By revealing that networks of calretinin nerve cells in the spinal cord act like an in-built pain amplifier, the experiments identify these cells as a potential target for new treatments for chronic pain.

Highlights • Calretinin is differentially expressed among excitatory interneurons in the superficial dorsal horn of mouse spinal cord. • Calretinin is present in many excitatory interneurons that express neurokinin B, substance P or gastrin-releasing peptide. • Consistent with recent transcriptomic data, we find that most inhibitory substance P-expressing neurons contain calretinin., Around 75% of neurons in laminae I-II of the mouse dorsal horn are excitatory interneurons, and these are required for normal pain perception. We have shown that four largely non-overlapping excitatory interneuron populations can be defined by expression of the neuropeptides neurotensin, neurokinin B (NKB), gastrin-releasing peptide (GRP) and substance P. In addition, we recently identified a population of excitatory interneurons in glabrous skin territory that express dynorphin. The calcium-binding protein calretinin is present in many excitatory neurons in this region, but we know little about its relation to these neuropeptide markers. Here we show that calretinin is differentially expressed, being present in the majority of substance P-, GRP- and NKB-expressing cells, but not in the neurotensin or dynorphin cells. Calretinin-positive cells have been implicated in detection of noxious mechanical stimuli, but are not required for tactile allodynia after neuropathic pain. Our findings are therefore consistent with the suggestion that neuropathic allodynia involves the neurotensin and/or dynorphin excitatory interneuron populations. Around a quarter of inhibitory interneurons in lamina I-II contain calretinin, and recent transcriptomic studies suggest that these co-express substance P. We confirm this, by showing that inhibitory Cre-expressing cells in a Tac1Cre knock-in mouse are calretinin-immunoreactive. Interestingly, there is evidence that these cells express low levels of peptidylglycine alpha-amidating monooxygenase, an enzyme required for maturation of neuropeptides. This may explain our previous finding that although the substance P precursor preprotachykinin A can be detected in some inhibitory interneurons, very few inhibitory axonal boutons are immunoreactive for substance P.