Tumor immunology is undergoing a renaissance due to the recent profound clinical successes of tumor immunotherapy. These advances have coincided with an exponential growth in the development of –omics technologies. Armed with these technologies and their associated computational and modeling toolsets, systems biologists have turned their attention to tumor immunology in an effort to understand the precise nature and consequences of interactions between tumors and the immune system. Such interactions are inherently multivariate, spanning multiple time and size scales, cell types, and organ systems, rendering systems biology approaches particularly amenable to their interrogation. While in its infancy, the field of ‘Cancer Systems Immunology’ has already influenced our understanding of tumor immunology and immunotherapy. As the field matures, studies will move beyond descriptive characterizations toward functional investigations of the emergent behavior that govern tumor-immune responses. Thus, Cancer Systems Immunology holds incredible promise to advance our ability to fight this disease. Systems Biology is an interdisciplinary field that aims to interrogate and predict complex behaviors of multivariate biological systems. It employs quantitative approaches to understand the integrated behaviors of multiple biological components. In contrast to reductionist approaches, which seek to identify how individual components affect particular phenotypes, systems biology attempts to query the simultaneous responses of many elements to uncover how they work in concert to elicit a given response. It is predicated upon the belief that many biological processes cannot be comprehensively understood by analyses of individual components alone , but rather require a holistic appreciation of entire networks and systems . By combining mathematical modeling and computation with experimental and clinical data, systems biologists can construct a framework for understanding the multiscale and temporal elements regulating biological responses and elucidate emergent behaviors.While the discipline of systems biology became well established around 2000 , its undRecently, researchers in the fields of both cancer biology and immunology have embraced systems approaches to advance their disciplines. In cancer biology, genomics and proteomics approaches have been implemented to identify the effects of defects in signaling networks on malignant transformation and progression . Next-geImmunology represents a field that is readily amenable to systems level approaches. Deciphering the immune system requires an understanding of the interactions between numerous cell types, immune receptors, and cytokines as they traverse multiple anatomical locations and organ systems in order to orchestrate effective immune responses. While the multivariate components governing an immune response have been slowly elucidated through reductionist approaches, they have recently become subject to a much more comprehensive characterization through advances in modeling and high-throughput technologies .Although the study of tumor immunology can be traced back at least to the advent of Coley’s toxins at the turn of the twentieth century , the recTraditionally, animal models have served as critical tools to cancer biologists and immunologists as they try to decipher how tumors affect the host organism or how the immune response is orchestrated across multiple tissues, respectively. Nonetheless, animal models are frequently imperfect surrogates for human biology. While orthologous genes typically elicit similar functions across species, there are many instances where there exists a stark divergence in phenotypes for orthologs of different species . FurtherComputational biologists have developed a variety of tools to translate findings from preclinical models to humans when simple matching of orthologs is insufficient for predicting responses . To overEven with improved animal models, however, there are many instances where they fail to predict clinical responses, and only 8% of drugs entering clinical trials succeed in Phase I . Thus, tThe multivariate nature of systems biology has rendered it particularly applicable to comprehensive datasets derived from quantification of systems-level parameters . Indeed, the beginning of modern-era systems biology largely coincides with the Human Genome Project , which eThe promise of the Human Genome Project and whole genome sequencing (WGS) has inspired the development of –omics technologies capable of characterizing the entirety of a particular attribute within a sample. Such approaches include, but are not limited to, genomics, transcriptomics, epigenomics, proteomics, metabolomics, lipidomics , and glyThe cornerstone technologies underlying both cancer systems biology and systems immunology are genomic sequencing  and transcriptomic sequencing (RNA sequencing (RNA-seq)) . At its + T cells and identify how polymorphisms in these regions can potentiate risk of autoimmune disease   can identify regions of open and closed chromatin (i.e. chromatin accessibility) across the genome . These aTAC-seq) . ChromatTAC-seq) , leukocyTAC-seq) , and tumTAC-seq) . Such apTAC-seq) . Other sogrammed .While regions of open chromatin reveal evidence of transcriptional regulation, higher order chromatin structures also play critical roles in controlling gene expression. Long-range distal elements, such as enhancers, affect gene expression even at distances greater than 1 Mb in linear genome space . To asseWhile light and electron microscopy endowed scientists with the ability to survey biology at the resolution of single cells, perhaps the most influential single-cell technological advance in immunology was the invention of flow cytometry and fluorescence activated cell sorting (FACS) . These tAdaptation of these bulk NGS technologies to single cells has recently led to insights at the single-cell level previously thought to be unattainable. These new technologies were largely enabled by advances in microfluidics and are predicated upon one of three general approaches: (1) single cells are sorted into individual wells of a plate by using conventional FACS, (2) single cells are captured in capture sites of a microfluidic chip, or (3) single cells are captured in emulsion droplets generated in a microfluidic chip. Both microfluidic approaches were derivatives of technologies developed at the turn of the century , whereinThe vast majority of bulk NGS approaches have been adapted to these single-cell formats see . The priIFNG within a tumor may reflect increased IFN-γ production by T cells already within tumors or an increase in T cell infiltration into the tumor. Recent computational approaches have helped deconvolve immune subsets from bulk RNA-seq data (discussed below), but single-cell sequencing presents an opportunity to accurately quantitate genome-wide changes at the resolution immunologists have become accustomed to from flow cytometry. Applied to tumor immunology, these studies have revealed heterogeneity in both the malignant and hematopoietic compartments, identified novel subsets, aided in reclassification of existing subsets, revealed activation, exhaustion, and suppression states of multiple immune types within tumors, shed light on responses to immunotherapy, and much more.The immune system is comprised of a myriad of cell types with distinct functions working in concert to elicit responses against a pathogenic insult. The multitude and diversity of these cell types render bulk sequencing approaches challenging in that the aggregation of reads from the pool of different cell types often masks differences exhibited by particular subsets. Furthermore, changes in the frequencies of cell types are difficult to distinguish from changes in gene expression within those cells. For example, an increase in Long before the advent of NGS, immunologists and cancer biologists have been performing low- to moderate-dimensional single cell protein analyses using a variety of platforms such as ELISPOTs, flow cytometry, and various forms of microscopy. More recently, scientists have developed new technologies to achieve higher dimensionality with theoretical ranges reaching the entire proteome. A recent study used confocal immunofluorescence (IF) to image and characterize the subcellular localization of over 12,000 human proteins at the single-cell level and presented the results in an interactive database known as the Cell Atlas . Using aTo assess heterogeneity in leukocyte populations, bioengineers have developed technologies to quantify secreted cytokines at the single-cell level. Using oligo-barcoded antibodies in microfluidic devices, researchers characterized heterogeneity in the secretome of tumor antigen-specific T cells from melanoma patients . SimilarOne of the most widely adopted technologies used by systems immunologists is mass cytometry (CyTOF) . This apWith the exception of the peripheral blood, regulation of the immune response relies upon tissue architecture to facilitate homotypic and heterotypic interactions between cells. Secondary lymphoid organs  are notable examples wherein local chemokine gradients and tissue architecture enable lymphocytes and APCs to efficiently interact in a manner that orchestrates adaptive immunity . SimilarRecently, new imaging approaches have been developed that enable increased multiplexing capacity. Following a similar approach as employed with mass cytometry, researchers have combined heavy metal isotope-labeled antibodies to image over 40 parameters simultaneously on histology slides . In one While mass spectrometry-based approaches enable multiplexing and simultaneous quantitation of all of the parameters at subcellular resolution, they require conjugation of heavy metal isotopes to antibodies as well as access to large and expensive instrumentation. One alternative is to use cycles of conventional immunohistochemistry (IHC) by inactivating dyes or stripping antibodies after imaging and restaining with additional antibodies in a cyclical process. A number of variations of this strategy exist , but appIn addition to immunohistochemistry (IHC) approaches, single molecule RNA fluorescence in situ hybridization (FISH) approaches have been adapted to enable multiplexed imaging of tens to thousands of RNA probes in cells and tissues . In partWhile sequencing, cytometry, and imaging technologies are currently the predominant tools employed by systems biologists, a number of other highly multiplexed tools have enhanced systems-level studies of tumor-immune interactions. Alterations in metabolic pathways is a key feature of many cancers . SimilarBoth tumor cells and immune cells rely heavily upon a variety of soluble proteins for their growth, development, and migration. These collections of secreted proteins, sometimes referred to as the ‘Secretome’ , have beFinally, it is worth noting that while the majority of the technologies discussed above enable characterization of endogenous states, the implementation of genetic screens, particularly those employing the CRISPR/Cas9 system, have made it possible to determine the genetic underpinnings of pathways and phenotypes in a variety of settings . These sWhile often disparate fields, mathematical modeling, computational modeling, informatics tools, and statistical analyses are often inextricably linked, as mathematical modeling  can be aided by computational approaches and bioinformatics tools often rely upon novel or existing mathematical analyses for their implementation. The breadth of modeling approaches and informatics tools in the field of Systems Biology  is too large to review here and has been discussed elsewhere . Many moBoth malignant and immune cells respond to their microenvironments. Factors such as the mechanics of the extracellular matrix (ECM), gradients in cytokines and chemokines, availability of nutrients, and much more drive cells to alter their behavior. Frequently, tumor cells and immune cells influence their own behavior and that of each other by inducing changes in these factors . To model these elements, mathematicians have frequently turned to systems of ordinary differential equations   and partA variety of approaches have been used to model competition between immune cells and different clones within tumors. Probabilistic models that utilize evolutionary game theory (EGT) can be amenable to such modeling . Rule-baOne of the most promising aspects of systems biology analyses is their potential to integrate observations across multiple physical and temporal scales to discover emergent behavior that is not discernable from analysis of the individual components. This potential is especially attractive in the tumor setting where orchestration of immune responses occurs across all these levels . To addrIn addition to the use of computational approaches to develop models of tumor-immune interactions, bioinformaticians have developed a large array of tools for analyzing the data that are produced by the technologies described earlier. While the full extent of these tools is beyond the scope of this review, we highlight a few topics that are particularly relevant to cancer systems immunology.The reduced cost and increased accessibility of DNA microarrays and NGS have resulted in vast amounts of publicly available human datasets. The Immunological Genome Project (ImmGen) provides transcriptional profiles from all the major immune subsets in mouse and human . ResourcEven with advances in deconvolution, however, scRNA-seq remains one of the most effective methods for evaluating immune profiles within tumors . This ap+ T cell population that is a key element of effective immunotherapy. As with mass cytometry, high-parameter imaging modalities require the advent of new analysis tools. A recent study exploring immune infiltration in triple-negative breast cancer patients by MIBI used a deep-learning approach to aid in image segmentation and revealed populational co-occurrence patterns that correlate with prognosis  overcomes the limitations of biaxial plots frequently employed in the analysis of conventional flow cytometry to facilitate analysis of mass cytometry data . This aprognosis . Deconvorognosis . This aprognosis . To visurognosis . In a rerognosis . These aStudies investigating the immune status of tumors have revealed that the prognosis of patients often strongly correlates with the degree of T cell infiltration into the local tumor microenvironment (TME) . Immune In the mid-nineteenth century, Rudolf Virchow first recognized that tumors frequently contain leukocytes. He posited that chronic inflammation lies at the origins of tumors , leadinglo nonclassical or patrolling monocytes typically remain within vessels and crawl along the endothelial walls to clean up debris from dying endothelium  represent a relative minority of the myeloid cells present within most tumors. Nonetheless, DCs are critical orchestrators of immune responses due to their exquisite capacity to present antigens and license, stimulate, or suppress T cells . They ca+ T cells. In lymphoid tissues, cDC1s typically express CD8α, while peripheral cDC1s express integrin αE (CD103) in mice (both express BDCA3 in humans) and exhibit the ability to efficiently migrate to LNs to present antigen. Both typically lack CD11b. cDC2 have been primarily associated with activation of CD4+ T cells, though both cDC subsets can activate both T cell subsets  and plasmacytoid DCs (pDCs), are derived from a common bone-marrow progenitor, the common DC precursor (CDP), which gives rise to a lineage distinct from other leukocytes . Traditi subsets . While a subsets .+ T cells, while MoDCs are frequently the most numerous in the TME. cDCs are critical for antitumor T-cell-mediated immunity  and engineered chimeric antigen receptor T cells (CAR-T cells) have stimulated a renewed interest in understanding T cell interactions with tumors. Consequently, many novel systems approaches have been applied to T cells. Due to their ability to recognize tumor-specific antigens and kill tumor cells in an antigen-specific manner, T cells represent one of the most critical components of anti-tumor immune responses. Nonetheless, T cells frequently fail to eliminate tumors likely due to immune evasion  or supprEx are not entirely ineffective and exhibit some anti-pathogen efficacy even if unable to eliminate the pathogen. Features of exhaustion include elevated expression of inhibitory receptors , reduced cytokine expression, reduced proliferation, altered metabolism, and reduced effector function  were the dysfunctional T cells.Studies interrogating the stability of T cell dysfunction and exhaustion in the context of viral infection, autoimmunity, and malignancy have identified a number of states, some of which are defined by their inherent reversibility and others by their proliferative or progenitor capacity, although they are frequently referred to as reprogrammable-non-reprogrammable, partial-complete, or progenitor-terminal exhaustion . Progeniated TEx . Of notegramming . Additiogramming . The resfunction  Surprisi+ T cells and Tregs that are enriched in hepatocellular carcinoma compared to other tissues and identified a gene, LAYN, that inhibits IFN-γ production (RM) can be found within tumors and correlate with improved prognosis , and even high endothial venules (HEVs) , which closely resemble lymphoid follicles, containing T cells, B cells, FDCs, Ts (HEVs) . Althougs (HEVs) , their ps (HEVs) . Like SLs (HEVs) , and thes (HEVs) . Thus, as (HEVs) . Furthers (HEVs) , we haves (HEVs) .Given the importance of B cells in both tumor progression and antitumor responses, researchers have begun to apply a variety of systems-level approaches to elucidate their roles in malignancy. While the use of TCR repertoire profiling is discussed in detail in the following section, analogous approaches have been developed for BCRs and employed in the context of malignancy to identify the sequences of tumor-reactive antibodies and identify their cognate antigens . Buildinfh-induced B cells in promoting ICB responses  responders and non-responders with deconvolution algorithms to identify a strong enrichment in B cell signatures in responders. They further analyzed the BCRs of these patients from the bulk RNA-seq and found increases in both clonal diversity and expansion of individual clones in responders, suggesting antigen-specific humoral responses. Finally, using mass cytometry, they demonstrated an enrichment for memory B cells, plasma cells, and GC B cells specifically within the tumors of responders, suggesting a role for B cell activation and humoral responses in patients benefiting from ICB . Other responses . While nAlthough T cells, B cells, TAMS, and DCs have been the subject of the majority of systems analyses of the TME, other lymphocytes, myeloid cells, and non-hematopoietic APCs play important roles in tumor progression. Similarly, the importance of NK cells and other innate lymphoid cells (ILCs)  and PMNsFor over a decade there has been interest in a group of cells frequently associated with tumors referred to as ‘myeloid derived suppressor cells’ (MDSCs). This nomenclature was based upon expression of the integrin subunit αM (CD11b) and staining (in mice) for a marker known as ‘Gr-1’ with an antibody that exhibits a high affinity for Ly-6G and weak affinity for Ly-6C . It shou+ cells exhibit an increased capacity to suppress T cell responses, it is unclear whether this is a feature of all LOX-1+ cells or a subset and whether the marker represents a distinct lineage rather than an activation or maturation state of PMNs. Furthermore, genetic ablation of the gene (Olr1) in mice had no impact on the suppressive function of the cells in vitro nor growth of tumors in wild-type mice reconstituted with -/-Olr1 bone marrow following lethal irradiation. In contrast to bulk approaches, single-cell analyses such as scRNA-seq are particularly useful for identifying distinguishing features of individual cells, evaluating heterogeneity of populations, and reconstructing lineage relationships between populations. Indeed, when unbiased clustering of systems level single-cell data has been performed under a myriad of conditions, none of the studies report the existence of distinct MDSC clusters J rearrangement that results in the generation of more possible sequences than there are T cells within an individual . While c+ T cells in tumors shared clonotypes with memory T cells but not with each other, suggesting that these distinct states are not shared between the same T cell clones. Even more notably, they found considerable expansion of TEx post-treatment that did not exist before therapy, with only minor contributions from pre-existing TCF7+ clones. These clones can be found within the blood at much lower percentages. In contrast with conventional wisdom suggesting that ICB works by reinvigorating existing T cells within the TME, these results suggest that anti-PD1 stimulates recruitment of new tumor-specific T cells to the TME and are in agreement with our own findings that trafficking of lymphocytes from SLOs is required for effective immunotherapy  has proven effective, and even curative, in a number of malignancies including melanoma, breast cancer, and multiple GI cancers (Eff and Tmem once reinfused. In either case, it is quite reasonable to expect that ICB and TIL therapy have highly distinct effects on the nature of the T cells eliciting the anti-tumor immunity. A systems-level characterization of TIL approaches might help shed light on the states of the expanded T cells, whether they were derived from progenitor TEx or other T cell subsets, and to what extent the ex vivo processing is capable of reprogramming them.Nonetheless, while these T cancers . Moreove cancers . These sH1 (H17 (+ CD8+ T cells (Listeria monocytogenes and augmented the efficacy of ICB. Similarly, among tumor-bearing mice, a comparison of germ-free to specific pathogen-free mice or mice from different vendors demonstrated differences in tumor growth depending on the microbiota. Moreover, specific commensals affected responses to ICB, with Bifidobacterium aiding anti-PD-1 (Bacteroidales fragilis aiding anti-CTLA-4 (+ T cell activity (Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium may also augment responses by expanding tumor-specific CD8+ T cells without affecting Treg numbers (+ T cell subset (Microbiota consist of the microorganisms that inhabit a host and include bacteria, fungi, viruses, and archaea. Sites such as the skin, respiratory tract, gastrointestinal tract, and vagina are colonized by these organisms, which play critical roles in health and disease. Systems approaches and –omics, in particular, have been utilized extensively to analyze the microbiota, resulting in the adoption of the term ‘microbiome’ to represent the collection of these organisms in a host. The microbiome affects everything from obesity, to resistance to colonization by pathogenic bacteria, to cancer . While tH1 , TH17 (IH1 (H17 , or IFN- T cells . The lasnti-PD-1  and Bacti-CTLA-4 . To inveactivity  and that numbers . Similarl subset . The abiCancer immunotherapy, and ICB in particular, represents one of the most significant advances in oncology in decades and has the ability to elicit durable responses and cures in some patients with advanced stage malignancies . NonetheMany of the systems approaches discussed in this review are now being applied to advancing our understanding of the effects of existing immunotherapies and designing new approaches. As discussed in the previous section, researchers and clinicians have combined WES of patient tumors with HLA-binding and TCR prediction algorithms to design personalized neoantigen peptide vaccines . Stainin+ T cells, we found that the key differentiator of effective immune responses is its orchestration from extratumoral sites such as LNs rather than a simple reinvigoration of existing TILs. Information gleaned from these types of systems-level analyses should facilitate the design of approaches that augment our current arsenal of immunotherapies (In addition to monitoring therapy in patients, systems approaches can reveal underlying biology about responses to treatment. A recent study revealing the clonal replacement of exhausted T cells following ICB is one such example demonstrating the power of integrative systems analyses to improve our understanding of the mechanisms of ICB . We beliherapies .Technological and computational advances in the life sciences and the profound clinical successes of tumor immunotherapy have ushered the fields of systems biology and tumor immunology to the forefront of biomedical research. Understandably, the application of systems biology to tumor immunology is intuitive and has generated considerable excitement. Once lauded as representing the future of optimal cancer treatment and potential cures, personalized medicine fell out of fashion with the failure of targeted therapies to realize their promise . While –Cancer systems immunology is at an important transition point in its maturation. To date, preclinical and clinical studies exploiting systems approaches have generated profound amounts of data enabling characterization of immune responses and the generation of data rich atlases and accompanying tools for analysis. These important advances have laid the groundwork for discovery in the field of tumor immunology. The challenge moving forward will be to expand these approaches to uncover new biology that can be functionally validated. Many of the studies in the field have been largely descriptive and devoid of functional validation. In order to ensure that the field does not fall short of its promise, cancer systems immunologists will need to meet the higher bar of not only characterizing differences in immune responses to tumors but also performing the requisite experiments to determine the significance of the findings. Compared to other fields in cancer, this task is considerably more challenging. By definition, systems immunology typically uncovers interactions that involve many cellular components operating across multiple organ systems and timescales making perturbation of the components in a physiologically relevant manner difficult. Investigations in immunocompetent animal models, despite their challenges, represent some of the best approaches for testing the hypotheses generated from systems analyses. These models have served as the backbone for many discoveries in the field of immunology and will be necessary for advancing our understanding of tumor immunology. Future studies in the field should utilize advances in modeling approaches, such as ABM, to inform preclinical studies and focus the parameter space to one that is experimentally feasible. In some instances, where animal models are incapable of predicting patient responses, the use of systems approaches to integrate data sets and model human biology can inform the design of new therapies. Despite the challenges that confront the field, cancer systems immunology will continue to provide discoveries that lead to the next generation of life-saving immunotherapies.


A variety of public health interventions have been undertaken in low- and middle-income countries (LMICs) to prevent morbidity and mortality associated with household air pollution (HAP) due to cooking, heating and lighting with solid biomass fuels. Pregnant women and children under five are particularly vulnerable to the effects of HAP, due to biological susceptibility and typically higher exposure levels. However, the relative health benefits of interventions to reduce HAP exposure among these groups remain unclear. This systematic review aims to assess, among pregnant women, infants and children (under 5 years) in LMIC settings, the effectiveness of interventions which aim to reduce household air pollutant emissions due to household solid biomass fuel combustion, compared to usual cooking practices, in terms of health outcomes associated with HAP exposure.ClinicalTrials.gov and Greenfile, combining terms for pregnant women and children with interventions or policy approaches to reduce HAP from biomass fuels or HAP terms and LMIC countries. Included studies will be those reporting (i) pregnant women and children under 5 years; (ii) fuel transition, structural, educational or policy interventions; and (iii) health events associated with HAP exposure which occur among pregnant women or among children within the perinatal period, infancy and up to 5 years of age. A narrative synthesis will be undertaken for each population-intervention-outcome triad stratified by study design. Clinical and methodological homogeneity within each triad will be used to determine the feasibility for undertaking meta-analyses to give a summary estimate of the effect for each outcome.This protocol follows standard systematic review processes and abides by the PRISMA-P reporting guidelines. Searches will be undertaken in MEDLINE, EMBASE, CENTRAL, WHO International Clinical Trials Registry Platform (ICTRP), The Global Index Medicus (GIM), This systematic review will identify the effectiveness of existing HAP intervention measures in LMIC contexts, with discussion on the context of implementation and adoption, and summarise current literature of relevance to maternal and child health. This assessment reflects the need for HAP interventions which achieve measurable health benefits, which would need to be supported by policies that are socially and economically acceptable in LMIC settings worldwide.PROSPERO CRD42020164998 Household cooking, heating and lighting with solid biomass fuel   is commo3 24-h average, PM2.5 25 mg/m3 annual average) [2.5 35 mg/m3 annual average) [Ultimately, economic development is associated with clean fuel transitions , electricity), which are fuels that have been recognised to reduce HAP levels to below World Health Organization indoor air quality (WHO-IAQ) guideline levels (CO 7 mg/maverage) ; howeveraverage) . Interimaverage) , solar saverage) , improveaverage)  and behaaverage) . LPG, foaverage) –17 or inaverage)  and are average)  to impleaverage) . Previouaverage)  and healaverage) , in addiaverage)  and geneThe objective of the systematic review protocol outlined here is to assess, among pregnant women, infants and children (under 5 years) in LMIC settings, the effectiveness of interventions which aim to reduce household air pollutant emissions due to household solid biomass fuel combustion, compared to usual cooking practices, in terms of health outcomes associated with HAP exposure. In addition, any information regarding measures of sustained uptake of the intervention within the selected studies will be extracted and discussed. The findings will inform future intervention studies and policy changes, by generating knowledge of effectiveness for achieving improved pregnancy, perinatal, infant and under 5 years child health outcomes in resource-poor settings worldwide.Established systematic review methods will be used. This protocol has been registered on the International Prospective Register of Systematic Reviews (PROSPERO) (ID: CRD42020164998)  and is pThe following Population-Intervention-Comparator-Outcome-Study design (PICOS) criteria will be used to determining primary study inclusion.Pregnant women (no limitation to trimester or number of previous pregnancies), children in infancy and children under the age of 5 years who are exposed to HAP originating from biomass solid fuel sources, used for cooking, heating and lighting within LMIC settings (World Bank definition 2020) . HAP expAny intervention implemented which aims to reduce household air pollution emissions arising from indoor cooking or heating using solid biomass fuel. This includes interventions such as those which seek to improve access and take-up to cleaner fuels ; structural interventions such as improved cookstoves (ICS), inbuilt stoves (e.g. plancha), ventilation and chimney hood; fuel policy; and behavioural/educational interventions . There will be no limitation to the length of duration of interventions or timing of deployment of intervention (e.g. anytime during pregnancy through to the fifth year of a child’s life).Alternative HAP intervention (e.g. any other intervention within inclusion criteria) or no intervention .Health outcomes relating to pregnancy and perinatal period  and early life  which have been previously associated with HAP exposure. There will be no limits to the follow-up duration of outcome measures.Eligible study designs are randomised control trials (RCTs), non-randomised control trials and quasi-experimental or natural experimental studies . Time-series or before-and-after studies will need to compare the same health outcomes in the same population pre- and post-intervention. It is recognised that before-and-after studies assessing pregnancy outcomes are unlikely to exist due to the difficulties in assessing changes in pregnancy outcomes within subsequent pregnancies, but will not be excluded if present.Any study that did not meet the inclusion criteria in all five areas  will be excluded.ClinicalTrials.gov, The Global Index Medicus (GIM) [The following databases will be used to search for published, in progress and grey literature: MEDLINE (in process and 1947–date), EMBASE (1947–present), The Cochrane Central Register of Controlled Trials (CENTRAL), WHO International Clinical Trials Registry Platform (ICTRP) , Clinicaus (GIM)  and Greeus (GIM) . Furtherus (GIM) .The search strategy, where the database platform allows, will include free-text terms and index terms that are contained within the following structure: “Population” AND (“Intervention” (“Household Air pollution” AND “LMICs”)) , with poTwo reviewers  will independently conduct article selection using the eligibility criteria, within Mendeley, after removal of duplicates. Relevant articles will be determined initially by title and abstracts, followed by retrieval and full paper assessment for selection of papers as per the inclusion criteria, with reasons for exclusion noted at each stage (including the screening stage). Authors will be contacted for clarification if required. Any difference in selected articles between reviewers will be discussed using a third independent reviewer (SEB) to adjudicate any remaining disagreements. The selection process will be graphically illustrated using a PRISMA flow diagram .○ Article title, author and year, geographical setting, study population characteristics , inclusion and exclusion criteria, funding sourcesStudy characteristics○ Type of interventions and comparators, length of intervention, baseline imbalances, issues with uptake and adoption○ Type of air pollution measurements, length of measurement, equipment used and results (if any)Intervention details○ Health outcomes and definitions, method of measurement/classification scales, appropriateness of method, time points measuredHealth outcomesData will be independently extracted from included studies by two reviewers  using an adapted (to type of study design) Cochrane Public Health Group data extraction form , in a MiGiven the likely variability between studies included in the review, in terms of design, population, intervention, comparator, outcomes and data type, the data extraction process will be piloted and then modified if required. Any differences between reviewers in data extracted will be discussed and using a third independent reviewer (SEB) to adjudicate any remaining disagreements.Risk of bias will be assessed using the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies  by two rA narrative synthesis will be undertaken for each population-intervention-outcome triad (as indicated in Fig. I2 value with 95% confidence interval.Following on from the narrative analysis, meta-analysis will be considered within each triad, for each outcome measure, stratified by study design and the type of data available for the outcome. Clinical and methodological homogeneity within each triad will be used to determine the feasibility for meta-analysis where two or more studies in the same grouping report data in the same format at the same/similar time points. Any meta-analysis will be undertaken using a random effects model, due to an assumption that the studies represent a distribution of true effects. Determination of the level of between-study variation not attributable to chance will be calculated and displayed as an It is not anticipated that there will be more than a few studies in each meta-analysis, if even such an analysis is possible. The potential for additional sub-group analysis, sensitivity analysis or the assessment for the existence of small study effects using a funnel plot, will likely not exist. Risk of bias information will be used descriptively to contextualise the findings for each outcome whether a meta-analysis is undertaken or not. Recommendation for the improved conduct of studies in the field will be made.Alternatives to standard practices of household biomass fuel use for cooking, heating and lighting are required within LMICs to combat the morbidity and mortality presented by HAP, with implications for maternal and child health and sustainable economic development. National and local policymakers increasingly recognise the need for effective policy changes to mitigate the health burden associated with HAP exposure; however, there is a lack of evidence regarding affordable, effective and culturally acceptable interventions. This may restrict the progress of such changes, notably in countries which lack widespread access to mains electricity or gas for household cooking, heating and lighting, in addition to limits in transferability of effectiveness of interventions from one context to another. Harm mitigation approaches would bridge the gap before there is widespread affordable access to electricity or gas, but the efficacy of such an intervention requires evaluation. Therefore, this proposed review aims to report the contemporary scientific evidence concerning the effectiveness of HAP mitigation interventions to improve maternal and child health, thus identifying existing research gaps and informing future research and impact activities.


Immune checkpoint inhibitors have revolutionized cancer treatment in the last decade. Despite the progress in immunotherapy, most pancreatic cancer patients still do not derive benefit when receiving immune-based therapies. Recently, resistance mechanisms to immune therapies have been mainly focused on tumor microenvironment properties. Pancreatic cancer is considered one of the most lethal and difficult to treat tumors due to its highly immunosuppressive and desmoplastic microenvironment. Low molecular weight heparins (LMWHs) have been used for the treatment and prevention of thromboembolic disease in these patients. However, many nonanticoagulant properties attributed to LMWHs have been described. Exploiting LMWH properties in a combined treatment modality with immune checkpoint inhibition and chemotherapy could provide a new approach in the management of pancreatic adenocarcinoma patients. The ability of LMWH to interfere with various aspects of the tumor microenvironment could result in both the alleviation of immunosuppression and improvement in drug delivery within the tumor, leading to higher cancer cell destruction rates and more potent immune system activity that would, ultimately, lead to better patient outcomes. Cancer therapy has traditionally been based on targeting tumor cells with cytotoxic chemotherapy or radiotherapy, while surgery is the prevailing modality for long-term disease control and cure . RecentlHowever, despite its proven efficacy in the treatment of many solid and hematological cancers, a significant proportion of patients do not derive benefit from the administration of immunotherapy .The exact mechanism of resistance to immunotherapy is still under investigation, but recent data indicate that the tumor microenvironment plays a major role in establishing immune-suppressive phenotypes, rendering cancers refractory to treatment. One such case is pancreatic adenocarcinoma (PDAC), where immunotherapy has shown only minimal benefit in a very small subgroup of patients bearing the microsatellite instability (MSI) high phenotype . CurrentPDAC has been recognized as a highly thrombogenic tumor, with over 20% of patients suffering from venous thromboembolism (VTE) during the course of their disease; VTE is considered to be the second leading cause of death in these patients . Low molMoreover, there have been numerous studies with experimental models such as cell lines, tissues, and mice in various types of cancers that have demonstrated the antitumor and antimetastatic effect LMWHs possess ,13,14. FCurrent knowledge supports the notion that PDAC consists of a minority of neoplastic epithelial cells surrounded by a high-density desmoplastic stroma that accounts for 60–90% of the total tumor mass . The preFibroblasts are the predominant cell type within the TME where they form a heterogeneous group of cells that contribute to the formation of ECM and support tumor growth . PancreaImmune cells resident in the TME are mostly myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-infiltrating lymphocytes. Regulatory T cells (Tregs) have the capacity to highly infiltrate various tumor types such as pancreatic cancer, and advanced cancers often display higher levels of Treg accumulation. Treg elevation inside the tumors is performed via transforming growth factor beta TGFb, which induces the differentiation of naïve CD4+ T cells into Tregs. In addition, chemokines produced by the tumor play an important role; one example is CCL22, which is able to stimulate CCR4. Tregs suppress the T cell immune responses of antigen-presenting cells, including dendritic cells (DCs) and macrophages. Tregs can kill effector T cells within tumors through the FasL–Fas signaling pathway as well as via granzyme B- and perforin-mediated cytotoxicity, through the reduction of interleukin (IL)-2 and the differentiation/maturation of DCs .The TME is further characterized by intense hypoxia, and when this is combined with vascular compression caused by desmoplasia, it triggers the process of angiogenesis in order to support the continuous nutrient requirement of the tumor . The essK-ras being the most frequent, and the inactivation of tumor suppressor genes, such as p16, p53, and Smad4 [Invasive pancreatic cancer evolves in a step-wise pattern from precursor lesions, most commonly initiated by pancreatic intraepithelial neoplasia. Early genetic events include the mutational activation of oncogenes, with nd Smad4 ,32. Neopnd Smad4 .Pancreatic cancer is considered an incurable malignancy with currently approved chemotherapeutics offering only minimal survival benefit; and immune-based approaches failing to produce satisfactory responses . The higBeyond their role in decreasing VTE occurrence in pancreatic cancer patients, LMWHs may help to increase survival by affecting tumor progression, metastasis formation, and angiogenesis ,36,37. OHeparan sulfate proteoglycans (HSPGs) are conjugates of heparan sulfate and amino acids with a critical role in extracellular matrix protein synthesis and integrity through various interactions with other elements of ECM and plasma membranes. The heparan sulfate chains, due to their broad structural diversity, are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, and enzymes in the TME, regulating the availability and action of these molecules ,39. HepaAlthough LMWHs have never been evaluated in regards to their direct effects on heparanase, they might exhibit a suppressing activity, taking into account that heparin is known to inhibit heparanase  and thatLMWHs exert a multitude of actions that can compromise the metastatic potential of pancreatic cancer and influence responsiveness to therapy. A vital component of the metastatic potential is the cancer cells detaching from the tumor and entering the circulation. There, they attract platelets and form a tumor cell–platelet clot that helps malignant cells evade immune recognition and attack by immune cells . This tuAn alternative mediator of tumor cell–platelet interplay, although not prevailing over P-selectin, is through platelet integrin aΙΙb3, which interacts with integrin ανβ3 on tumor cells, thus contributing to tumor thrombi vascular arrest . The forAnother pathway that contributes to metastasis formation in pancreatic cancer is the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis. PDAC cells overexpress CXCR4, and CXCL12 is expressed in target organs attracting malignant cells to promote metastasis formation . Formingx/a carrying glycoproteins that exist in normal leukocytes and endothelium. Tumor cell surface molecules carrying sialyl Lewisx/a can also be distinguished from selectins, mediating tumor cell interactions with platelets and leukocytes, promoting metastasis. VLA-4 is expressed under physiological conditions in different subtypes of leukocytes but is also found in tumor cells. VLA-4 is able to bind to its ligand VCAM-1 expressed by activated endothelium, thereby mediating adhesion and a subsequent transmigration of tumor cells [LMWHs inhibit P- and L-selectin and VLA-4/VCAM-1-mediated cellular interactions, as shown in or cells ,50. Regaor cells , while Cor cells . Interesor cells . It coulAngiogenesis is a defining prerequisite for tumor growth beyond a specific size, as neovascularization is substantial for oxygen and nutrient support ,55. MainPancreatic cancer angiogenesis is a decisive phenomenon. It is closely related to the hypercoagulable state observed even in early precancerous lesions, such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs), which are correlated with high levels of tissue factor (TF) expression , which iVEGF, also activated by hypoxia-inducible factor-1a (HIF-1a) and released by tumor cells, dominates this extremely complex mechanism, while other proangiogenic features include angiopoietin-2, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), and interleukin-8 (IL-8) . Tumor aWhile primarily used in the treatment and prevention of venous thrombosis, LMWHs have been found to impair tumor neoangiogenesis, as shown in Hypoxia has a significant role in the establishment of immune suppression; apart from inducing neoangiogenesis, hypoxia prompts the release of specific cytokines that promote the recruitment of regulatory T cells (Tregs), polarization of tumor-associated macrophages (TAMs) toward the immunosuppressive tumor-promoting M2 phenotype, expression of immune checkpoints, and downregulation of dendritic cells (DCs) maturation that results in reduced antigen presentation . HIF-1a VEGF has a defining role in immunosuppression by indirectly enhancing hypoxic conditions as a result of an abnormal vasculature. VEGF also acts directly on immune cells within the TME and causes an increase of Tregs, MDSCs, and TAMs as well as the inhibition of DCs and antitumor TAMs .Cancer-associated fibroblasts (CAFs) represent a dominant cell population in the PDAC microenvironment; once activated by cytokines produced by tumor cells, CAFs are responsible for excessive ECM protein production  and desmoplasia as well as cytokine and growth factor release ,82. GrowAs already described, LMWHs inhibit VEGF via TFPI release and alleviate hypoxia in the TME, thus downregulating the expression of HIF-1a and further driving the tumor toward normoxia. LMWHs also inhibit CXCR4, which potentially results in promoting the activity of Teff cells. It is possible that LMWHs also reduce TGF-β expression and the formation of fibrin monomers similar to the effect of enoxaparin in the breast cancer model , which cPancreatic adenocarcinoma remains one of the most challenging neoplasms, exhibiting great treatment hurdles and a dismal long-term overall survival. This is the result of specific features found in PDAC, including a highly desmoplastic stromal TME that acts by limiting effective drug delivery to malignant cells and by suppressing the host immune system to escape cancer cell elimination. Current research focuses on a multitarget approach that utilizes chemotherapy, immune checkpoint inhibitors, and a variety of adjuncts. These are considered to affect different sites within the TME in order to promote effective drug delivery and the normalization of the TME. This could reverse the elevated immunosuppression and allow immune cells to recognize and destroy the malignant ones. Our hypothesis is based on the ability of LMWHs to counteract many of the features described above that characterize the TME by promoting vascular normalization and the reprogramming of the microenvironment to obtain a more immune-supportive type. LMWHs are safely used in the prevention and treatment of VTE, which in PDAC is a significant factor associated with disease-related mortality. However, LMWHs are also attributed to various nonanticoagulant activities that can be exploited to target elements in the TME. Achieving this would allow both efficient chemotherapeutic drug delivery as well as effective immune cells that would infiltrate the tumor site, ultimately resulting in ameliorating the treatment efficacy and outcomes for patients.


NETosis is a type of regulated cell death dependent on the formation of neutrophil extracellular traps (NET), where net-like structures of decondensed chromatin and proteases are produced by polymorphonuclear (PMN) granulocytes. These structures immobilise pathogens and restrict them with antimicrobial molecules, thus preventing their spread. Whilst NETs possess a fundamental anti-microbial function within the innate immune system under physiological circumstances, increasing evidence also indicates that NETosis occurs in the pathogenic process of other disease type, including but not limited to atherosclerosis, airway inflammation, Alzheimer’s and stroke. Here, we reviewed the role of NETosis in the development of organ injury, including injury to the brain, lung, heart, kidney, musculoskeletal system, gut and reproductive system, whilst therapeutic agents in blocking injuries induced by NETosis in its primitive stages were also discussed. This review provides novel insights into the involvement of NETosis in different organ injuries, and whilst potential therapeutic measures targeting NETosis remain a largely unexplored area, these warrant further investigation. Cell death is commonly segregated into necrosis and apoptosis; apoptosis being programmed cell death, for instance during development and physiological cellular turnover, whilst necrosis predominantly takes place in an unregulated manner . NETosisAlthough NETosis is closely associated with NET formation, not all NET formation requires the process of cell death to take place beforehand. According to Nomenclature Committee on Cell Death, the term ‘NETosis’ should only be used in the context of cell death, and not just based on the presence of NET formation .Two main pathways of NET formation have been described and categorised according to their dependence on the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathway Fig.  5].Fig..Fig.5].FThe NADPH oxidase-dependent molecular pathway of NET formation begins with activation of neutrophil surface receptors by stimuli derived from pathogenic or non-pathogenic sources, such as cholesterol or urate, and ends with cellular lysis. These stimuli trigger calcium release from the endoplasmic reticulum (ER), resulting in the activation of protein kinase C (PKC) and the assembly of the NADPH oxidase complex generating reactive oxygen species (ROS) . FollowiDegradation of NETs can take place through several pathways, for example, by DNases , or endo2 and HCO3− levels, which modulate neutrophil activation. This explains why NETs form more readily in the periphery of an inflammatory site, where the pH is more alkaline . Exa. Exa4]. in vitro to reduce NETosis in neutrophils that are stimulated with Staphylococcus aureus but not in those stimulated with PMA. The TLRs involved in S. aureus-induced NET formation seem to be TLR2 and TLR4, as agonists of these receptors rescued Dex inhibition. Interestingly, although Dex reduced NET formation, it did not significantly affect ROS production [Dexamethasone (Dex) has been shown oduction .Calcineurin is a calcium-dependent serine/threonine protein phosphatase that is important for neutrophil activity. Many stages of NETosis induction depend upon calcium mobilisation. Hence, modulators of the calcineurin pathway are potential pharmacological inhibitors of NET formation. Cyclosporine A (CsA), an antagonist of the calcineurin pathway, has been shown to reduce the effect of key physiological activators of neutrophils. This effect on NETosis may in part explain CsA’s efficacy in RA  and sterThe mitochondria are a powerful source of ROS . ROS scaUsing a murine model of atherosclerosis, Knight and colleagues have shown that pharmacological inhibition of PAD4 using 11 weeks of daily Cl-amidine injections reduced NET-induced vascular damage, with delayed plaque progression in the carotid arteries . The samDNase therapy has been proposed to improve outcomes in CF patients through reducing mucous viscosity. However, it appears that recombinant DNAse does not reduce the load of DNA/protein complexes seen in NETosis. One solution to this is to combine elastase with DNAse, in order to degrade histones and provide DNAse access to chromatin. This combination has been shown to enhance solubilisation of sputum .In contrary to the aforementioned mechanisms of NETosis inhibitors, tetrahydroisoquinolines (THIQs) are a new class of NET formation inhibitors that do not target ROS formation or granular protein activity. As functional neutrophils are paramount to maintaining immune reactivity, this difference offers an advantage to selectively target NET overproduction without impairing normal function. The exact molecular mechanisms of THIQs are yet to be determined; however, it is known that THIQ inhibition of NETosis take place at micromolar concentrations and possibly at different stages of NET formation .When regulated as part of normal physiology, NETs are anti-microbial and fundamental to the innate immune system. Dysregulated NET formation contributes to the pathogenesis of a plethora of diseases. This review has summarised the role of NETosis in pathologies of multiple body systems, as well as highlighted the stages of NETosis that has so far been investigated as emerging pharmacological targets. These putative strategies seem to hold therapeutic potential and warrant further investigation.


There are reports of outbreaks of COVID-19 in prisons in many countries. Responses to date have been highly variable and it is not clear whether public health guidance has been informed by the best available evidence. We conducted a systematic review to synthesise the evidence on outbreaks of highly contagious diseases in prison.We searched seven electronic databases for peer-reviewed articles and official reports published between 1 January 2000 and 28 July 2020. We included quantitative primary research that reported an outbreak of a given contagious disease in a correctional facility and examined the effects of interventions. We excluded studies that did not provide detail on interventions. We synthesised common themes using the Synthesis Without Meta-analysis (SWiM) guideline, identified gaps in the literature and critically appraised the effectiveness of various containment approaches.We identified 28 relevant studies. Investigations were all based in high-income countries and documented outbreaks of tuberculosis, influenza (types A and B), varicella, measles, mumps, adenovirus and COVID-19. Several themes were common to these reports, including the public health implications of infectious disease outbreaks in prison, and the role of interagency collaboration, health communication, screening for contagious diseases, restriction, isolation and quarantine, contact tracing, immunisation programmes, epidemiological surveillance and prison-specific guidelines in addressing any outbreaks.Prisons are high-risk settings for the transmission of contagious diseases and there are considerable challenges in managing outbreaks in them. A public health approach to managing COVID-19 in prisons is required.CRD42020178827 Prisons and other custodial facilities are high-risk environments for infectious disease outbreaks such as COVID-19.People in prison (PIP) may be susceptible to serious complications of COVID-19 due to increased prevalence of underlying health conditions.Prisons are porous environments, and thereby prison outbreaks have the potential to spread to surrounding communities.Screening, contact tracing and isolation appear to be the most applicable infection control strategies.Symptom screening can be ineffective as PIP may hide symptoms due to stigma, lack of trust in medical confidentiality in prisons, and to avoid prolonged medical isolation.Effective prison population reduction strategies, such as releasing persons at low risk of future serious offending and not incarcerating those charged with low-level offences, represent a major research gap.PIP and correctional staff should be communicated clear and up-to-date information about health risks, and prevention and control measures being implemented.Extensive collaboration between prisons and public health authorities is essential to leading a comprehensive public health response that takes into account the particular environmental and physical conditions, healthcare services and security constraints of each prison.The benefits of prolonged infection control strategies need to be weighed against the potential negative consequences of such measures on the mental health of PIP.COVID-19 has developed into an international public health crisis accompanied by restrictions on daily life and more targeted measures . In prisons, barriers to translating such interventions are considerable, and there is a high risk of rapid transmission due to high population density and turnover, overcrowding and frequent movements within and between establishments.15–17There is some evidence of high rates of infection of COVID-19 in prison. One non-governmental organisation estimated that in early June 2020, across 79 countries, 73 254 PIP had tested positive for COVID-19, of which more than 1100 had died from complications.28A number of commentaries and surveys in specific geographical areas have been published about the implications of COVID-19 in prison,We conducted a systematic review of outbreaks of contagious diseases in correctional facilities according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Synthesis Without Meta-analysis guidelines.10.1136/bmjgh-2020-003201.supp1Supplementary dataCitations were screened independently by two researchers (GB and SZ). Studies were eligible for inclusion if they were published after 2000, reported a suspected or confirmed outbreak of a given contagious disease, as defined by authors, in a correctional facility and examined intervention effects. Correctional facilities were defined as those housing people in custody . We solely included quantitative studies of primary research that were written in English and were published as either peer-reviewed journal articles or official governmental reports. Studies using different research designs to provide an empirical evaluation of diverse intervention effects were considered.We developed a standard data extraction form to collect information from eligible studies on year of publication, geographical location, outbreak setting, population, type of contagious disease, outbreak period, number of confirmed cases, and detailed information regarding contaminated individuals and deaths, if applicable. Three reviewers  conducted qualitative data analyses by identifying common themes across the included studies. GB and SZ read and extracted findings from all included studies, with a particular focus on (1) presentation of the outbreak; (2) description of outbreak control measures; (3) their impact on PIP, staff and the local community. The two reviewers independently identified common themes in the included studies using a thematic analysis approach, and subsequently compared their analyses. Overlapping themes were combined and unique ones were retained (including specific recommendations). Discrepancies were resolved through discussions with another reviewer (DW). Finally, we organised the themes to provide an overall interpretation of the findings, and referenced each element with the study from which it was derived. This narrative synthesis was performed using NVivo V.12 Software for qualitative data analysis.41People-centred language is employed to describe people who experience incarceration . This terminology refers to incarcerated persons only and does not include members of staff.42This research was done without patient or public involvement.The initial search yielded 5959 relevant articles, of which 154 full-text articles were screened. Twenty-eight publications met inclusion criteria and were included in the final sample .43–70 ChTwenty reports were based on single-centre studies that gave a chronological description of an outbreak and the measures employed by the institution. Some also reported on multiple custodial facilities.70Twelve studies underscored the potential community impact of prisons during an outbreak.56 62 63 70Interagency collaboration is integral to managing infectious disease outbreaks.59Prisons have limited access to external information (and mostly no internet provision within cells), so special measures are required to convey public health messages.52 66Fourteen reports suggested that screening was essential to mitigate the impact of the outbreak.66Both symptom screening  and serial testing were used to mitigate transmission of SARS-CoV-2 infection in the one COVID-19 study. Persons in affected dormitories were tested on three separate occasions during the investigation period in order to classify cases as asymptomatic, presymptomatic, or symptomatic.74All studies on varicella, measles and mumps reported information in regards to serology screening to detect susceptibility and identify at-risk individuals.61Restrictions on movement and mixing between PIP can be challenging, with logistical implications for essential legal and prison processes, as well as potential effects on rehabilitation and well-being because of disruption to structured therapeutic programmes, social contacts and legal advice. The range of restrictions varied, including limiting movements within a prison,53Isolating PIP, either due to suspected or confirmed disease or for quarantining potential contacts,50Contact investigation to identify potential asymptomatic cases is a key component of outbreak response, especially where there is prevalent nosocomial transmission (as is the case with COVID-19) , screening new entrants, contact tracing and isolation of suspected cases. Some unique challenges to prisons were also described, including high rates of movement between and within establishments, and the large number of potential contacts based on the high turnover in many prisons, regular visitors and regular association with prison staff. These may be exacerbated in certain settings, such as local jails and immigration removal centres, where there can be very high turnover and overcrowding is common with poorer physical infrastructure. Epidemiological surveillance is therefore more important in these settings.PIP may be more likely to hide symptoms due to stigma, lack of trust in medical confidentiality in prisons, and the implications of further restrictions in people whose liberty has already been deprived. At the same time, COVID-19 is quite different to the outbreaks described in previous work, which have been all been self-limiting. It could spread widely and quickly within an institution in the absence of the right interventions .Although we did not formally assess study quality, all included investigations were observational and reported on a specific outbreak, subsequent prison responses and their impact. The literature was confined to either highly contagious diseases with low morbidity and mortality (measles and varicella), moderate contagious outbreaks with low mortality (influenza), moderate contagious outbreaks with potentially high morbidity, but for which treatment is available (TB) and the rate of tertiary spread is not rapid. Only one study described an outbreak of COVID-19 in prison.Six main challenges to managing outbreaks of contagious infections were identified, with relevance to different interventions . Low uptThe most notable gap was how to most effectively reduce the prison population during any outbreak. This would involve releasing persons at low risk of future serious offending and not incarcerating people charged with low-level offences.All included studies were based in high-income countries and some recommendations may not translate to low-income and middle-income settings. There is a pressing need for research to be conducted in those settings, who make up a majority of PIP worldwide.Although there is some observational evidence on highly contagious disease outbreaks in prison, COVID-19 represents a unique challenge to prisons due to its distinct epidemiology. Previous outbreaks of other diseases have been self-limiting, while prisons could become reservoirs for COVID-19 infection to the community if appropriate public health measures are not instituted. All prisons should consider communicating clear and regular health information updates to PIP and staff, isolating all new prison entrants, contact tracing, and providing a highly responsive testing regime to all people who are incarcerated and prison staff, including prioritisation for early adoption and implementation of diagnostic assays and tests. Overcrowding needs to be tackled by reducing the number of new arrivals and releasing low risk persons, while taking into account that many individuals released from prisons will find themselves in shelters and other unstable housing situations, which necessitates planning and coordination between public agencies. Such planning will require time and interagency cooperation so that risks are mitigated, including of initial placements breaking down.


Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients. The incidence of thyroid cancer has steadily increased over the past decades, with an annual percent change of +4.7 for both genders in the period between 2004 and 2013 . ApproxiThe mechanisms of this resistance have been partially elucidated and include the up-regulation of multidrug resistance and antiapoptotic proteins ,16,17 anRecent experimental evidence has demonstrated the presence of a small subpopulation of cells within the tumor mass, namely cancer stem cells (CSCs), which may play a role in tumor initiation, growth and metastatic spread . These CIn this regard, we reviewed the possible role of CSCs in promoting progression and resistance to current anti-cancer treatment in advanced and PDTCs.The thyroid gland may give rise to several histological tumor types and subtypes that differ in cellular shape, molecular profile, biological behavior and prognosis. Based upon histopathological features, thyroid cancer is divided into four main subtypes: papillary; follicular; anaplastic, which is follicular-derived thyroid cancer; and medullary thyroid cancer (MTC), which originates from the neuroendocrine C-cells. Papillary (PTC) and follicular (FTC) thyroid cancers are usually classified as differentiated thyroid cancers (DTCs), as they maintain several histological features of follicular cells. DTC is three times more frequent in women than in men and has a peak incidence in the third and fourth decades . ApproxiDNA sequencing studies have identified the most relevant genetic alterations in thyroid carcinomas. Several of these mutations occur in genes with kinase activity, which are involved in the mitogen-activated protein kinase (MAPK), the phosphatidylinositol 3-kinase (PI3K) pathways or both. These signaling cascades transmit growth signals to the nucleus and their aberrant activation has been implicated in the onset, progression and aggressiveness of thyroid cancer. The increasing knowledge about these molecular alterations has allowed the development of new drugs targeting these pathways, such as multi-tyrosine kinase inhibitors (MKIs) .The Cancer Genome Atlas (TCGA) program  has receAs BRAF and RAS mutants are the predominant driver of oncogenes, they determine two different signaling patterns and tumor phenotypes. Tumors with true papillary architecture are characterized by BRAFV600E mutations and RET fusions and are classified as “BRAFV600E-like”, which display higher MAPK transcriptional output and lower expression of genes involved in iodine metabolism. On the other hand, tumors with follicular architecture are characterized by RAS mutations and classified as “RAS-like”, with a lower MAPK signaling output and relatively preserved expression of iodine-related genes . Thirty TCGA genomic study in PTCs, along with some recent next-generation sequencing studies performed in PDTCs and ATCs, support a gradual tumor progression from well-differentiated to poorly differentiated and ultimately to ATCs through the accumulation of key additional genetic alterations. While RAS and BRAF V600E mutations remain the main drivers in PTCs and PDTCs, other mutations such as TERT and TP53, as well as alterations of the PI3K/AKT pathway are more frequent in ATC .Most MTCs display a mutation in the RET proto-oncogene, while rarely H-RAS, K-RAS or N-RAS mutation . RET mutAlong with other malignances, experiments based upon the exposure to chemicals led to hypothesizing the multi-step carcinogenesis model in thyroid cancer. According to this model, thyroid cancer cells arise from the gradual accumulation of genetic alterations within normal thyroid epithelial cells, leading to progressive acquisition of increased proliferation and an invasive phenotype  Figure .In this respect, mutations in both tumor suppressor genes and proto-oncogenes are crucial in the carcinogenesis model (driving mutations). As discussed above, a key mutation in PTC is V600EBRAF , and RASIdentifying molecular abnormalities that underlie tumor onset and progression may be helpful to better depict the multi-step carcinogenesis model and also analyze those mechanisms responsible for drug resistance.Development of either pre-existing or acquired resistance is based upon either the presence or progressive accumulation of specific molecular alterations in thyroid cancer (TC) cells. On the other hand, several studies, indicating that the cancer cell population is heterogeneous and molecular alterations are not present in the whole tumor bulk, were allowed to depict the “cancer stem cell hypothesis”. This hypothesis was firstly established by the previous observation that leukemia may contain hierarchical multi-lineage cells . In thisIn this perspective, some authors hypothesized that thyroid cancer may be a cancer stem cell driven disease ,41,42. AThe presence of adult stem/progenitors within the thyroid gland was first postulated by Dumont who estimated the theoretical number of 1 stem cell every 1000 mature thyroid follicular cells . Later, Finally, the observation that patients who received hematopoietic stem cell transplantation have an increased risk of thyroid cancer led to the hypothesis that hematopoietic stem cells from bone marrow may migrate to thyroid tissue and reside there for a long time . HoweverAccording to this view, a given tumor may behave as an organoid containing both cancer stem cells and cancer differentiated cells. These CSCs may originate from either normal stem cells (NSCs) through a transformation process or from differentiated cancer cells as the result of a dedifferentiation process  Figure b. The CSThe fetal cell carcinogenesis hypothesis in thyroid cancer previously proposed by Takano is in line with this notion. Indeed, he postulated an initial carcinogenetic event occurring in fetal thyroid cells, which are present during the fetal life until childhood . This muThis hypothesis implies that the carcinogenetic event occurs in the early phases of thyroid development and the transforming potency of BRAF and RET oncogenes mostly depends on the inhibition of differentiation of thyroid precursors. On the other hand, this model is in accordance with the low proliferation rate of thyroid cells, the late appearance of the tumor in adult age and is partially supported by recent molecular studies ,59,60,61To explain the possible involvement of thyroid cancer stem cells in chemoresistance, the peculiar features of both normal and cancer stem cells are described below. Normal stem cells display two hallmark properties: (a) self-renewal  and (b) potency  . As a coSimilar to NSCs, CSCs are a subpopulation within a tumor mass with long-term self-renewal and the ability to generate a progeny differentiating into different tumor cells that variably contribute to tumor expansion . After iA growing body of evidence highlights the importance of the IGF system in the biological behavior of thyroid CSCs ,83. SeveResistance to therapy continues to be the main challenge in achieving long-term remission or cure in patients with advanced thyroid cancer. Multiple underlying mechanisms have been identified over the past several years. For example, the mutations in downstream effector molecules of tyrosine kinase receptors ,93, the Thyroid cancer is historically refractory to chemotherapy and radiotherapy. Since their identification and characterization in thyroid cancer, CSCs have emerged as the possible main player in cancer for the resistance to conventional therapies. Indeed, CSCs exhibit a quiescent state characterized by slow cell cycling. Thus, it is possible that, unlike the highly proliferating cells, the CSC subpopulations may not be eradicated by chemotherapy and radiotherapy, causing the relapse of the disease. This hypothesis is reinforced by the observation by Giuffrida et al.  who treaIt is well-known that CSCs have an increased ability to extrude drugs via several multidrug resistance-related ABC transporters, including ABCB1/P-gp and ABCG2/BCRP, which confer drug resistance to the cell. A significant increase in the SP has been detected in a doxorubicin-resistant thyroid cancer cell subline, Hth74R, enriched with Oct4-positive cancer stem-like cells with respect to the parental Hth74 cell line. Furthermore, pharmacological inhibition of ABC transporters restored the sensitivity of Hth74R cells to doxorubicin . Carina One of the most important mechanisms by which CSCs survive cancer treatment is represented by deregulation of signaling pathways involved in stem cell self-renewal . The actAnother factor contributing to the therapy resistance of CSCs is the activation of the bypass pathways to therapeutic insult. Our recent report indicates that treatment with the BRAF inhibitor vemurafenib causes a paradoxical stimulatory effect on mutant BRAF V600E in thyroid cancer stem cells, differing from their parental monolayer cultures. Indeed, while the of BRAFV600E activity inhibition by vemurafenib resulted in decreased ERK phosphorylation and inhibition of cell growth in a mutant BRAFV600E whole thyroid cancer cell population, it induced a re-activation of ERK and a progressive increase in AKT activation in a CSC subpopulation. Importantly, we found that the resistance of thyroid CSCs to vemurafenib depends on the higher MAP3K8 expression. Indeed, pharmacological inhibition of MAP3K8 sensitizes thyroid BRAFV600E mutant CSCs to treatment with vemurafenib, suggesting therefore that this cell subpopulation can be involved in the failure of the therapies targeting BRAFV600E in advanced thyroid cancer .EMT has also been shown to promote resistance to treatment with kinase inhibitors, establishing a link with the resistant phenotype of CSCs . As discAt the same time, many non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), are reported to promote drug resistance by regulating the EMT process and specific signaling pathways in CSCs . LncRNAsMost importantly, the interactions of lncRNA with signaling pathways can regulate the therapy resistance property of thyroid CSCs. For example, papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) is a recently recognized tumor-suppressive lncRNA whose expression has been found to be strongly down-regulated in thyroid cancer tissue compared to healthy counterparts. PTCSC3 has been reported to regulate thyroid cancer cell proliferation and migration via modulating Wnt/β-catenin signaling . MoreoveBRAF-activated non-coding RNA (BANCR) has been observed to be over-expressed in cancer tissue compared with the adjacent normal tissue in patients with thyroid cancer, which promotes the growth of thyroid cancer cells and CSC-like phenotypic characteristics via the RAF/MEK/ERK signaling pathway . Given tAccumulating evidence has suggested that the well-described oncogene nuclear enriched abundant transcript 1 (NEAT1) plays a significant role in the therapy resistance of various tumors, including thyroid cancer . Yan andInterestingly, lncRNAs can also be packaged into exosomes, a subset of multi-vesicular bodies (MVB), and act as modulators in cell–cell communication . In a reThe ability of CSCs to be resistant to current anti-cancer therapies, suggests the needed development of novel and effective therapeutic strategies to eradicate CSCs specifically. A promising strategy could be the inhibition of specific CSC-generating and CSC-expanding pathways, such as the Wnt, Shh, JAK/STAT3 and PI3/AKT signaling pathways, which regulate thyroid CSC self-renewal and tumor growth. Although encouraging preclinical findings have suggested that the agents that inhibit CSC pathways suppress thyroid cancer cell growth and indeed enhance cellular sensitivity to both targeted and conventional therapy. Unfortunately, there are no ongoing clinical trials targeting CSCs in advanced thyroid cancer. The inhibition of mTOR, a component of the PI3K/AKT signaling pathway, has shown limited activity in advanced or metastatic thyroid cancer , while tFinally, the effective eradication of CSCs will require a better understanding of the properties of CSCs, including lncRNA and exosome-mediated cell-cell communication. Several lncRNAs have been shown to contribute to the mechanisms of anti-cancer therapy resistance in thyroid CSCs. However, further research is needed to determine whether lncRNAs may represent a therapeutic approach to overcome resistance in thyroid cancer. Interestingly, modified exosomes delivering therapeutic agents, such as pro-apoptotic proteins, ncRNAs, and drugs could be used to treat cancer. Thus, the understanding of resistance mechanisms involving exosome-mediated cell-to-cell communication needs to be addressed by future therapeutic strategies for advanced thyroid cancer.The vast majority of thyroid carcinomas are cured well by surgery and radioiodine, while a minor but consistent group are refractory to radioiodine therapy and, unfortunately, very resistant to conventional chemotherapy. This carcinoma subgroup is often progressive and may cause patient death in the short term. Molecular studies identifying mutations driving thyroid cancer progression allowed the use of selective inhibitors targeted to deregulated pathways. To date, however, these drugs have not provided any significant and durable effect, and their actions are often cytostatic rather than toxic. In addition, selective inhibitor use in the long term often results in the progressive development of tumor resistance and sometimes in impressive tumor dedifferentiation and relapse.Recently, the identification of normal stem cells in human thyroid and, more specifically, cancer stem cells within thyroid carcinomas has shed light onto a possible mechanism of thyroid cancer progression, dedifferentiation, relapse and chemoresistance due to their great ability for DNA repair and sustaining epithelial to mesenchymal transition. Hence, understanding the mechanisms regulating thyroid cancer stem cell proliferation and survival may provide valuable tools for tumor targeting that may be adjuvant in the treatment of aggressive thyroid carcinomas. In this light, studies aimed at describing pathways specifically activated in thyroid cancer stem cells and responsible for the interaction with the stem cell niche microenvironment are useful to developing novel drugs for these lethal tumors. Moreover, evaluation of the mechanisms underlying the differentiation process of both normal and cancer thyroid stem cells may prove useful for tailoring re-differentiating therapies aimed at restoring radioiodine uptake in less differentiated forms. It is also reasonable to suppose that isolation of thyroid cancer stem cells ex vivo after tumor surgery and debulking may provide a useful preclinical model for testing more selective and effective drugs.Although these are promising and intriguing results, several issues and limitations should be better addressed. A comparative analysis of the characteristics of CSCs from different types of tumors and thyroid carcinomas has not yet been performed. Moreover, the in vivo models used in these studies do not recapitulate the biological complexity of tumors. Most studies on CSCs in general, and in thyroid CSCs in particular, addressing the ability to form tumors and to respond to therapies were performed in immune-deficient mice, in the absence of an active immune response. It should also be taken into account that thyroid CSCs live in a specific niche that sustains their survival. Most studies were performed with isolated CSCs devoid of the microenvironment present in the whole patient. Hence, the environmental factors in thyroid CSC niches that could influence the response to the different specific therapies are not well understood and should be studied in detail. A limit to studying isolated thyroid CSCs is also to ignore the possibility that CSCs share some signaling pathways with normal stem cells in vivo. Hence, not all the regulatory pathways that contribute to the biology of CSCs are appropriate targets in cancer treatment because of the important side effects. Another open question is whether CSCs should be activated or arrested by cancer therapy, because this action is dependent on tumor type and histotype and may be crucial for the restoration of RAI uptake. In conclusion, despite the compelling evidence in this field, targeting thyroid cancer stem cells at bedside is not available to date. However, this therapeutic option remains a useful possibility to prevent tumor relapse and progression, as well as to restore RAI uptake. Clinical trials in this direction should be encouraged.


Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant cancer. Five-year survival rate is about 9%, one of the lowest among all solid tumors. Such a poor outcome is partly due to the limited knowledge of tumor biology, and the resulting lack of effective treatment options and robust predictive biomarkers. The leukemia inhibitory factor (LIF) has recently emerged as a potential biomarker and therapeutic target for PDAC. Accumulating evidence has suggested that LIF plays a role in supporting cancer evolution as a regulator of cell differentiation, renewal and survival. Interestingly, it can be detected in the serum of PDAC patients at higher concentrations than healthy individuals, this supporting its potential value as diagnostic biomarker. Furthermore, preliminary data indicate that testing for LIF serum concentration or tissue expression may help with treatment response monitoring and prognostication. Finally, studies in PDAC mouse models have also shown that LIF may be a valuable therapeutic target, and first-in-human clinical trial is currently ongoing. This article aims to review the available data on the role of LIF in PDAC promotion, and to discuss the evidence supporting its potential role as a biomarker and target of effective anti-cancer therapy in this setting. For all cancers combined, the 5-year relative survival rate between 2009 and 2015 in the USA was 67%  and the inherent chemoresistance. There is still limited knowledge of the mechanisms underlying PDAC growth, resistance to treatment and progression, this ultimately resulting in the lack of robust predictive and prognostic biomarkers and scarce availability of effective treatment options. CA 19-9 is the only biomarker approved for PDAC by Food and Drug Administration in 2002. Since then, no improvement has been made in this area. As far as systemic treatment is concerned, only marginal progress has been made especially if compared with other tumor types and, with the only exception of erlotinib and olaparib, the therapeutic armamentarium for PDAC is orphan of targeted treatments that could substantially improve survival.The leukemia inhibitory factor (LIF) is a cytokine involved in a number of physiological processes including regulation of cell differentiation, renewal and survival. Further to the results of preliminary studies supporting its role also in the mechanisms of PDAC promotion Fig. , a substIn this article, we provide an overview of LIF involvement in key cancer-promoting processes. Furthermore, possible clinical applications of this cytokine in the setting of PDAC are discussed.LIF was named after its ability to trigger final differentiation and prevent continuous growth of myeloid leukemic cells -β direct stimulation, this contention was questioned by the results of a recent study showing mediation of LIF that directly binds on the surface of CAFs and induces their activation via the JAK/STAT3 pathway  and JAK/STAT3 pathway-dependent genes transcription in pancreatic cancer cells are three primary mechanisms responsible for the maintenance of PDAC growth, invasion and metastatization. The ECM is a complex network of non-cellular components, mostly collagen fibres, that is responsible for cell-to-cell interactions, adhesion and proliferation. ECM remodelling occurs through increased deposition of polarised collagen bundles, tissue stiffening and metalloproteinase overexpression. This results in a number of events such as cell invasiveness along aligned collagen fibres, a pro-metastatic environment phenotype, insensitivity to growth inhibitors, and self-maintained growth and angiogenesis  is a poor prognostic factor in PDAC, being associated with higher local recurrence rate, shorter survival and increased neuropathic pain  and the poorly immunogenic microenvironment  are known to contribute to treatment resistance in PDAC. As discussed already, maintaining cancer stem cell-like phenotype contributes largely to chemoresistance  to 7th week (median LIF concentration level reaching 50 pg/mL) after caerulein exposure. In contrast, LIF serum concentrations were at the lowest levels of detection in a chronic pancreatitis model and in a control group  in PDAC tissue samples has also been assessed. In 77 PDAC patients LIF median tumor expression was up to sevenfold higher than in paired healthy pancreatic tissue samples  cohort of early-stage (I or IIa) PDAC patients, high LIF mRNA expression was associated with shorter disease-free survival (DFS) when compared with low LIF mRNA expressing tumors   . In orthotopic mouse models, this was found to be effective against various types of cancer including glioblastoma, NSCLC, ovarian cancer, CRC and PDAC , the leading effector pathway of LIF stimulation in cancer cells, were stopped due to futility (Boston Biomedical LIF was extensively studied in embryology, immunology, transplantology and hematology over last 30 years. The renowned interest for this cytokine has recently been prompted by the discovery of analogies between LIF functions in aforementioned areas and cancer evolution. LIF is involved in a number of key processes underlying cancer growth and progression including immunotolerance, PNI, chemo and radioresistance, cancer stem cell-like phenotype maintenance, EMT, and TME development Fig. , Table 1


Blood-contacting medical devices of different biomaterials are often used to treat various cardiovascular diseases. Thrombus formation is a common cause of failure of cardiovascular devices. Currently, there are no clinically available biomaterials that can totally inhibit thrombosis under the more challenging environments . Although some biomaterials reduce protein adsorption or cell adhesion, the issue of biomaterial associated with thrombosis and inflammation still exists. To better understand how to develop more thrombosis-resistant medical devices, it is essential to understand the biology and mechano-transduction of thrombus nucleation and progression. In this review, we will compare the mechanisms of thrombus development and progression in the arterial and venous systems. We will address various aspects of thrombosis, starting with biology of thrombosis, mathematical modeling to integrate the mechanism of thrombosis, and thrombus formation on medical devices. Prevention of these problems requires a multifaceted approach that involves more effective and safer thrombolytic agents but more importantly the development of novel thrombosis-resistant biomaterials mimicking the biological characteristics of the endothelium and extracellular matrix tissues that also ameliorate the development and the progression of chronic inflammation as part of the processes associated with the detrimental generation of late thrombosis and neo-atherosclerosis. Until such developments occur, engineers and clinicians must work together to develop devices that require minimal anticoagulants and thrombolytics to mitigate thrombosis and inflammation without causing serious bleeding side effects. In pathological states involving arterial and/or venous thrombosis, the close interrelationship between inflammation and thrombosis becomes apparent. In both arterial and venous thromboses, inflammation can trigger thrombosis and thrombosis can amplify inflammation  and venous thromboembolism that involves leg deep vein thrombosis and pulmonary embolism are significant contributors to worldwide disease burden  endothelial injury, (b) venous stasis, and (c) hypercoagulability Virchow, . An extein vivo during inflammation (10–100 mg/L), CRP can increase 75 times the tissue factor procoagulant activity in monocytes with concomitant increase in tissue factor antigen levels  contribute to thrombosis since at concentrations commonly found Tissue factor is pivotal in initiating inflammation-induced thrombin generation . The comEndothelial cells have antithrombotic properties , participate in the formation of platelet and fibrin thrombi , synthesize and secrete plasminogen activators and inhibitors, synthesize and secrete angiotensin-converting enzyme, bind hormones, bind lipoproteins, are targets of autoimmune diseases, and directly participate in immune reactions. Endothelial cells are the first barrier between the blood and extravascular space influencing circulation's structural and functional integrity Jaffe, . The endThe first step in intravascular thrombosis involves tissue factor –3 exposeMicroparticles, extracellular microvesicles  detached from activated  or apoptotic cells and platelets , 2, harbA link between venous and arterial thrombosis is preeminent since (a) both venous and arterial thromboses share risk factors ; (b) several conditions  account for both venous and arterial thromboses; (c) patients with venous thromboembolism have greater risk for developing arterial thrombosis; and (d) both venous and arterial thromboses are triggered by biological stimuli concomitantly activating coagulation and inflammation  and veins  to restore and maintain homeostasis.These devices must meet various requirements for a patient's long-term use. We will focus on blood compatibility with device “foreign” surfaces. Although normal endothelium is thromboresistant, foreign surfaces have no such safeguards. Thrombosis is the result of flow disturbance and surface biocompatibility   or anticoagulants . Modification of material surfaces to minimize defense reaction or localize specific anticoagulant release can have clinical benefits, so medical device manufacturers have concentrated on the prevention of protein and cell adsorption, avoidance of thrombin generation and fibrin formation, as well as avoidance of platelet activation.This phenomenon is based on a physical principle where protein adsorption is facilitated by electrostatic and hydrophobic interactions between the adsorbed protein and an external surface. Different materials have been developed to coat surfaces minimizing these interactions. Some of these include albumin, poly(ethylene oxide), and pyrolytic carbon.in vitro  in peripheral circulation that functionally arterialize have not been possible primarily due to thrombosis  and the venous system.Coronary artery bypass grafting remains an essential procedure to treat patients with multivessel coronary artery disease, especially in diabetic patients. Coronary artery bypass grafting remains key to treat multivessel coronary artery disease. Over 400,000 US patients/year undergo coronary artery bypass grafting  studies are key to predict performance in humans. There is not one ideal stent, but different stents are better suited for different situations. For example, small diameter stents have been designed for the treatment of narrow vessels (<2.5 to 3.0 mm). Since real-world experience showed frequent off-label usage, there has been a broadening of the indications for drug-eluting stent placement. Bare-metal stents are not outdated, but drug-eluting stents have largely replaced them. It has been argued that practice adaption and application of drug-eluting stents have been too fast. Bare-metal stents are still used in about 20% of percutaneous coronary interventions. Bare-metal stents may be preferable in large vessel lesions with acute myocardial infarction. Bare-metal stent device costs are lower than drug-eluting stent device costs. Comparing costs requires considering long-term outcomes that favor drug-eluting stents because of less reinterventions and thus improved cost-benefit analyses  increased substantially from 2.2 to 8.4% from March 2011 to January 2013  is limb ischemia needing thrombectomy with an incidence of 0.9 to 26.7%  are broadly used, relatively safe, and cost-effective providing long-term intravenous access for extended antibiotic therapy, chemotherapy, total parenteral nutrition, and other applications. Central venous catheter-related thrombosis becomes symptomatic in about 5% of patients (Kamphuisen and Lee, Inferior vena cava filters used in venous thromboembolism patients with contraindications to anticoagulation reduce pulmonary embolism but have increased long-term risks of recurrent deep vein thrombosis and inferior vena cava filter thrombosis (Andreoli et al., In the past several years, research has been conducted to identify proinflammatory molecules, like CRP and its distinct isoforms native pentameric CRP and mCRP, as markers/mediators of atherosclerosis and other inflammatory diseases, and also as mediators of thrombus formation and growth, major early and late complications of any medical device placement. Since CRP enhances thrombosis after vascular injury and inflammation upregulates the expression of CRP, CRP appears to be a mechanistic link between inflammation and thrombosis Fay, . Serum nelimination of device thrombogenesis since it causes failure, patient morbidity, and mortality. More effective and safer antithrombotic and anti-inflammatory agents and less thrombogenic biomaterial surfaces can overcome the problem. More research and development is needed to understand biological processes involved in coagulation at blood-contacting device surfaces. It is likely that biomaterials used in arterial vs. venous devices would be different since processes participating in both blood-contacting surfaces have some differences, e.g., venous low shear rates can lead to regional accumulation of activated coagulation factors and thrombogenesis on a nearby surface, leading to larger thrombi and increasing the risk for developing thromboembolic disease. Until such developments occur, engineers and clinicians need to work together to develop devices that mitigate thrombosis and inflammation.Medical devices use will increase as people live longer. The prevailing challenge is All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.