Community Endocrine Surgical Experience With False-Negative Afirma Gec® Results: 2011–2017

Objective: Afirma Gene Expression Classifier® (Afirma GEC) molecular analysis (Veracyte, Inc, San Francisco, CA) is a negative predictive value test developed to reduce the number of thyroidectomies in thyroid nodule patients with indeterminate cytology. GEC technology has reportedly reduced unnecessary thyroid surgery, but few studies have examined Afirma GEC false-negative rates, since usually patients with GEC benign nodules do not undergo surgery for definitive diagnosis. Occasionally, Afirma GEC benign patients require removal of their thyroid nodules for other reasons; this work describes the incidence of malignancy and noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in this population.Methods: We reviewed our community endocrine surgical practice database for patients who had undergone thyroid surgery from January 2011 through April 2017 despite benign Afirma GEC results.Results: Afirma GEC testing was completed for 475 patients during the study period. Surgery was clinically indicated for other reasons in 42 of the 193 patients (22%) with Afirma GEC benign results. Malignancy or NIFTP in the targeted nodule was found in the final histologic evaluation of 14 of the 42 Afirma GEC benign surgical patients. The Afirma GEC false-negative percentage for our incomplete surgical group (FNP-ISG), defined as the surgically proven false negatives divided by the total Afirma GEC benign patients, was 7.3%.Conclusion: Our high surgical rate in Afirma GEC benign nodules reveals an FNP-ISG of 7.3% in our community endocrine surgical patient population; this value exceeds the 5.7% reported in the multicenter 2012 Afirma GEC validation study.Abbreviations: Afirma GEC = Afirma Gene Expression Classifier; FNA = fine-needle aspiration; FNP = false-negative percentage; FNP-ISG = false-negative percentage for an incomplete surgical group; NIFTP = noninvasive follicular thyroid neoplasms with papillary-like nuclear features     

Differential protein expression profiles of gastric epithelial cells following Helicobacter pylori infection using ProteinChips

Helicobacter pylori infects approximately half of the world's population and the bacterium is associated with gastric cancer and peptic and duodenal ulcers. In this study, Surface Enhanced Laser Desorption /Ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was used to identify the biomarkers from H. pylori infected gastric epithelial cells (GEC) to understand key mechanisms associated with pathogenesis. Using different chip surfaces, differential protein expression profile of GEC was obtained and several upregulated or downregulated biomarkers were detected on GEC, following H. pylori infection. Four different H. pylori infected GECs were compared based on their expression of MHC class II, a receptor reported to trigger apoptosis. One biomarker was identified in H. pylori infected GEC as Annexin A2 (Annexin II) from the flow through of the anion-exchange resin. The increased expression of Annexin II in GEC following H. pylori infection was further confirmed by Western Blot analyses and indicates its involvement in H. pylori pathogenesis.     

Surgical Utility of Afirma: Effects of High Cancer Prevalence and Oncocytic Cell Types in Patients with Indeterminate Thyroid Cytology

ObjectiveThe Afirma Gene Expression Classifier (GEC) molecular marker assay was developed for the purpose of improving surgical decision-making with indeterminate fine-needle aspiration (FNA) biopsies of thyroid nodules. In this paper, we analyze the performance of the GEC over 27 months in a community hospital-based thyroid surgery practice.MethodsWe began using GEC and Thyroid Cytopathology Partners (TCP) exclusively for thyroid FNA analysis in January 2011, shortly after the Afirma GEC became commercially available. In this paper, we focus on patients with indeterminate FNA results and the outcomes of GEC analysis, with particular attention paid to the calculation of the negative predictive value (NPV) of the Afirma test.ResultsWe performed 645 FNAs in 519 patients over 27 months. Overall, 58 FNAs (9%) were read as indeterminate, with 36 of these classified as suspicious by GEC (62%), 20 characterized as GEC benign (34%), and 2 determined to be inadequate due to low mRNA content. Of the 36 suspicious GEC patients, 30 underwent thyroidectomy, and 21 of the 30 had malignant final pathology. Of the 20 benign GEC patients, 5 underwent thyroid surgery, and 2 were discovered to have malignancies. The NPV for the Afirma GEC in our practice environment was 89.6%.ConclusionIn a practice with a high incidence of thyroid cancer in patients with indeterminate FNAs (33% for our practice), the NPV of the Afirma GEC test may not be as robust as suggested in the existing literature. (Endocr Pract. 2014;20:364-369)     

Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection

Helicobacter pylori infection is associated with gastritis, ulcers, and gastric cancer. The infection becomes chronic as the host response is unable to clear it. Gastric epithelial cells (GEC) play an important role during the host response, and their expression of class II MHC and costimulatory molecules such as CD80 and CD86 suggests their role in local Ag presentation. Although T cells are recruited to the infected gastric mucosa, they have been reported to be hyporesponsive. In this study, we detected the expression of B7-H1 (programmed death-1 ligand 1), a member of B7 family of proteins associated with T cell inhibition on GEC. Quantitative real-time RT-PCR revealed that B7-H1 expression increased significantly on GEC after H. pylori infection. Western blot analysis showed that B7-H1 expression was induced by various H. pylori strains and was independent of H. pylori virulence factors such as Cag, VacA, and Urease. The functional role of B7-H1 in the cross talk between GEC and T cells was assessed by coculturing GEC or H. pylori-infected GEC with CD4+ T cells isolated from peripheral blood. Using blocking Abs to B7-H1 revealed that B7-H1 was involved in the suppression of T cell proliferation and IL-2 synthesis, and thus suggested a role for B7-H1 on the epithelium as a contributor in the chronicity of H. pylori infection.     

Global change and species interactions in terrestrial ecosystems

The main drivers of global environmental change (CO₂ enrichment, nitrogen deposition, climate, biotic invasions and land use) cause extinctions and alter species distributions, and recent evidence shows that they exert pervasive impacts on various antagonistic and mutualistic interactions among species. In this review, we synthesize data from 688 published studies to show that these drivers often alter competitive interactions among plants and animals, exert multitrophic effects on the decomposer food web, increase intensity of pathogen infection, weaken mutualisms involving plants, and enhance herbivory while having variable effects on predation. A recurrent finding is that there is substantial variability among studies in both the magnitude and direction of effects of any given GEC driver on any given type of biotic interaction. Further, we show that higher order effects among multiple drivers acting simultaneously create challenges in predicting future responses to global environmental change, and that extrapolating these complex impacts across entire networks of species interactions yields unanticipated effects on ecosystems. Finally, we conclude that in order to reliably predict the effects of GEC on community and ecosystem processes, the greatest single challenge will be to determine how biotic and abiotic context alters the direction and magnitude of GEC effects on biotic interactions.     

Incorporating Sustainability into Community-Based Healthcare Practice

There is now irrefutable evidence that climate change and increasing environmental degradation negatively affect population health. Healthcare plays an important role in addressing these emerging environmental challenges, considering its core aim is to protect and promote health. Preliminary research in Victoria, Australia, suggests that healthcare practitioners are endeavouring to factor in environmental concerns into their practice. Health promotion, an integral part of the healthcare system, is considered an area of practice that can support action on sustainability. Based on five qualitative case studies and key stakeholder interviews, this article explores key barriers and facilitators to incorporating sustainability into community-based healthcare practice. The findings demonstrate that despite multiple barriers, including funding and lack of policy direction, health promotion principles and practices can enable action on sustainability.     

Untapped potential of physiology,behaviour and immune markers to predict range dynamics and marginality

Linking environmental conditions to the modulators of individual fitness is necessary to predict long‐term population dynamics, viability, and resilience. Functional physiological, behavioral, and reproductive markers can provide this mechanistic insight into how individuals perceive physiological, psychological, chemical, and physical environmental challenges through physiological and behavioral responses that are fitness proxies. We propose a Functional Marginality framework where relative changes in allostatic load, reproductive health, and behavior can be scaled up to evidence and establish causation of macroecological processes such as local extirpation, colonization, population dynamics, and range dynamics. To fully exploit functional traits, we need to move beyond single biomarker studies to develop an integrative approach that models the interactions between extrinsic challenges, physiological, and behavioral pathways and their modulators. In addition to providing mechanistic markers of range dynamics, this approach can also serve as a valuable conservation tool for evaluating individual‐ and population‐level health, predicting responses to future environmental change and measuring the impact of interventions. We highlight specific studies that have used complementary biomarkers to link extrinsic challenges to population performance. These frameworks of integrated biomarkers have untapped potential to identify causes of decline, predict future changes, and mitigate against future biodiversity loss.     

Protease-activated receptor signaling increases epithelial antimicrobial peptide expression

Epithelial tissues provide both a physical barrier and an antimicrobial barrier. Antimicrobial peptides of the human beta-defensin (hBD) family are part of the innate immune responses that play a role in mucosal defense. hBDs are made in epithelia including oral epithelium where the bacterial load is particularly great. hBD-2 and hBD-3 are up-regulated in response to bacterial stimuli. Previous studies show that hBD-2 expression in human gingival epithelial cells (GEC) is stimulated by both nonpathogenic and pathogenic bacteria, including Porphyromonas gingivalis, a Gram-negative pathogen associated with periodontitis. Present evidence suggests that hBD-2 expression in GEC uses several signaling pathways, including an NF-kappaB-mediated pathway but without apparent LPS-TLR4 signaling. Protease-activated receptors (PAR) are G-protein-coupled receptors that mediate cellular responses to extracellular proteinases. P. gingivalis secretes multiple proteases that contribute to its virulence mechanisms. To determine whether PAR signaling is used in hBD-2 induction, GEC were stimulated with wild-type P. gingivalis or mutants lacking one or more proteases. hBD-2 mRNA expression was reduced in GEC stimulated with single protease mutants (11-67% compared with wild type), strongly reduced in double mutants (0.1-16%), and restored to wild-type levels (93%) in mutant with restored protease activity. Stimulation by wild type was partially blocked by inhibitors of phospholipase C, a main signaling pathway for PARs. Expression of hBD-3 was unaffected. Peptide agonist of PAR-2, but not PAR-1 activator, also induced hBD-2 in GEC. Thus, P. gingivalis proteases are directly involved in regulation of hBD-2 in cultured GEC, and this induction partially uses the PAR-2 receptor and signaling pathway.     

Population responses within a landscape matrix: a macrophysiological approach to understanding climate change impacts

Global environmental change (GEC) is a significant concern. However, forecasting the outcomes of this change for species and ecosystems remains a major challenge. In particular, predicting specific changes in systems where initial conditions, instabilities, and model errors have large impacts on the outcome is problematic. Indeed, predictive community ecology has been deemed unworthy of pursuit or an unreachable goal. However, new developments in large-scale biology provide ways of thinking that might substantially improve forecasts of local and regional impacts of climate change. Most notably, these are the explicit recognition of the regional and landscape contexts within which populations reside, the matrix approach that can be used to investigate the consequences of population variation across space and within assemblages, and the development of macrophysiology, which explicitly seeks to understand the ecological implications of physiological variation across large spatial and temporal scales. Here we explore how a combination of these approaches might promote further understanding and forecasting of the effects of global climate change and perhaps other GEC drivers on biodiversity. We focus on the population level, examining the ways in which environmental variation might be translated through performance and its plasticity to variation in demography.     

Prevalence and Correlates of Physical Inactivity in Community-Dwelling Older Adults in Ireland

The public health challenges associated with rapid population ageing are likely to be exacerbated by poor physical activity levels. The purpose of this study was to identify correlates of physical inactivity in a population-representative sample of older adults in Ireland. This paper reports a secondary analysis of data from 4892 adults aged 60+ from the Irish Longitudinal Study on Ageing (TILDA). TILDA includes an assessment of the mental and physical health, and social and financial circumstances of participants assessed in a home interview and self-completion questionnaire. Chi squared statistics and forced entry logistic regression were used to identify factors associated with physical inactivity. Females were over twice as likely to be inactive as their male counterparts (Odds Ratio 2.2). Increasing old age was associated with inactivity among males and females. Those who reported above secondary level education, no reported falls in the last year and no fear of falling were less likely to be physically inactive. While older adults who noted poor/fair self-reported health, that they did not look after grandchildren, did not own a car or did not attend a course were also more likely to be inactive than those who reported positively for these items. Gender displayed a strong but often contrasting influence on factors that affect physical activity among older adults. Among females, living alone or in a rural area, retirement, fair/poor emotional health and activity being limited by illness were all significantly associated with inactivity. While cohabiting, being employed and residing in an urban area were related to low levels of activity in males. Our findings identify specific groups of the older Irish population who may be at particular risk of physical inactivity and thereby the associated physiological and psychological hazards. These results can support the development of tailored interventions to promote healthy ageing.     

PR3 and Elastase Alter PAR1 Signaling and Trigger vWF Release via a Calcium-Independent Mechanism from Glomerular Endothelial Cells

Neutrophil proteases, proteinase-3 (PR3) and elastase play key roles in glomerular endothelial cell (GEC) injury during glomerulonephritis. Endothelial protease-activated receptors (PARs) are potential serine protease targets in glomerulonephritis. We investigated whether PAR1/2 are required for alterations in GEC phenotype that are mediated by PR3 or elastase during active glomerulonephritis. Endothelial PARs were assessed by flow cytometry. Thrombin, trypsin and agonist peptides for PAR1 and PAR2, TFLLR-NH(2) and SLIGKV-NH(2,) respectively, were used to assess alterations in PAR activation induced by PR3 or elastase. Endothelial von Willebrand Factor (vWF)release and calcium signaling were used as PAR activation markers. Both PR3 and elastase induced endothelial vWF release, with elastase inducing the highest response. PAR1 peptide induced GEC vWF release to the same extent as PR3. However, knockdown of PARs by small interfering RNA showed that neither PAR1 nor PAR2 activation caused PR3 or elastase-mediated vWF release. Both proteases interacted with and disarmed surface GEC PAR1, but there was no detectable interaction with cellular PAR2. Neither protease induced a calcium response in GEC. Therefore, PAR signaling and serine protease-induced alterations in endothelial function modulate glomerular inflammation via parallel but independent pathways.     

Graphite-epoxy composites as a new transducing material for electrochemical genosensing

The use of a rigid carbon-polymer composite material as an electrochemical transducer in hybridisation genosensors is reported. Graphite-epoxy composites (GEC) have an uneven surface where DNA can be adsorbed using a simple dry-adsorption procedure. Single-stranded-DNA binds strongly to GEC in a way that prevents the strands from self-associating, while permitting hybridisation with complementary DNA. Hybridisation has been detected through biotin-streptavidin interaction using a streptavidin conjugated to horseradish peroxidase. Non-specific adsorption onto GEC is almost non-existent even when the surface has not been treated by blocking reagents. The analytical signal obtained was higher when compared with other electrochemical genosensors. Results can be achieved in 150 min, and the detection limit is in the order of fmol. Additionally, surface regeneration is possible using a simple polishing procedure, allowing for multiple use. The new genosensor based on GEC fulfils the requirements desired for these devices: ease of preparation as dry-adsorption of DNA is very simple and easily automated, robustness, sensitivity, low cost of production, ease of miniaturisation and simple use and fast response. Additionally, it can be used for field measurements and can be produced as a genosensor kit. Also, this material can be implemented for screen-printing procedures for the mass production of genosensors. The utility of the genosensor based on GEC is also illustrated with the detection of a sequence related to novel determinant of beta-lactamase resistance in Staphylococcus aureus.     

Heymann antibodies induce complement-dependent injury of rat glomerular visceral epithelial cells

The aim of this study was to investigate the in vitro role of the complement membrane attack complex (MAC) in the injury induced by nephritogenic anti-brush border vesicle (Fx1A) antibodies on rat glomerular visceral epithelial cells (GEC). Both sheep and rabbit anti-rat brush border vesicle IgG-induced complement-dependent lysis of cultured GEC. Fab fragments of sheep anti-rat brush border vesicles and polyclonal or monoclonal gp330 IgG were devoid of lytic activity. Shedding of cell-surface antigens induced by sheep or rabbit anti-rat brush border vesicle IgG protected GEC from subsequent exposure to lytic antibodies and complement, an effect that was not obtained with Fab fragments. When GEC were incubated with sheep or rabbit anti-rat brush border vesicle IgG in capping conditions, the C3 component was co-redistributed with Heymann immune complexes; in contrast, the MAC remained diffusely bound to the cell surface, indicating that it was not associated with the antigen-antibody complexes. The MAC was demonstrated on the surface of GEC by immunofluorescence staining with anti-MAC neoantigen and by electron microscopy of negatively stained membranes showing focal clusters of 110 A MAC lesions. When GEC were treated with sheep IgG or rabbit IgG plus C6-deficient sera, the cells were not lysed and MAC was not demonstrable on the surface; however, lytic activity was restored when C6-deficient sera were reconstituted with purified C6. The results are consistent with the interpretation that injury induced by Heymann antibodies on GEC is MAC-dependent.     

The promise of e-Health – a Canadian perspective

Canadians value their health care system above any other social program. Canada's system of health care faces significant financial and population pressures, relating to cost, access, quality, accountability, and the integration of information and communication technologies (ICTs). The health-system also faces certain unique challenges that include care delivery within a highly decentralised system of financing and accountability, and care delivery to a significant portion of the population sparsely distributed across a landmass of 10 million square kilometres, in areas of extreme climatic conditions. All of these challenges are significant catalysts in the development of technologies that aim to significantly mitigate or eliminate these selfsame challenges.The system is undergoing widespread review, nationally, and within each province and territory, where the bulk of care provision is financed and managed. The challenges are being addressed by national, regional and provincial initiatives in the public, private and not-for-profit sectors.The promise of e-Health lies in the manner and degree to which it can mitigate or resolve these challenges to the health system and build on advancements in ICTs supporting the development of a health infostructure. Canada is actively developing and implementing technological solutions to deliver health information and health care services across the country. These solutions, while exciting and promising, also present new challenges, particularly in regard to acceptable standards, choice of technologies, overcoming traditional jurisdictional boundaries, up-front investment, and privacy and confidentially.Many organisations and governments are working to address these challenges. The Canadian Institute for Health Information (CIHI) will play an increasingly significant role in these initiatives, as the management of health information becomes a more crucial factor in the successful delivery of health care services in the new millennium.     

Considerations for a Human Rights Impact Assessment of a Population Wide Treatment for HIV Prevention Intervention

Increasing attention is being paid to the potential of anti‐retroviral treatment (ART) for HIV prevention. The possibility of eliminating HIV from a population through a universal test and treat intervention, where all people within a population are tested for HIV and all positive people immediately initiated on ART, as part of a wider prevention intervention, was first proposed in 2009. Several clinical trials testing this idea are now in inception phase. An intervention which relies on universally testing the entire population for HIV will pose challenges to human rights, including obtaining genuine consent to testing and treatment. It also requires a context in which people can live free from fear of stigma, discrimination and violence, and can access services they require. These challenges are distinct from the field of medical ethics which has traditionally governed clinical trials and focuses primarily on patient researcher relationship. This paper sets out the potential impact of a population wide treatment as prevention intervention on human rights. It identifies five human right principles of particular relevance: participation, accountability, the right to health, non‐discrimination and equality, and consent and confidentiality. The paper proposes that explicit attention to human rights can strengthen a treatment as prevention intervention, contribute to mediating likely health systems challenges and offer insights on how to reach all sections of the population.     

Decay accelerating factor regulates complement activation on glomerular epithelial cells

Epithelial cells of the glomerular capillary are the site of C5b-9 mediated injury in rat membranous nephropathy. We investigated the regulation of C activation by cultured glomerular epithelial cells (GEC). Rat and human GEC were more resistant to C injury by homologous C than heterologous C. In human GEC homologous C cytotoxicity was enhanced by antiserum to decay accelerating factor (DAF) indicating that homologous C activation was, at least in part, restricted by membrane DAF. Anti-DAF immunoprecipitated a 67-kDa protein from human glomeruli. In rat GEC, pronase and phosphatidylinositol-specific phospholipase C (which are known to inactivate human DAF) enhanced cytotoxicity by homologous C. Thus, DAF is present on human GEC in culture and in human kidney glomeruli, and a DAF-like protein is present on cultured rat GEC. These proteins regulate C activation in vitro and may play a role in controlling C activation on GEC in vivo.     

Epidemiological profile of India: Historical and contemporary perspectives

Knowledge and understanding of the epidemiological profile is an essential pre-requisite to assess and address public health needs in the country and to enable efficient programme planning and management. The need for adequate and accurate health information and data to undertake such an exercise cannot be over-emphasized. The present effort is a modest attempt to critically analyse the epidemiological profile of India from the historical and contemporary perspective. In order to assess the successes achieved as well caution against the daunting challenges awaiting the country, parameters such as disease burden and health status indicators, are increasingly being used. Changes in the population age structure, improvements in the nation’s economic status, altered life-styles of people and duality of disease burden testify to the demographic, development and health transition occurring in the country. Population stabilization, poverty alleviation, life-style modification, surveillance and control of communicable and non-communicable diseases constitute the major challenges demanding urgent attention in the future.     

Effect of nephritogenic antibody on complement regulation in cultured rat glomerular epithelial cells

In passive Heymann nephritis, a rat model of membranous nephropathy, antibody (anti-Fx1A) activates C on the surface of the glomerular epithelial cell (GEC), leading to GEC injury and proteinuria. In this study, we examined C activation by anti-Fx1A in cultured rat GEC. In addition to anti-Fx1A IgG, anti-Fx1A F(ab')2 and Fab' led to GEC injury in the presence of rat or human sera as sources of C. Cytotoxicity was Mg2+ and factor B dependent, but Ca2+ independent, indicating that anti-Fx1A activated the C alternative pathway (AP). Furthermore, in the presence of Mg2+ and factor B, anti-Fx1A enhanced 125I-C3b deposition on GEC in the absence of classical pathway activation. AP C3 and C5 convertases formed on GEC (GEC-C3bBbP) were inactivated over time, probably due to binding of GEC C regulatory proteins. This inactivation was prevented when GEC-C3bBbP were incubated with anti-Fx1A IgG. An antibody raised against cultured GEC that binds to GEC in vitro and in vivo had no effect on C3 and C5 convertases, suggesting that stabilization of C3bBbP is unique to anti-Fx1A. Anti-Fx1A Fab' also stabilized GEC-C3bBbP, indicating that cross-linking of membrane Ag was not required. C3bBbP on E were not affected by anti-Fx1A, excluding direct stabilization of convertases by anti-Fx1A. Therefore, anti-Fx1A inhibits C regulation on GEC, which can account for its ability to activate the AP. This represents a potentially powerful mechanism of producing disease in vivo.     

Statistical Comparison of Afirma Gsc and Afirma Gec Outcomes in a Community Endocrine Surgical Practice: Early Findings

Objective: The Veracyte Afirma Gene Expression Classifier (GEC) has been the most widely used negative predictive value molecular classifier for indeterminate cytology thyroid nodules since January 2011. To improve the specificity and further reduce unnecessary thyroid surgeries, a second-generation assay (Afirma Genetic Sequence Classifier [GSC]) was released for clinical use in August 2017. We report 11 months of clinical outcomes experience with the GSC and compare them to our 6.5-year experience with the GEC.Methods: We searched our practice registry for FNAB nodules with Afirma results from January 2011through June 2018. GEC versus GSC results were compared overall, in oncocytic and nononcocytic aspirates and by pathologic outcomes.Results: GSC identified less indeterminate cytology nodules as suspicious (38.8%; 54/139) when compared to GEC (58.4%; 281/481). There was a decrease of in the percentage of oncocytic fine-needle aspiration thyroid biopsy (FNAB) subjects classified as suspicious in the GSC group, with 86 of 104 oncocytic indeterminates (82.7%) classified as suspicious by GEC and 12 of 34 (35.3%) classified as suspicious by GSC. The surgery rate in patients with oncocytic aspirates fell from 56% in the GEC group to 31% in the GSC-evaluated group (45%). Pathology analysis demonstrated a false-negative percentage for an incomplete surgical group of 9.5% for GEC and 1.2% for GSC.Conclusion: Our GSC data suggest that the GSC further reduces surgery in indeterminate thyroid nodules by improving the specificity of Afirma technology without compromising sensitivity. A primary determinant for this change is a significant improvement in the specificity of the Afirma GSC test in oncocytic FNAB aspirates.Abbreviations: FNAB = fine-needle aspiration biopsy; GEC = Gene Expression Classifier; GSC = Genetic Sequence Classifier     

Focus: Health Equity: Lung Disease in Central Appalachia: It’s More than Coal Dust that Drives Disparities

The population living in Central Appalachia is disproportionately impacted by lung disease. This is driven, in part, by occupational hazards and environmental exposures. However, it is more than coal dust that is driving the ongoing disparity of lung disease in the region. This review describes how the decline of the coal mine industry and subsequent rise of unemployment, poverty, and educational disparities have increased risk for worse pulmonary health outcomes in the region. Additional challenges related to healthcare access, substance use, cultural characteristics, and social capital are highlighted in their relation to pulmonary health within Central Appalachia. Lastly, the review describes strategies that hold promise to reduce regional health disparities. Several healthcare and community-centered initiatives are highlighted as successful examples of collaborative efforts working towards improving pulmonary health outcomes in the region. However, significant challenges related to social, economic, and environmental factors remain. Addressing these social determinants of health must be a paramount concern for healthcare, community and political leaders seeking to impact change and improve the health and well-being of this vulnerable population.