Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Genome-wide SNP-sex interaction analysis of susceptibility to idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females.

Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK.

Background: Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting. Methods: 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey. Results: 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD. Conclusion: We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting.

Identification of biomarkers for the early detection of non-small cell lung cancer: a systematic review and meta-analysis.

Lung cancer (LC) causes few symptoms in the earliest stages, leading to one of the highest mortality rates among cancers. Low-dose computerised tomography (LDCT) is used to screen high-risk individuals, reducing the mortality rate by 20%. However, LDCT results in a high number of false positives and is associated with unnecessary follow-up and cost. Biomarkers with high sensitivities and specificities could assist in the early detection of LC, especially in patients with high-risk features. Carcinoembryonic antigen (CEA), cytokeratin 19 fragments and cancer antigen 125 have been found to be highly expressed during the later stages of LC but have low sensitivity in the earliest stages. We determined the best biomarkers for the early diagnosis of LC, using a systematic review of eight databases. We identified 98 articles that focussed on the identification and assessment of diagnostic biomarkers and achieved a pooled area under curve of 0.85 (95% CI 0.82-0.088), indicating that the diagnostic performance of these biomarkers when combined was excellent. Of the studies, 30 focussed on single/antigen panels, 22 on autoantibodies, 31 on miRNA and RNA panels, and 15 suggested the use of circulating DNA combined with CEA or neuron-specific enolase (NSE) for early LC detection. Verification of blood biomarkers with high sensitivities (Ciz1, exoGCC2, ITGA2B), high specificities (CYFR21-1, antiHE4, OPNV) or both (HSP90α, CEA) along with miR-15b and miR-27b/miR-21 from sputum may improve early LC detection. Further assessment is needed using appropriate sample sizes, control groups that include patients with non-malignant conditions, and standardised cut-off levels for each biomarker.

Long term nitrofurantoin induced interstitial lung disease: a case series and literature review.

BACKGROUND AND AIM: In the UK, prophylactic use of nitrofurantoin is recommended in women who have 3 or more UTI per year. Reported cases of nitrofurantoin-induced pulmonary toxicity are limited and the exact mechanism of chronic nitrofurantoin induced lung reaction is unclear. In England, the national trend for prescribing Nitrofurantoin has gone up significantly in the last 10 years. We reviewed 10 cases of nitrofurantoin-induced pulmonary fibrosis diagnosed in last 8 years at our ILD Service. We aimed to reviewe patient demographics, time to presentation, lung function and imaging characteristics. METHODS: We reviewed our ILD database from the year 2012 to 2020. 10 patients were identified diagnosed as Nitrofurantoin Induced Interstitial Lung Disease. All the cases were reviewed in MDT comprising Radiologists and clinicians with interest for ILD. We documented age, sex, initial renal function, eosinophil count, spirometry and radiology findings. In this case series, we focus on various CT findings and reversibility of radiological abnormality following cessation of Nitrofurantoin. RESULTS: The mean age of our patient cohort is 80 years and all were female. The mean time to presentation from prescription was 17 months. Pre-treatment mean eGFR was 76ml/min/1.73m2.7 out of 10 patients had CT findings of ground glass opacity and traction bronchiectasis. 4 patients were treated with prednisolone. The patients in this series improved symptomatically with or without treatment with steroid following cessation of nitrofurantoin therapy, but irreversible changes in the chest imaging may contribute to long term morbidity. CONCLUSIONS: Cautious counselling should be undertaken prior to nitrofurantoin prescription regardless of renal function.

Examining the relationship between inflammatory biomarkers during COVID-19 hospitalization and subsequent long-COVID symptoms: A longitudinal and retrospective study.

INTRODUCTION: Long-COVID is a heterogeneous condition with a litany of physical and neuropsychiatric presentations and its pathophysiology remains unclear. Little is known about the association between inflammatory biomarkers, such as interleukin-6 (IL-6) and C-reactive protein (CRP) in the acute phase, and persistent symptoms after hospitalization in COVID-19 patients. METHODS: IL-6, CRP, troponin-T, and ferritin were analyzed at admission for all patients with COVID-19 between September 1, 2020 to January 10, 2021. Survivors were followed up 3-months following hospital discharge and were asked to report persistent symptoms they experienced. Admission data were retrospectively collected. Independent t-tests and Mann-Whitney U tests were performed. RESULTS: In a sample of 144 patients (62.5% male, mean Age 62 years [SD = 13.6]) followed up 3 months after hospital discharge, the commonest symptoms reported were fatigue (54.2%), breathlessness (52.8%), and sleep disturbance (37.5%). In this sample, admission levels of IL-6, CRP and ferritin were elevated. However, those reporting myalgia, low mood, and anxiety at follow-up had lower admission levels of IL-6 (34.9 vs. 52.0 pg/mL, p = .043), CRP (83 vs. 105 mg/L, p = .048), and ferritin (357 vs. 568 ug/L, p = .01) respectively, compared with those who did not report these symptoms. Multivariate regression analysis showed that these associations were confounded by gender, as female patients had significantly lower levels of IL-6 and ferritin on admission (29.5 vs. 56.1, p = .03 and 421.5 vs. 589, p = .001, respectively) and were more likely to report myalgia, low mood and anxiety, when compared to males. CONCLUSIONS: Our data demonstrate that female patients present more often with lower levels of inflammatory biomarkers on admission which are subsequently associated with long-term post-COVID symptoms, such as myalgia and anxiety, in those discharged from hospital with severe COVID-19. Further research is needed into the role of serum biomarkers in post-COVID prognostication.

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

PCSK6 and Survival in Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. Objectives: To identify and validate molecular determinants of IPF survival. Methods: A staged genome-wide association study was performed using paired genomic and survival data. Stage I cases were drawn from centers across the United States and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplantation-free survival (TFS). Stage I variants with nominal significance (P < 5 × 10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (P < 5 × 10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. Measurements and Main Results: After quality controls, 1,481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of PCSK6 (proprotein convertase subtilisin/kexin type 6) reaching genome-wide significance (hazard ratio, 4.11 [95% confidence interval, 2.54-6.67]; P = 9.45 × 10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression, and plasma concentration were associated with reduced TFS. Conclusions: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression.

Does deterministic coexistence theory matter in a finite world?

Contemporary studies of species coexistence are underpinned by deterministic models that assume that competing species have continuous (i.e., noninteger) densities, live in infinitely large landscapes, and coexist over infinite time horizons. By contrast, in nature, species are composed of discrete individuals subject to demographic stochasticity and occur in habitats of finite size where extinctions occur in finite time. One consequence of these discrepancies is that metrics of species' coexistence derived from deterministic theory may be unreliable predictors of the duration of species coexistence in nature. These coexistence metrics include invasion growth rates and niche and fitness differences, which are now commonly applied in theoretical and empirical studies of species coexistence. In this study, we tested the efficacy of deterministic coexistence metrics on the duration of species coexistence in a finite world. We introduce new theoretical and computational methods to estimate coexistence times in stochastic counterparts of classic deterministic models of competition. Importantly, we parameterized this model using experimental field data for 90 pairwise combinations of 18 species of annual plants, allowing us to derive biologically informed estimates of coexistence times for a natural system. Strikingly, we found that for species expected to deterministically coexist, community sizes containing only 10 individuals had predicted coexistence times of more than 1000 years. We also found that invasion growth rates explained 60% of the variation in intrinsic coexistence times, reinforcing their general usefulness in studies of coexistence. However, only by integrating information on both invasion growth rates and species' equilibrium population sizes could most (>99%) of the variation in species coexistence times be explained. This integration was achieved with demographically uncoupled single-species models solely determined by the invasion growth rates and equilibrium population sizes. Moreover, because of a complex relationship between niche overlap/fitness differences and equilibrium population sizes, increasing niche overlap and increasing fitness differences did not always result in decreasing coexistence times, as deterministic theory would predict. Nevertheless, our results tend to support the informed use of deterministic theory for understanding the duration of species' coexistence while highlighting the need to incorporate information on species' equilibrium population sizes in addition to invasion growth rates.

Nalbuphine Tablets for Cough in Patients with Idiopathic Pulmonary Fibrosis.

Nalbuphine for Cough with Idiopathic Pulmonary FibrosisIn patients with idiopathic pulmonary fibrosis, cough may have a negative impact on daily life. In a randomized, 22-day treatment period, placebo-controlled, crossover trial, extended-release nalbuphine (NAL ER), an opioid agonist-antagonist, was compared to placebo for cough control and adverse effects. During active treatment there was a 75.1% reduction in daytime objective cough frequency compared with 22.6% in the placebo treatment period. Nausea, fatigue, constipation, and dizziness were more common with NAL ER than with placebo.

Mixed-methods feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE): study findings.

Introduction: One-fifth of emergency department presentations by ambulance are due to acute-on-chronic breathlessness. We explored the feasibility of an evaluation-phase, cluster randomised controlled trial (cRCT) of the effectiveness and cost-effectiveness of a paramedic-administered, non-pharmacological breathlessness intervention for people with acute-on-chronic breathlessness at ambulance call-out (BREATHE) regarding breathlessness intensity and conveyance to hospital. Methods: This mixed-methods, feasibility cRCT (ISRCTN80330546) randomised paramedics to usual care or intervention plus usual care. Retrospective patient consent to use call-out data (primary end-point) and prospective patient/carer consent for follow-up was sought. Potential primary outcomes included breathlessness intensity (numerical rating scale) and conveyance. Follow-up included: interviews with patients/carers and questionnaires at 14 days, 1 and 6 months; paramedic focus groups and surveys. Results: Recruitment was during COVID-19, with high demands on paramedics and fewer call-outs by eligible patients. We enrolled 29 paramedics; nine withdrew. Randomisation/trial procedures were acceptable. Paramedics recruited 13 patients, not meeting recruitment target (n=36); eight patients and three carers were followed-up. Data quality was good but insufficient for future sample size estimation. The intervention did not extend call-out time, was delivered with fidelity and was acceptable to patients, carers and paramedics. There were no repeat call-outs within 48 h. All trained paramedics strongly recommended BREATHE as a highly relevant, simple intervention. Conclusion: Patient recruitment to target was not feasible during the pandemic. Training and intervention were acceptable and delivered with fidelity. Results include valuable information on recruitment, consent, attrition and data collection that will inform the design and delivery of a definitive trial.

Investigating the diagnostic utility of high-resolution oesophageal manometry in patients with refractory respiratory symptoms.

BACKGROUND: The interaction between the respiratory and gastrointestinal systems, and the role of the latter in the development of respiratory pathology, has been examined with a focus on gastro-oesophageal reflux disease (GORD). However, little data exists examining the link between oesophageal motility and respiratory disease. AIMS AND OBJECTIVES: In this study, we examined patterns in oesophageal motility using high-resolution oesophageal manometry (HROM) in patients with refractory respiratory symptoms. METHODS: Data were collected retrospectively for all patients that were investigated using HROM at a single centre for refractory respiratory symptoms between January 1st, 2011-December 1st, 2021. Patients were selected for investigation based on airway reflux symptoms, measured by the Hull Airways Reflux Questionnaire (HARQ). RESULTS: 441 patients were investigated with HROM (64% female, mean age = 56.5 [SD = 13.9]). The commonest diagnoses of these patients were Chronic Cough (77%, n = 339), Asthma (10%, n = 44), and Interstitial Lung Disease (7%, n = 29). The prevalence of oesophageal dysmotility was 66% in our cohort. Those with oesophageal dysmotility had significantly higher HARQ scores than those with normal motility (40.6 vs 35.3, p < 0.001) and there was a significant inverse correlation between HARQ scores and distal contractile integral (DCI), a measure of oesophageal contractility. CONCLUSIONS: Two-thirds of patients with refractory respiratory symptoms were found to have oesophageal dysmotility on HROM. These findings suggest motility disorders of the oesophagus may contribute to the development and progression of respiratory disease. This study highlights the need for further prospective study of the relationship between oesophageal dysmotility and respiratory disease.

Phenotypic plasticity promotes species coexistence.

Ecological explanations for species coexistence assume that species' traits, and therefore the differences between species, are fixed on short timescales. However, species' traits are not fixed, but can instead change rapidly as a consequence of phenotypic plasticity. Here we use a combined experimental-theoretical approach to demonstrate that plasticity in response to interspecific competition between two aquatic plants allows for species coexistence where competitive exclusion is otherwise predicted to occur. Our results show that rapid trait changes in response to a shift in the competitive environment can promote coexistence in a way that is not captured by common measures of niche differentiation.

Bruton's Tyrosine Kinase Inhibitors Impair FcγRIIA-Driven Platelet Responses to Bacteria in Chronic Lymphocytic Leukemia.

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown. FcγRIIA is a tyrosine kinase-dependent receptor critical for platelet activation in response to IgG-coated pathogens. Crosslinking of this receptor with monoclonal antibodies causes downstream activation of Btk and Tec in platelets, however, this has not been investigated in response to bacteria. We asked whether ibrutinib impacts on FcγRIIA-mediated activation of platelets derived from CLL patients and healthy donors after exposure to Staphylococcus aureus Newman and Escherichia coli RS218. Platelet aggregation, α-granule secretion and integrin αIIbß3-dependent scavenging of bacteria were detected in CLL platelets but impaired in platelets from ibrutinib-treated patients and in healthy donor-derived platelets exposed to ibrutinib in vitro. While levels of surface FcγRIIA remained unaffected, CLL platelets had reduced expression of integrin αIIbß3 and GPVI compared to controls regardless of therapy. In respect of intracellular signaling, bacteria induced Btk and Tec phosphorylation in both CLL and control platelets that was inhibited by ibrutinib. To address if Btk is essential for platelet activation in response to bacteria, platelets derived from X-linked agammaglobulinemia patients (lacking functional Btk) were exposed to S. aureus Newman and E. coli RS218, and FcγRIIA-dependent aggregation was observed. Our data suggest that ibrutinib impairment of FcγRIIA-mediated platelet activation by bacteria results from a combination of Btk and Tec inhibition, although off-target effects on additional kinases cannot be discarded. This is potentially relevant to control infection-risk in CLL patients and, thus, future studies should carefully evaluate the effects of CLL therapies, including Btk inhibitors with higher specificity for Btk, on platelet-mediated immune functions.

A feasibility cluster randomised controlled trial of a paramedic-administered breathlessness management intervention for acute-on-chronic breathlessness (BREATHE).

Chronic breathlessness, persistent and disabling despite optimal treatment of underlying causes, is a prevalent and frightening symptom and is associated with many emergency presentations and admission to hospital. Breathlessness management techniques used by paramedics may reduce the need for conveyance to hospital. The Breathlessness RElief AT HomE study (BREATHE) aims to explore the feasibility of conducting a definitive cluster randomised controlled trial (cRCT) for people with acute-on-chronic breathlessness who have called an ambulance, to evaluate the effectiveness and cost-effectiveness of a paramedic-administered non-pharmacological breathlessness intervention. The trial is a mixed-methods feasibility cRCT. Eight paramedics will be randomised 1:1 to deliver either the BREATHE intervention in addition to usual care or usual care alone at call-outs for acute-on-chronic breathlessness. Sixty participants will be recruited to provide access to routine data relating to the index call-out with optional follow-up questionnaires at 14 days, 1 month and 6 months. An in-depth interview will be conducted with a subgroup. Feasibility outcomes relating to recruitment, data quality (especially candidate primary outcomes), and intervention acceptability and fidelity will be collected as well as providing data to estimate a sample size for a definitive trial. Yorkshire and The Humber-Sheffield Research Ethics Committee approved the trial protocol (19/YH/0314). The study results will inform progression to, or not, and design of a main trial according to predetermined stop-go criteria. Findings will be disseminated to relevant stakeholders and submitted for publication in a peer-reviewed journal.

Distinct immune regulatory receptor profiles linked to altered monocyte subsets in sarcoidosis.

BACKGROUND: In sarcoidosis, blood monocytes, circulating precursors of granuloma macrophages, display enhanced inflammatory cytokine production, reduced expression of the regulatory (inhibitory) receptor CD200R, and altered subsets defined by CD14 and CD16. Regulatory receptors serve to dampen monocyte and macrophage inflammatory responses. We investigated the relationship between monocyte subsets and regulatory receptor expression in sarcoidosis. METHODS: Multiparameter flow cytometry was used to perform detailed analyses of cell surface regulatory molecules on freshly isolated blood immune cells from patients with chronic pulmonary sarcoidosis and age-matched healthy controls. RESULTS: 25 patients with chronic pulmonary sarcoidosis (median duration of disease 22 months) who were not taking oral corticosteroids or other immunomodulators were recruited. Nonclassical monocytes were expanded in sarcoidosis and exhibited significantly lower expression of regulatory receptors CD200R, signal regulatory protein-α and CD47 than classical or intermediate monocytes. In sarcoidosis, all three monocyte subsets had significantly reduced CD200R and CD47 expression compared with healthy controls. A dichotomous distribution of CD200R was seen on classical and intermediate monocytes in the sarcoidosis population, with 14 out of 25 (56%) sarcoidosis patients having a CD200Rlow phenotype and 11 out of 25 (44%) having a CD200Rhigh phenotype. These distinct sarcoidosis monocyte phenotypes remained consistent over time. CONCLUSIONS: Nonclassical monocytes, which are expanded in sarcoidosis, express very low levels of regulatory receptors. Two distinct and persistent phenotypes of CD200R expression in classical and intermediate monocytes could be evaluated as sarcoidosis biomarkers.

On the Origin of Coexisting Species.

Speciation is frequently initiated but rarely completed, a phenomenon hypothesized to arise due to the failure of nascent lineages to persist. Although a failure to persist often has ecological causes, key gaps exist between ecological and evolutionary theories that, if filled, would clarify when and why speciation succeeds or fails. Here, we apply ecological coexistence theory to show how the alignment between different forms of niche opportunity and niche use shape the initiation, progression, and completion of speciation. Niche evolution may drive coexistence or competitive exclusion, and an ability to coexist ecologically may help or hinder speciation. Our perspective allows progress towards unifying the origin and maintenance of species diversity across the tree of life.