Effect of Supplemental Oxygen on Physiological Responses to Exercise in Fibrotic Interstitial Lung Disease.

PURPOSE: We studied the effect of O2 supplementation on physiological response to exercise in patients with moderate to severe interstitial lung disease (ILD). METHODS: 13 patients (age 66 ± 10 yrs., 7 males) with ILD (TLC 71 ± 22% predicted, carbon monoxide diffusion capacity (DLCO) 44 ± 16% predicted) and 13 healthy individuals (age 50 ± 17 yrs., 7 males) were tested. ILD patients performed symptom-limited cardiopulmonary exercise tests and constant work-rate tests (CWRTs) at 80% of the work-rate (WR) at the gas exchange threshold (GET). Tests breathing room air (RA, 21% O2) were compared to tests performed breathing 30% O2. Oxygen-uptake (V̇O2) kinetics were calculated from the CWRT results. RESULTS: In the ILD group, peak WR, peak V̇O2 and V̇O2 at the GET improved significantly when breathing 30% O2 compared to RA (mean ± SD 66 ± 23 vs 75 ± 26 watts, 15 ± 2 vs 17 ± 4 ml/kg/min and 854 ± 232 vs 932 ± 245 ml/min; p = 0.004, p = 0.001 and p = 0.01, respectively). O2 saturation (SPO2%) at peak exercise was higher with 30% O2 (97 ± 4% vs 88 ± 9%, p = 0.002). The time constant (tau) of V̇O2 kinetics was faster in ILD patients while breathing 30% O2 (41 ± 10 sec) compared to RA (52 ± 14 sec, p = 0.003). There was a negative linear relation between tau and SPO2% with RA (r = -0.76, p = 0.006) and while breathing 30% O2 (r = -0.68, p = 0.02). CONCLUSIONS: Using a clinically applicable level of O2 supplementation (30%) improved maximal, aerobic exercise capacity and V̇O2 kinetics in ILD patients, likely due to increased blood O2 content subsequently increasing the O2 delivery to the working muscles.

Asymmetric Dimethylarginine and NT-proBNP Levels Provide Synergistic Information in Pulmonary Arterial Hypertension.

BACKGROUND: Plasma asymmetric dimethylarginine (ADMA) is elevated in pulmonary arterial hypertension (PAH) and is associated with unfavorable outcomes. OBJECTIVES: The aim of this study was to assess changes in ADMA plasma levels for monitoring disease progression and outcomes during PAH-specific therapy. METHODS: ADMA was measured at baseline and after at least 6 months of follow-up using enzyme-linked immunosorbent assay and high-performance liquid chromatography. Changes in ADMA were analyzed in relation to changes in established PAH markers, including hemodynamic status, N-terminal pro-brain natriuretic peptide (NT-proBNP) and risk assessment scores. Impact on survival was assessed using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Between 2008 and 2019, ADMA samples were collected prospectively from 215 patients with PAH. Change in ADMA plasma level was a predictor of disease progression and survival. ΔADMA (median -0.03 µmol/L; 95% CI: -0.145 to 0.0135) was correlated with change in mean pulmonary arterial pressure (P < 0.005; rS = 0.287) but was not significantly correlated with ΔNT-proBNP (P = 0.056; rS = 0.135). Patients with decreased ADMA plasma levels at follow-up had better 3-year and 5-year survival rates (88% and 80%, respectively, vs 72% and 53% in those without decreases in ADMA) (P < 0.005; pulmonary hypertension-related mortality or lung transplantation). Patients with decreases in both ADMA and NT-proBNP had better survival rates compared with patients in whom only 1 parameter improved (P < 0.005). ΔADMA was a significant predictor of survival in Cox regression analysis and also when corrected for ΔNT-proBNP (HRs: 1.27 and 1.35, respectively; P < 0.005). CONCLUSIONS: ADMA and NT-proBNP provide synergistic prognostic information for patients with PAH. ADMA could be used as an objective and distinct biomarker for monitoring treatment response in PAH.

Human paraneoplastic antigen Ma2 (PNMA2) forms icosahedral capsids that can be engineered for mRNA delivery.

A number of endogenous genes in the human genome encode retroviral gag-like proteins, which were domesticated from ancient retroelements. The paraneoplastic Ma antigen (PNMA) family members encode a gag-like capsid domain, but their ability to assemble as capsids and traffic between cells remains mostly uncharacterized. Here, we systematically investigate human PNMA proteins and find that a number of PNMAs are secreted by human cells. We determine that PNMA2 forms icosahedral capsids efficiently but does not naturally encapsidate nucleic acids. We resolve the cryoelectron microscopy (cryo-EM) structure of PNMA2 and leverage the structure to design engineered PNMA2 (ePNMA2) particles with RNA packaging abilities. Recombinantly purified ePNMA2 proteins package mRNA molecules into icosahedral capsids and can function as delivery vehicles in mammalian cell lines, demonstrating the potential for engineered endogenous capsids as a nucleic acid therapy delivery modality.

Persistent Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia in Patients Treated With Anti-CD20 Monoclonal Antibodies.

We report 8 cases of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia in patients previously treated with anti-CD20 monoclonal antibodies. Polymerase chain reaction of nasopharyngeal swabs for SARS-CoV-2 was negative in most cases; viral cell cultures confirmed that viable SARS-Co-2 virus was present. Four patients were treated with anti-SARS-CoV-2 hyperimmune globulins with rapid resolution of disease.

Management of acute COPD exacerbations in the internal medicine departments in Israel-a national survey.

Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Acute exacerbations of COPD (AECOPD) drastically affect the clinical course of the disease. We aimed to evaluate the treatment of AECOPD in the internal medicine departments in Israel, nationwide. Methods: The COPD Israeli survey (COPDIS) is the first national survey of patients admitted with AECOPD to internal medicine departments between 2017 and 2019. The survey includes prospective (n = 344) and retrospective (n = 1,166) data from 13 medical centers. We analyzed the pre-hospital, in-hospital, and pre-discharge care. Hospital evaluation, outcomes and discharge recommendations were assessed as well. Results: The mean (±SD) age was 74 (±8) years, and 54% were males. 74% had comorbidities, and 88% had a diagnosis of COPD in their history. 70% of the patients received systemic steroids and antibiotics during their hospitalization, yet upon discharge, a lower rate of antibiotics prescription (10%) was found. Treatment with most long-acting bronchodilators dramatically dropped during admission, compared with their pre-hospital use. Overall, a long-acting bronchodilator (LABD) was used by 47% before admission, 28% in-hospital, and was prescribed to 54% at discharge. The discharge plan included a referral to pulmonary rehabilitation in only 11% and a smoking cessation recommendation in 43% of active smokers. The in-hospital mortality was 3% and the 1-year mortality rate was 25%. In multivariate analysis, performing a chest X-ray (adjusted OR 0.64, 95% CI 0.46-0.90) and prescribing LABD at discharge (AOR 0.73, 95% CI 0.57-0.95) were independent predictors for lower 1-year mortality. Conclusion: Our results demonstrate AECOPD characteristics in Israel, and highlight several important gaps in AECOPD healthcare, which must be addressed to improve patient care.

Targeted evolution of adeno-associated virus capsids for systemic transgene delivery to microglia and tissue-resident macrophages.

Tissue macrophages, including microglia, are notoriously resistant to genetic manipulation. Here, we report the creation of Adeno-associated viruses (AAV) variants that efficiently and widely transduce microglia and tissue macrophages in vivo following intravenous delivery, with transgene expression of up to 80%. We use this technology to demonstrate manipulation of microglia gene expression and microglial ablation, thereby providing invaluable research tools for the study of these important cells.

Nontuberculous mycobacteria infections of the pleura: A systematic review.

BACKGROUND: Nontuberculous mycobacterial (NTM) pleuritis is an uncommon manifestation of NTM infection. Case reports and small case series have shown a variable clinical course and high mortality rates. OBJECTIVE: To describe patients' characteristics, clinical presentation and outcomes of NTM pleural infections. METHODS: A systematic review of cases of NTM pleural infections published in PubMed-indexed journals from 1980 to 2021. RESULTS: A total of 206 cases of NTM pleural infections were found and analyzed. Fifty-eight percent of cases were males. The mean age was 57.5 yrs (range 9-87 yrs). Forty-three percent of patients were immunosuppressed, and 43% had a chronic lung disease; thirty-two percent had neither risk factor. In addition to the pleural infection, 67% of cases had a concurrent pulmonary NTM infection, and in 18 cases there was another extrapulmonary site of NTM infection. In 29% of cases the pleural infection was the sole manifestation of NTM disease. The most common isolated mycobacterium was Mycobacterium avium complex (65%). Fifty-three percent and 26% of patients required pleural effusion drainage and a surgical intervention, respectively, to treat the infection, in addition to anti-NTM chemotherapy. Forty percent of patients developed pneumothorax, 16% suffered from empyema, and 16.5% had broncho-pleural fistula. The reported mortality rate was 24%. CONCLUSION: NTM pleural infections may arise in immunocompetent and immunosuppressed patients, with or without chronic lung disease or concurrent NTM pulmonary infection. These infections carry a poor prognosis and a high risk of complications requiring surgical interventions in addition to anti-NTM chemotherapy.

Pleuritis due to Mycobacterium xenopi without pulmonary infection.

Nontuberculous mycobacteria (NTM) may cause pulmonary and extra-pulmonary disease in both immunocompetent and immunocompromised patients. Pleuritis is an uncommon manifestation on NTM disease, and pleuritis caused by Mycobacterium xenopi has only been described once before. Because it is considered to be an environmental contaminant, isolation of M. xenopi from bronchopulmonary secretions or other sites is often dismissed. The disease caused by M. xenopi is usually a pulmonary infection and typically occurs in severely immunocompromised individuals or in immunocompetent patients with an underlying chronic lung disease. We describe an unusual case of pleuritis caused by M. xenopi in a patient without an underlying chronic lung disease and with no evidence of a concurrent M. xenopi pulmonary infection.

GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis.

The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion.

The importance of having good quality indicators for care of patients with COPD: a look at hospital readmission rates.

BACKGROUND: Readmission after hospitalization for acute COPD exacerbation (AE-COPD) has been proposed as a healthcare quality indicator (QI) in Israel. We studied patients hospitalized for AE-COPD, towards determining whether AE-COPD readmission is an appropriate national QI in order to improve COPD patient care. METHODS: Data were retrieved for all Clalit Health Service (CHS) members age 40-90 years hospitalized in CHS hospitals during 2016 with a diagnosis of acute COPD exacerbation. Information retrieved included demographics, medical history, Charleson comorbidity score, readmissions within 90 days, chronic medication use and family physician and pulmonologist visits. Patients readmitted within 90 days were compared to those who were not readmitted. Patients were also analyzed according to whether they were hospitalized during the year before the index hospitalization. RESULTS: In 2016 there were 70,601 members with a recorded diagnosis of COPD in CHS. Of these, 1,203 patients (1.7%) were hospitalized in a CHS hospital with a diagnosis of acute COPD exacerbation during 2016. Average age was 70.6 years, 63% were men. 78% were active smokers. 61% of the patients were readmitted to internal medicine wards within 90 days of the index hospitalization. Patients who were readmitted were more likely to have been hospitalized during the year before the index hospitalization (Odds ratio (OR) 2.5, Confidence Interval ((CI)(1.85, 3.38)) and had a higher Charlson comorbidity score (OR 1.07 (CI 1.01, 1.11)). Healthcare utilization by patients who were readmitted, both before and after admission, was generally greater. One yr mortality was 15.1% and 9.2% in those readmitted and not readmitted, respectively (p = 0.003). CONCLUSIONS: Readmitted COPD patients appear to be the sickest group of COPD patients with advanced disease and poor prognosis, and it may not be possible to prevent readmissions. This questions the utility of COPD readmissions as a healthcare quality indicator.

The role of inspiratory capacity and tidal flow in diagnosing exercise ventilatory limitation in Cystic Fibrosis.

BACKGROUND: Exercise ventilatory limitation conventionally defined by reduced breathing reserve (BR) may underestimate the effect of lung disease on exercise capacity in patients with mild to moderate obstructive lung diseases. OBJECTIVE: To investigate whether ventilatory limitation may be present despite a normal BR in Cystic Fibrosis (CF). METHODS: Twenty adult CF patients (age 16-58y) with a wide range of pulmonary obstruction severity completed a symptom-limited incremental exercise test on a cycle ergometer. Operating lung volumes were derived from inspiratory capacity (IC) measurement during exercise and exercise tidal flow volume loop analysis. RESULTS: six patients had a severe airway obstruction (FEV1<45% predicted) and conventional evidence of ventilatory limitation (low BR). Fourteen patients had mild to moderate-severe airway obstructive (FEV1 46-103% predicted), and a normal BR [12-62 L/min, BR% (17-40)]. However, dynamic respiratory mechanics demonstrated that even CF patients with mild to moderate-severe lung disease had clear evidence of ventilatory limitation during exercise. IC was decreased by (median) 580 ml (range 90-1180 ml) during exercise, indicating dynamic hyperinflation. Inspiratory reserve volume at peak exercise was 445 ml (241-1350 ml) indicating mechanical constraint on the respiratory system. The exercise tidal flow met or exceeded the expiratory boundary of the maximal flow volume loop over 72% of the expiratory volume (range 40-90%), indicating expiratory flow limitation. CONCLUSION: Reduced BR as a sole criterion underestimates ventilatory limitation during exercise in mild to moderate-severe CF patients. Assessment of dynamic respiratory mechanics during exercise revealed ventilatory limitation, present even in patients with mild obstruction.

Oxygen uptake kinetics during exercise reveal central and peripheral limitation in patients with iliofemoral venous obstruction.

OBJECTIVE: Pulmonary oxygen uptake (V˙O2) kinetics measured during the initiation of exercise mirror energetic transition during daily activity. The aim of this study was to elucidate the pathophysiological mechanisms of exercise limitation of patients with chronic iliofemoral vein obstruction after deep vein thrombosis by measuring V˙O2 kinetics compared with patients with peripheral arterial disease (PAD) and healthy individuals. METHODS: Eleven patients with iliofemoral vein obstruction (7 men; age, 20-65 years), seven patients with PAD (all men; age 44-60 years) and eight healthy participants (5 men; age 28-58 years) were studied. Participants performed upper and lower limb symptom-limited cardiopulmonary exercise tests on cycle ergometers; and four repeat lower limb tests at a constant work rate corresponding with 90% of the gas exchange threshold for determining V˙O2 kinetics. RESULTS: Phase I V˙O2 amplitude in the constant work rate tests (percent increase over resting V˙O2), representing the initial surge in cardiac output caused by the emptying of leg veins, was 59 ± 19% in the iliofemoral vein obstruction group, 73 ± 22% in PAD, and 85 ± 26% in healthy participants (P = .055 for iliofemoral vein obstruction vs healthy). Phase II V˙O2 kinetics, which largely reflect the kinetics of O2 consumption in the exercising muscles, were slower in iliofemoral vein obstruction (tau = 42 ± 6 seconds), and PAD (tau = 49 ± 19 seconds), compared with healthy participants (23 ± 4 seconds; P < .01). CONCLUSIONS: Slow phase II V˙O2 kinetics reflect a slow onset of muscular aerobic metabolism in both iliofemoral vein obstruction and PAD. The low amplitude phase I of V˙O2 kinetics observed in iliofemoral vein obstruction suggests a damped cardiodynamic phase, consistent with decreased venous return from the obstructed veins. These abnormalities of V˙O2 kinetics may contribute to exercise intolerance in iliofemoral vein obstruction and PAD.

Echocardiographic Ventricular Septal Motion Abnormalities Are Associated With Pre-Capillary Pulmonary Hypertension in Patients With Preserved Left Ventricular Function.

BACKGROUND: Ventricular septal motion abnormalities (VSMA) are common echocardiographic finding in patients with pulmonary hypertension (PHTN). This study sought to evaluate the relationship between echocardiographic findings and the classification of PHTN. METHODS: This study retrospectively studied 146 consecutive patients referred for right heart catheterisation for clinically suspected PHTN. VSMA were defined as any echocardiographic description of leftward abnormal septal motion or position. RESULTS: VSMA were present in 42 patients (29%). Patients with VSMA were younger and more likely to have prior pulmonary embolism. They also had less obstructive sleep apnoea, hypertension and dyslipidaemia. By echocardiography, patients with VSMA had lower left ventricular mass, left atrial size and lateral wall E/e' ratio. At cardiac catheterisation, PHTN was confirmed in all (100%) patients with VSMA (compared with 75% in patients without VSMA); 98% with VSMA had elevated pulmonary vascular resistance (compared with 55% without VSMA; p<0.005 for all). VSMA were found to have 91% sensitivity and 51% specificity for the diagnosis of pre-capillary PHTN. On multivariate analysis, VSMA were found to be strong independent predictors for the diagnosis of pre-capillary PHTN (HR, 9.15; 95% CI, 3.0-28.2; p<0.001). Left atrial enlargement was also a strong negative predictor for pre-capillary PHTN (HR, 0.14; 95% CI, 0.05-0.36; p<0.001). CONCLUSION: Ventricular septal motion abnormalities were strongly associated with pre-capillary PHTN in patients with suspected PHTN. The findings suggest that patients with VSMA should be further evaluated by right heart catheterisation.

Chronic thromboembolic pulmonary hypertension in patients with antiphospholipid syndrome: Risk factors and management.

BACKGROUND: Antiphospholipid syndrome (APS) may cause chronic thromboembolic pulmonary hypertension (CTEPH). Current knowledge regarding prevalence and risk factors for CTEPH among APS patients is limited. We sought to determine clinical features and biomarkers that could identify APS subjects suffering from CTEPH, and describe the prevalence, course and treatment outcomes of patients with APS-CTEPH. METHODS: 504 APS patients were treated in our center during 2008 to 2019. We studied clinical and laboratory features of 69 APS patients, comparing 19 patients diagnosed with CTEPH (APS-CTEPH) and treated accordingly, with 50 consecutive age and gender matched patients with no evidence of pulmonary hypertension (APS-No-CTEPH). RESULTS: CTEPH prevalence was 3.8% in our APS cohort and was linked with the following parameters: primary APS (p < 0.05); prior pulmonary embolism (p < 0.001); recurrent venous thromboembolism (VTE) (p < 0.001); lower platelet counts (p < 0.001); triple anti-phospholipid antibodies positivity (p < 0.001), higher titers of anti-cardiolipin IgG (p < 0.001), anti-B2GPI IgG (p < 0.001), and high Russell viper venom time ratio (RVVT-ratio) (p < 0.05). Additionally, history of catastrophic APS was more prevalent in APS-CTEPH vs APS-No-CTEPH (p < 0.05). Of APS-CTEPH patients, 15/19 underwent pulmonary endarterectomy (PEA): In 12/15 the procedure was elective and resulted in good perioperative and long-term outcomes, while only 1 of 3 patients that underwent urgent PEA survived. CONCLUSIONS: CTEPH is relatively common in APS. Primary APS, prior PE, recurrent VTE, thrombocytopenia and specific anti-phospholipid antibodies predict CTEPH in APS. Active assessment for CTEPH in APS patients should be considered, as PEA was found to be effective and relatively safe, especially if electively performed.

Pulmonary Hypertension Is Associated With Systemic Arterial Hypertension Among Patients With Normal Left Ventricular Diastolic Function.

Background The association of pulmonary and systemic arterial hypertension is believed to be mediated through hypertensive left heart disease. The purpose of the current study was to investigate whether pulmonary hypertension (PHT) is associated with systemic arterial hypertension among patients with apparently normal left ventricular diastolic function. Methods and Results Consecutive patients who had echocardiographic evaluation between 2007 and 2019 were enrolled. Patients with disease states that are known to be associated with PHT, including diastolic dysfunction, were excluded from the analysis. Estimated right ventricular systolic pressure was extracted for all patients from the echocardiographic reports. PHT was defined as estimated right ventricular systolic pressure >40 mm Hg. Multivariate logistic regression models were applied. Final study population included 25 916 patients with a median age of 59 (interquartile range, 44-69) years, of whom 12 501 (48%) were men and 13 265 (51%) had systemic arterial hypertension. Compared with normotensive patients, hypertensive patients were 3.2 times more likely to have PHT (95% CI, 2.91-3.53; P<0.001). A multivariate model adjusted for clinical and echocardiographic parameters that are known to be associated with PHT demonstrated that hypertensive patients are almost 3 times more likely to have PHT (95% CI, 2.45-3.15; P<0.001). The association was significant in multiple subgroups but was more significant among women compared with men (odds ratio, 3.1 versus 2.4; P for interaction <0.001). Conclusions PHT is associated with systemic arterial hypertension irrespective of left heart disease. The association is more pronounced among women.

Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery.

Eukaryotic genomes contain domesticated genes from integrating viruses and mobile genetic elements. Among these are homologs of the capsid protein (known as Gag) of long terminal repeat (LTR) retrotransposons and retroviruses. We identified several mammalian Gag homologs that form virus-like particles and one LTR retrotransposon homolog, PEG10, that preferentially binds and facilitates vesicular secretion of its own messenger RNA (mRNA). We showed that the mRNA cargo of PEG10 can be reprogrammed by flanking genes of interest with Peg10's untranslated regions. Taking advantage of this reprogrammability, we developed selective endogenous encapsidation for cellular delivery (SEND) by engineering both mouse and human PEG10 to package, secrete, and deliver specific RNAs. Together, these results demonstrate that SEND is a modular platform suited for development as an efficient therapeutic delivery modality.

A Machine Learning Approach to the Interpretation of Cardiopulmonary Exercise Tests: Development and Validation.

OBJECTIVE: At present, there is no consensus on the best strategy for interpreting the cardiopulmonary exercise test's (CPET) results. This study is aimed at assessing the potential of using computer-aided algorithms to evaluate CPET data for identifying chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD). METHODS: Data from 234 CPET files from the Pulmonary Institute, at Sheba Medical Center, and the Givat-Washington College, both in Israel, were selected for this study. The selected CPET files included patients with confirmed primary CHF (n = 73), COPD (n = 75), and healthy subjects (n = 86). Of the 234 CPETs, 150 (50 in each group) tests were used for the support vector machine (SVM) learning stage, and the remaining 84 tests were used for the model validation. The performance of the SVM interpretive module was assessed by comparing its interpretation output with the conventional clinical diagnosis using distribution analysis. RESULTS: The disease classification results show that the overall predictive power of the proposed interpretive model ranged from 96% to 100%, indicating very high predictive power. Furthermore, the sensitivity, specificity, and overall precision of the proposed interpretive module were 99%, 99%, and 99%, respectively. CONCLUSIONS: The proposed new computer-aided CPET interpretive module was found to be highly sensitive and specific in classifying patients with CHF or COPD, or healthy. Comparable modules may well be applied to additional and larger populations (pathologies and exercise limitations), thereby making this tool powerful and clinically applicable.

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

Baseline spirometry parameters as predictors of airway hyperreactivity in adults with suspected asthma.

BACKGROUND: Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma. METHODS: Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle ß, FEV1, FVC, FEV1/FVC, FEF50%, FEF25-75%) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified. RESULTS: A total of 2983 tests were analyzed in adults aged 18-40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p < 0.001). FEF50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF50% ≥ 110% as a cutoff level. CONCLUSIONS: This study highlights the role of FEF50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.

Myc determines the functional age state of oligodendrocyte progenitor cells.

Like many adult stem cell populations, the capacity of oligodendrocyte progenitor cells (OPCs) to proliferate and differentiate is substantially impaired with aging. Previous work has shown that tissue-wide transient expression of the pluripotency factors Oct4, Sox2, Klf4 and c-Myc extends lifespan and enhances somatic cell function. Here we show that just one of these factors, c-Myc, is sufficient to determine the age state of OPC: c-Myc expression in aged OPCs drives their functional rejuvenation, while its inhibition in neonatal OPCs induces an aged-like phenotype, as determined by in vitro assays and transcriptome analysis. Increasing c-Myc expression in aged OPCs in vivo restores their proliferation and differentiation capacity, thereby enhancing regeneration in an aged central nervous system environment. Our results directly link Myc to cellular activity and cell age state, with implications for understanding regeneration in the context of aging, and provide important insights into the biology of stem cell aging.