Prediction of chemical bioactivity and physical properties has been one of the most important applications of statistical and more recently, machine learning and artificial intelligence methods in chemical sciences. This field of research, broadly known as quantitative structure–activity relationships (QSAR) modeling, has developed many important algorithms and has found a broad range of applications in physical organic and medicinal chemistry in the past 55+ years. This Perspective summarizes recent technological advances in QSAR modeling but it also highlights the applicability of algorithms, modeling methods, and validation practices developed in QSAR to a wide range of research areas outside of traditional QSAR boundaries including synthesis planning, nanotechnology, materials science, biomaterials, and clinical informatics. As modern research methods generate rapidly increasing amounts of data, the knowledge of robust data-driven modelling methods professed within the QSAR field can become essential for scientists working both within and outside of chemical research. We hope that this contribution highlighting the generalizable components of QSAR modeling will serve to address this challenge.

QSAR without borders

BACKGROUND
Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Drugs with antioxidant and anti-inflammatory properties, such as N-acetylcysteine, might provide a useful therapeutic approach for COPD. We aimed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD.


METHODS
In our prospective, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 40-80 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <0·7 and FEV1 of 30-70% of predicted) at 34 hospitals in China. We stratified patients according to use of inhaled corticosteroids (regular use or not) at baseline and randomly allocated them to receive N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year. The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after randomisation. This study is registered with the Chinese Clinical Trials Registry, ChiCTR-TRC-09000460.


FINDINGS
Between June 25, 2009, and Dec 29, 2010, we screened 1297 patients, of whom 1006 were eligible for randomisation (504 to N-acetylcysteine and 502 to placebo). After 1 year, we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit (1·16 exacerbations per patient-year) and 641 acute exacerbations in 482 patients in the placebo group (1·49 exacerbations per patient-year; risk ratio 0·78, 95% CI 0·67-0·90; p=0·0011). N-acetylcysteine was well tolerated: 146 (29%) of 495 patients who received at least one dose of N-acetylcysteine had adverse events (48 serious), as did 130 (26%) of 495 patients who received at least one dose of placebo (46 serious). The most common serious adverse event was acute exacerbation of COPD, occurring in 32 (6%) of 495 patients in the N-acetylcysteine group and 36 (7%) of 495 patients in the placebo group.


INTERPRETATION
Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity. Future studies are needed to explore efficacy in patients with mild COPD (GOLD I).


FUNDING
Hainan Zambon Pharmaceutical.

TWICE DAILY N-Acetylcysteine 600 MG FOR EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (PANTHEON): A RANDOMISED, DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL ; РАНДОМИЗИРОВАННОЕ ДВОЙНОЕ СЛЕПОЕ ПЛАЦЕБО-КОНТРОЛИРУЕМОЕ ИССЛЕДОВАНИЕ PANTHEON: ПРИМЕНЕНИЕ N-АЦЕТИЛЦИСТЕИНА В ДОЗЕ 600 МГ 2 РАЗА В ДЕНЬ ПРИ ОБОСТРЕНИЯХ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЕГКИХ

On-line analysis of exhaled breath offers insight into a person's metabolism without the need for sample preparation or sample collection. Due to its noninvasive nature and the possibility to sample continuously, the analysis of breath has great clinical potential. The unique features of this technology make it an attractive candidate for applications in medicine, beyond the task of diagnosis. We review the current methodologies for on-line breath analysis, discuss current and future applications, and critically evaluate challenges and pitfalls such as the need for standardization. Special emphasis is given to the use of the technology in diagnosing respiratory diseases, potential niche applications, and the promise of breath analysis for personalized medicine. The analytical methodologies used range from very small and low-cost chemical sensors, which are ideal for continuous monitoring of disease status, to optical spectroscopy and state-of-the-art, high-resolution mass spectrometry. The latter can be utilized for untargeted analysis of exhaled breath, with the capability to identify hitherto unknown molecules. The interpretation of the resulting big data sets is complex and often constrained due to a limited number of participants. Even larger data sets will be needed for assessing reproducibility and for validation of biomarker candidates. In addition, molecular structures and quantification of compounds are generally not easily available from on-line measurements and require complementary measurements, for example, a separation method coupled to mass spectrometry. Furthermore, a lack of standardization still hampers the application of the technique to screen larger cohorts of patients. This review summarizes the present status and continuous improvements of the principal on-line breath analysis methods and evaluates obstacles for their wider application.

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On-Line Analysis of Exhaled Breath Focus Review.

BACKGROUND: The impacts of chronic airway diseases on coronavirus disease 2019 (COVID-19) are far from understood. OBJECTIVE: To explore the influence of asthma and chronic obstructive pulmonary disease (COPD) comorbidity on disease expression and outcomes, and the potential underlying mechanisms in COVID-19 patients. METHODS: A total of 961 hospitalized COVID-19 patients with a definite clinical outcome (death or discharge) were retrospectively enrolled. Demographic and clinical information were extracted from the medical records. Lung tissue sections from patients suffering from lung cancer were used for immunohistochemistry study of angiotensin-converting enzyme II (ACE2) expression. BEAS-2B cell line was stimulated with various cytokines. RESULTS: In this cohort, 21 subjects (2.2%) had COPD and 22 (2.3%) had asthma. After adjusting for confounding factors, COPD patients had higher risk of developing severe illness (OR: 23.433; 95% CI 1.525-360.135; P < .01) and acute respiratory distress syndrome (OR: 19.762; 95% CI 1.461-267.369; P = .025) than asthmatics. COPD patients, particularly those with severe COVID-19, had lower counts of CD4+ T and CD8+ T cells and B cells and higher levels of TNF-α, IL-2 receptor, IL-10, IL-8, and IL-6 than asthmatics. COPD patients had increased, whereas asthmatics had decreased ACE2 protein expression in lower airways, compared with that in control subjects without asthma and COPD. IL-4 and IL-13 downregulated, but TNF-α, IL-12, and IL-17A upregulated ACE2 expression in BEAS-2B cells. CONCLUSION: Patients with asthma and COPD likely have different risk of severe COVID-19, which may be associated with different ACE2 expression.

Distinct effects of asthma and COPD comorbidity on disease expression and outcome in patients with COVID-19.

In the most recent years, an extraordinary research effort has emerged to disentangle osteoarthritis heterogeneity, opening new avenues for progressing with therapeutic development and unravelling the pathogenesis of this complex condition. Several phenotypes and endotypes have been proposed albeit none has been sufficiently validated for clinical or research use as yet. This review discusses the latest advances in OA phenotyping including how new modern statistical strategies based on machine learning and big data can help advance this field of research.

Phenotypes of osteoarthritis: current state and future implications.

Global Strategy for the Diagnosis, Management, and Prevention of COPD 2018 is a consensus report published periodically since 2001 by an international panel of health professionals from respiratory medicine, socioeconomics, public health, and education comprising the Global Initiative for Chronic Obstructive Lung Disease (GOLD). The GOLD documents endeavor to incorporate latest evidence and expert consensus and are intended for use as "strategy documents" for implementation of effective care for chronic obstructive lung disease (COPD) on a global level. The GOLD 2018 report defines COPD as a "common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities, usually caused by significant exposure to noxious particles or gases," with the criteria of "persistent respiratory symptoms" being a new and controversial inclusion since 2017. With the availability of newer pharmacotherapy options, treatment recommendations are made on the basis of a review of the latest literature and directed by symptom burden and health care utilization. Apart from the change in definition, a major shift in the recommendations is the exclusion of severity of airflow limitation as one of the major factors in guiding therapy. We review the salient features of the GOLD 2018 document and provide commentary on features that merit further discussion based on our clinical experience and practice as well as literature review current as of February 2018.

COPD Guidelines: A Review of the 2018 GOLD Report.

Chronic obstructive pulmonary disease (COPD) phenotyping can help define clusters of patients with common characteristics that relate to clinically meaningful outcomes. In this review, we describe 7 clinically meaningful COPD phenotypes that can be identified by primary care physicians as well as specialists and that have specific management and prognostic implications: (1) asthma-COPD overlap phenotype, (2) frequent exacerbator phenotype, (3) upper lobe-predominant emphysema phenotype, (4) rapid decliner phenotype, (5) comorbid COPD phenotype, (6) physical frailty phenotype, and (7) emotional frailty phenotype.

Chronic Obstructive Pulmonary Disease Phenotypes: Implications for Care.

Autoimmune serologies are often obtained in the initial evaluation of uncharacterized interstitial lung disease (ILD). Whether this practice is helpful in delineating connective-tissue disease related ILD (CTD-ILD) is not well known. We assessed the frequency of incident CTD-ILD as detected by autoimmune serology testing and presenting clinical signs and symptoms. Consecutive patients seen at our institution over a four year period with newly diagnosed uncharacterized ILD and autoimmune serologic testing were included. Serologic assessment was performed as a standardized order set of 13 laboratory tests. Presenting demographics and clinical signs or symptoms suggestive of autoimmune disease were correlated with the presence or absence of positive serology studies and final CTD-ILD diagnoses. Overall prevalence of newly diagnosed CTD-ILD was 6.9% (42 of 605). Positive serology was seen in 35.2% (213 of 605) of screened ILD. CTD-ILD was diagnosed in 19.2% of those with positive serology, and 52.8% of those with both positive serology and suggestive clinical signs or symptoms. Only 1.4% of those with positive serology and negative review of systems were diagnosed with CTD-ILD. CTD-ILD diagnoses were made more frequently in younger patients ≤60 years with no diagnoses made after the age of 80 (P = 0.009). Positive serology in non-CTD-ILD cases did not appear to confer any survival advantage. The yield of autoimmune serology testing in uncharacterized ILD appears greatest in those with suggestive clinical signs or symptoms on presentation for CTD-ILD.

Utility of autoimmune serology testing in the assessment of uncharacterized interstitial lung disease: a large retrospective cohort review

Frailty is a state of functional decline and increased vulnerability to adverse health outcomes, associated with increased inflammation and dysregulated immune and physiological systems. Frailty plays an important role in morbidity and mortality in elderly patients and is emerging as an important risk factor in chronic diseases and solid organ transplant patients. There is no consensus as to the best frailty measure, and a multitude of options are available to researchers and clinicians. The prevalence in chronic lung disease and solid organ transplant varies by organ and frailty measurement type but appears higher than in elderly community populations. Frailty has been linked to removal from the transplant waiting list, mortality, delayed graft function, and length of stay in transplant populations. Much work remains to discover methods to prevent or reverse frailty. Encouragingly, studies suggest that frailty is not a permanent state and may be responsive to exercise training.

Shireen Mirza

Papers

COPD Guidelines: A Review of the 2018 GOLD Report.

Chronic Obstructive Pulmonary Disease Phenotypes: Implications for Care.

Utility of autoimmune serology testing in the assessment of uncharacterized interstitial lung disease: a large retrospective cohort review

The importance of frailty in lung transplantation and chronic lung disease

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