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Objective: Freezing of Gait (FOG) is prevalent in people with Parkinson's disease (PD) and severely disrupts mobility. Detecting the exact boundaries of FOG episodes may facilitate new technologies in "breaking" FOG in real-time. This study investigates the performance of automatic device-based FOG detection., Methods: Eight machine-learning classifiers (including Neural Networks, Ensemble methods, and Support Vector Machines) were developed using (i) accelerometer and (ii) combined accelerometer and gyroscope data from a waist-worn device. While wearing the device, 107 people with PD completed mobility tasks designed to elicit FOG. Two clinicians independently annotated exact FOG episodes using synchronized video and a flowchart algorithm based on international guidelines. Device-detected FOG episodes were compared to annotated episodes using 10-fold cross-validation and Interclass Correlation Coefficients (ICC) for agreement., Results: Development used 50,962 windows of data and annotated activities (>10 hours). Strong agreement between clinicians for precise FOG episodes was observed (90% sensitivity, 92% specificity, and ICC1,1 = 0.97 for total FOG duration). Device performance varied by method, complexity, and cost matrix. The Neural Network using 67 accelerometer features achieved high sensitivity to FOG (89% sensitivity, 81% specificity, and ICC1,1 = 0.83) and stability (validation loss 5%)., Conclusion: The waist-worn device consistently reported accurate detection of precise FOG episodes and compared well to more complex systems. The strong clinician agreement indicates room for improvement in future device-based FOG detection., Significance: This study may enhance PD care by reducing reliance on visual FOG inspection, demonstrating that high sensitivity in automatic FOG detection is achievable.

Objectives: Digital gait biomarkers collected from body-worn devices can remotely and continuously collect movement types, quantity, and quality in real life. This study assessed whether digital gait biomarkers from a wrist-worn device could identify people with frailty in a large sample of middle-aged and older adults., Design: Cross-sectional study., Setting and Participants: A total of 5822 middle-aged (43-64 years) and 4344 older adults (65-81 years) who participated in the UK Biobank study., Measures: Frailty was assessed using a modified Fried's frailty assessment and was defined as having ≥3 of the 5 frailty criteria (weakness, low activity levels, slowness, exhaustion, and weight loss). Fourteen digital gait biomarkers were extracted from accelerometry data collected from wrist-worn sensors worn continuously by participants for up to 7 days., Results: A total of 238 (4.1%) of the middle-aged group and 196 (4.5%) of the older group were categorized as frail. Multivariable logistic regression analysis revealed that less daily walking (as assessed by step counts), slower maximum walking speed, and increased step time variability best-identified people with frailty in the middle-aged group [area under the curve (95% CI): 0.70 (0.66-0.73)]. Less daily walking, slower maximum walking speed, increased step time variability, and a lower proportion of walks undertaken with a manual task best-identified people with frailty in the older group [0.73 (0.69-0.76)]., Conclusions and Implications: Our findings indicate that measures obtained from wrist-worn wearable devices worn in everyday life can identify individuals with frailty in both middle-aged and older people. These digital gait biomarkers may facilitate screening programs and the timely implementation of frailty-prevention interventions., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Walking is crucial for independence and quality of life. This study leverages wrist-worn sensor data from UK Biobank participants to establish normative daily-life walking data, stratified by age and sex, to provide benchmarks for research and clinical practice. The Watch Walk digital biomarkers were developed, validated, and applied to 92,022 participants aged 45-79 who wore a wrist sensor for at least three days. Normative data were collected for daily-life walking speed, step-time variability, step count, and 17 other gait and sleep biomarkers. Test-retest reliability was calculated, and associations with sex, age, self-reported walking pace, and mobility problems were examined. Population mean maximal and usual walking speeds were 1.49 and 1.15 m/s, respectively. The daily step count was 7749 steps, and step regularity was 65%. Women walked more regularly but slower than men. Walking speed, step count, longest walk duration, and step regularity decreased with age. Walking speed is associated with sex, age, self-reported pace, and mobility problems. Test-retest reliability was good to excellent (ICC ≥ 0.80). This study provides large-scale normative data and benchmarks for wrist-sensor-derived digital gait and sleep biomarkers from real-world data for future research and clinical applications.

Objectives: Physical decline can be associated with the onset of depressive symptoms in later life. This study aimed to identify physical and lifestyle risk factors for depressive symptom trajectories in community-dwelling older adults., Methods: Participants were 553 people aged 70-90 years who underwent baseline physical, psychological and lifestyle assessments. Group-based trajectory analysis was used to identify patterns of depressive symptom development over 6 years of follow-up. Strengths of associations between baseline functional test performances and depressive symptom trajectories were evaluated with univariable ordinal models. Subsequently, the adjusted cumulative odds ratio for the association between identified risk factors, demographic factors and baseline anti-depressant use were measured using multivariable ordinal logistic regression., Results: Three distinct depressive symptom trajectories were identified: a low-and-stable course (10% of participants), a low-and-increasing course (81%) and a moderate-and-increasing course (9%). Timed Up and Go test time was the strongest risk factor of depressive symptom trajectory, followed by Five Times Sit-to-Stand test performance, planned physical activity levels, and knee extension strength (adjusted standardised ORs 1.65, 95% CI 1.34-2.04; 1.44, 95% CI 1.16-1.77; 1.44, 95% CI 1.17-1.76 and 1.41, 95% CI 1.15-1.73 respectively). After adjusting for age, sex, body mass index and baseline anti-depressant use, Timed Up and Go test performance and knee extension strength were independently and significantly associated with depressive trajectories., Conclusions: Timed Up and Go test times, Five Times Sit-to-Stand test performance, planned physical activity levels and knee extension strength are associated with three discrete depressive symptom trajectories. These clinical tests may help identify older adults aged 70-90 years at risk of developing depressive symptoms and help guide subsequent strength and mobility interventions., (© 2024 AJA Inc’.)

Bats are reservoir hosts for various zoonotic viruses with pandemdic potential in humans and livestock. In vitro systems for studying bat host-pathogen interactions are of significant interest. Here, we establish protocols to generate bat airway organoids (AOs) and airway epithelial cells differentiated at the air-liquid interface (ALI-AECs) from tracheal tissues of the cave-nectar bat Eonycteris spelaea . In particular, we describe steps which enable laboratories that do not have access to live bats to perform extended experimental work upon procuring an initial batch of bat primary airway tissue. Complete mucociliary differentiation required treatment with IL-13. E. spelaea ALI-AECs supported productive infection with PRV3M, an orthoreovirus for which Pteropodid bats are considered the reservoir species. However, these ALI-AECs did not support SARS-CoV-2 infection, despite E. spelaea ACE2 receptor being capable of mediating SARS-CoV-2 spike pseudovirus entry. This work provides critical model systems for assessing bat species-specific virus susceptibility and the reservoir likelihood for emerging infectious agents.

Objectives: To determine whether digital gait biomarkers captured by a wrist-worn device can predict injurious falls in older people and to develop a multivariable injurious fall prediction model., Design: Population-based longitudinal cohort study., Setting and Participants: Community-dwelling participants of the UK Biobank study aged 65 and older (n = 32,619) in the United Kingdom., Methods: Participants were assessed at baseline on daily-life walking speed, quality, quantity and distribution using wrist-worn accelerometers for up to 7 days. Univariable and multivariable Cox proportional hazard regression models were used to analyse the associations between these parameters and injurious falls for up to 9 years., Results: Five percent of the participants (n = 1,627) experienced at least one fall requiring medical attention over a mean of 7.0 ± 1.1 years. Daily-life walking speed, gait quality, quantity of walking and distribution of daily walking were all significantly associated with the incidence of injurious falls (P < 0.05). After adjusting for sociodemographics, lifestyle factors, comorbidities, handgrip strength and reaction time; running duration, total step counts and usual walking speed were identified as independent and significant predictors of falls (P < 0.01). These associations were consistent in those without a history of previous fall injuries. In contrast, step regularity was the only risk factor for those with a previous fall history after adjusting for covariates., Conclusions: Daily-life gait speed, quantity and quality, derived from wrist-worn sensors, are significant predictors of injurious falls in older people. These digital gait biomarkers could potentially be used to identify fall risk in screening programs and integrated into fall prevention strategies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Mobile phone use is known to be a distraction to pedestrians, increasing their likelihood of crossing into oncoming traffic or colliding with other people. However, the effect of using a mobile phone to text while walking on gait stability and accidental falls in young adults remains inconclusive. This study uses a 70 cm low friction slip hazard and the threat of hazard to investigate the effects of texting while walking on gait stability, the ability to recover balance after a slip hazard and accidental falls., Methods: Fifty healthy young adults performed six walking tasks, and one seated texting task in random order. The walks were conducted over a 10-m walkway. Four progressive hazard levels were used: 1) Seated; 2) Normal Walk (walking across the walkway with no threat of a slip); 3) Threat (walking with the threat of a slip); and 4) Slip (walking with an actual 70 cm slip hazard). The three walking conditions were repeated twice with and without the mobile phone texting dual-task. Gait kinematics and trunk posture were recorded using wearable sensors attached to the head, trunk, pelvis and feet. Study outcomes were analyzed using repeated measures analysis of variance with significance set to P≤.05 ., Results: Mobile phone use significantly impaired postural balance recovery when slipping, as demonstrated by increased trunk sway. Mobile phone use negatively impacted gait stability as demonstrated by increased step time variability and decreased harmonic ratios. Increased hazard levels also led to reduced texting accuracy., Conclusions: Using a mobile phone to text while walking may compete with locomotor tasks, threat assessment and postural balance control mechanisms, which leads to an increased risk of accidental falls in young adults. Pedestrians should therefore be discouraged through new educational and technology-based initiatives (for example a "texting lock" on detection of walking) from texting while walking on roadside footpaths and other environments where substantial hazards to safety exist., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Objectives: To determine if digital gait biomarkers captured by a wrist-worn device can predict the incidence of depressive episodes in middle-age and older people., Design: Longitudinal cohort study., Setting and Participants: A total of 72,359 participants recruited in the United Kingdom., Methods: Participants were assessed at baseline on gait quantity, speed, intensity, quality, walk length distribution, and walk-related arm movement proportions using wrist-worn accelerometers for up to 7 days. Univariable and multivariable Cox proportional-hazard regression models were used to analyze the associations between these parameters and diagnosed incident depressive episodes for up to 9 years., Results: A total of 1332 participants (1.8%) had incident depressive episodes over a mean of 7.4 ± 1.1 years. All gait variables, except some walk-related arm movement proportions, were significantly associated with the incidence of depressive episodes (P < .05). After adjusting for sociodemographic, lifestyle, and comorbidity covariates; daily running duration, steps per day, and step regularity were identified as independent and significant predictors (P < .001). These associations held consistent in subgroup analysis of older people and individuals with serious medical conditions., Conclusions and Implications: The study findings indicate digital gait quality and quantity biomarkers derived from wrist-worn sensors are important predictors of incident depression in middle-aged and older people. These gait biomarkers may facilitate screening programs for at-risk individuals and the early implementation of preventive measures., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Older people are at increased risk of many adverse health outcomes, including dementia and depression, that burden the global health system. This paper presents algorithms for the large-scale assessment of daily walking speeds. We hypothesize that (i) data from wrist-worn sensors can be used to assess walking speed accurately; and that (ii) maximal daily walking speed is a better predictor of health outcomes than usual daily walking speed. First, algorithms were developed and tested using data from 101 participants aged 19 to 91 (47 ± 18) years. Participants wore an AX3 accelerometer (Axivity, UK) on their dominant wrist while undertaking daily life activities with electronic walkway data used for ground truth. Subsequently, prediction models for dementia, depression and death were developed using the data of 47,406 participants (≥ 60 years) from the UK Biobank study. Daily walking speeds were derived from 7-day AX3 data with time-to-events using electronic health records. The accuracy of derived walking speeds was assessed using root mean square error (RMSE). Time-to-events were modelled using Cox regression with inverse hazard ratios reported for univariable models and Harrell's concordance for multivariable models. Derived walking speeds had an RMSE of between 3% and 4% depending on arm position. We found that for simple models, maximal walking speed was significantly better than usual walking speed at predicting time to dementia (1.62 vs 1.34), depression (1.29 vs 1.17) and death (1.56 vs 1.27). However, the addition of known risk factors in subsequent multivariable models reduced the apparent benefit of using maximal as opposed to usual daily walking speed as the gait parameter. In summary, walking speed was accurately measured with a wrist-worn device, and maximal daily waking speed may be better than usual daily walking speed at predicting some adverse health outcomes.Clinical Relevance- This study demonstrated the validity of using a simple and unobtrusive wrist-worn sensor to remotely assess daily walking speed. As a single, modifiable and easily understood measure, maximal walking speed was shown to be better than usual walking speed at predicting time-to-dementia, depression and death. Therefore, the inclusion of maximal daily walking speed into screening programs and clinical interventions presents a promising area for further research.

Background: SARS-CoV-2, the causative agent of COVID-19, is a threat to public health. Evidence suggests increased neutrophil activation and endothelial glycocalyx (EG) damage are independently associated with severe COVID-19. Here, we hypothesised that an increased level of blood neutrophil myeloperoxidase (MPO) is associated with soluble EG breakdown, and inhibiting MPO activity may reduce EG damage., Methods: Analysing a subset of acute and convalescent COVID-19 plasma, 10 from severe and 15 from non-severe COVID-19 cases, and 9 from pre-COVID-19 controls, we determined MPO levels, MPO activity and soluble EG proteins (syndecan-1 and glypican-1) levels by enzyme-linked immunosorbent assay. In vitro primary human aortic endothelial cells were cultured with plasma untreated or treated with specific MPO inhibitors (MPO-IN-28, AZD5904) to determine EG shedding. We then investigated whether inhibiting MPO activity decreased EG degradation., Results: In COVID-19 plasma, MPO levels, MPO activity and levels of soluble EG proteins are significantly raised compared to controls, and concentrations increase in proportion to disease severity. Despite clinical recovery, protein concentrations remain significantly elevated. Interestingly, there is a trend of increasing MPO activity in convalescent plasma in both severe and non-severe groups. MPO levels and MPO activity correlate significantly with soluble EG levels and inhibiting MPO activity leads to reduced syndecan-1 shedding, in vitro., Conclusions: Neutrophil MPO may increase EG shedding in COVID-19, and inhibiting MPO activity may protect against EG degradation. Further research is needed to evaluate the utility of MPO inhibitors as potential therapeutics against severe COVID-19., (© 2023. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation and infective exacerbations, however, in-vitro model systems for the study of host-pathogen interaction at the individual level are lacking. Here, we describe the establishment of nasopharyngeal and bronchial organoids from healthy individuals and COPD that recapitulate disease at the individual level. In contrast to healthy organoids, goblet cell hyperplasia and reduced ciliary beat frequency were observed in COPD organoids, hallmark features of the disease. Single-cell transcriptomics uncovered evidence for altered cellular differentiation trajectories in COPD organoids. SARS-CoV-2 infection of COPD organoids revealed more productive replication in bronchi, the key site of infection in severe COVID-19. Viral and bacterial exposure of organoids induced greater pro-inflammatory responses in COPD organoids. In summary, we present an organoid model that recapitulates the in vivo physiological lung microenvironment at the individual level and is amenable to the study of host-pathogen interaction and emerging infectious disease., (© 2022. The Author(s).)

Digital gait biomarkers (including walking speed) indicate functional decline and predict hospitalization and mortality. However, waist or lower-limb devices often used are not designed for continuous life-long use. While wrist devices are ubiquitous and many large research repositories include wrist-sensor data, widely accepted and validated digital gait biomarkers derived from wrist-worn accelerometers are not available yet. Here we describe the development of advanced signal processing algorithms that extract digital gait biomarkers from wrist-worn devices and validation using 1-week data from 78,822 UK Biobank participants. Our gait biomarkers demonstrate good test-retest-reliability, strong agreement with electronic walkway measurements of gait speed and self-reported pace and significantly discriminate individuals with poor self-reported health. With the almost universal uptake of smart-watches, our algorithms offer a new approach to remotely monitor life-long population level walking speed, quality, quantity and distribution, evaluate disease progression, predict risk of adverse events and provide digital gait endpoints for clinical trials., (© 2022. The Author(s).)

Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group., Competing Interests: Declaration of interests J.D.C. has received research grants from GSK, BI, AZ, Gilead Sciences, Grifols, and Insmed and has received personal fees from GSK, BI, AZ, Chiesi, Grifols, Napp, Novartis, Insmed, and Zambon, all outside the submitted work. S.H.C. is on advisory boards for CSL Behring, Pneumagen, and BI, serves on Data and Safety Monitoring Boards for Inovio Pharmaceuticals and Imam Abdulrahman Bin Faisal University, and has received personal fees from AZ, all outside of the submitted work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to assess whether the amount and quality of daily-life walking obtained using wearable technology can predict depression onset over a 2-year period, independently of self-reported health status., Design: Longitudinal cohort study., Setting and Participants: Three-hundred twenty-two community-dwelling older people recruited in Sydney, Australia., Methods: Participants were assessed at baseline on (1) depressive symptoms using the Patient Health Questionnaire-9; (2) average weekly physical activity levels over the past month using the Incidental and Planned Activity Questionnaire, (3) clinical mobility tests (ie, short physical performance battery, timed up-and-go test, 6-m walk test); and (4) amount and quality of daily-life walking assessed with a trunk accelerometer (MoveMonitor, McRoberts) for 1 week. Participants were followed up for onset of depressive symptoms for 2 years at 6-monthly intervals., Results: Daily-life walking (ie, gait intensity in the mediolateral axis, daily step counts, duration of longest walk) and self-rated health predicted the new onset of depressive symptoms at 2 years in univariable logistic regression models. In multivariable models containing a self-rated health measure, clinical mobility tests were not predictive of the onset of depressive symptoms. In contrast, a measure of daily-life walking (duration of longest walking bout) was identified as a significant predictor of depressive symptom onset [standardized odds ratio (SOR) 2.44, 95% CI 1.62-3.76] independent of self-rated health (SOR 1.51, 95% CI 1.16-1.96), with these 2 measures achieving a satisfactory prediction accuracy (area under the curve = 0.67, sensitivity: 0.78, specificity: 0.52)., Conclusions and Implications: A risk algorithm based on daily-life walking bouts and self-reported health demonstrated good accuracy for the prediction of depression onset in older people over 2 years. Wearable sensor data compared favorably with clinical mobility screens and may add important independent information for screening for depression among older people., (Copyright © 2022 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have declared that no competing interests exist

Objective: To summarize evidence regarding the prevalence and incidence of low back pain and associated risk factors in nursing and medical students. TYPE: Systematic review and meta-analysis., Literature Survey: The protocol was registered with PROSPERO (CRD42015029729). Its reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seven databases were searched until August 2020 to identify relevant studies., Methodology: Two independent reviewers screened, extracted, and evaluated the risk of bias of the selected studies. Meta-analyses were used to estimate 12-month prevalence/incidence rates of low back pain and associated risk factors in these students. Levels of evidence for risk factors were determined by the updated Guidelines for Systematic Reviews in the Cochrane Collaboration Back Review Group., Synthesis: Sixteen studies involving 7072 students were included. The pooled 12-month prevalence rates of low back pain for nursing and medical students were 44% (95% confidence interval [95% CI]: 27%-61%) and 53% (95% CI: 44%-62%), respectively. The 12-month incidence of low back pain in nursing students ranged from 29% to 67%. No incidence rate was reported in medical students. Strong/moderate-quality evidence supported that final year of study (pooled odds ratio [OR] from five studies, 1.96, 95% CI: 1.13-3.40), anxiety (OR ranging from 3.12 to 4.61), or high mental pressure or psychological distress (OR ranging from 1.37 to 4.52) was associated with a higher 12-month low back pain prevalence in both student groups. Moderate-quality evidence suggested that prior history of low back pain (pooled OR from two studies: 3.46, 95% CI: 1.88-6.36) was associated with a higher 12-month low back pain incidence in nursing students. Similarly, moderate-quality evidence suggested that female medical students (pooled OR from two studies: 1.77, 95% CI: 1.09-2.86) demonstrated a higher 12-month low back pain prevalence than male counterparts., Conclusions: Although it is impossible to alter nonmodifiable risk factors for low back pain, universities may develop and implement proper strategies to mitigate modifiable risk factors in these students., (© 2021 American Academy of Physical Medicine and Rehabilitation.)

Introduction: Dyspnoea-12 scale is a validated assessment tool, capturing the perception of dyspnoea and its physical and affective effects in individuals with chronic obstructive pulmonary disease (COPD). A validated version for the Chinese-speaking population has been unavailable., Objective: To develop a Chinese version of D-12 (D-12-C) scale and evaluate its validity and reliability., Methods: D-12 was translated from English to traditional Chinese in collaboration with a physician and a linguist. Back translation was adopted to ensure accuracy of the translation. A total of 155 COPD patients were recruited to test the reliability and validity of the D-12-C scale. Internal reliability and test-retest reliability were measured with Cronbach's alpha coefficient and intra-class correlation coefficient, respectively. Construct validity was assessed through exploratory factor analysis (EFA). Concurrent validity was assessed by the correlation of D-12-C total score and sub-scores and the Chinese version of Saint George's Respiratory Questionnaire (SGRQ), 36-Item Short Form Health Survey (SF-36), COPD Assessment Test (CAT) and Hospital Anxiety and Depression Scale (HADS) total score and sub-scores., Results: The two-factor structure of D-12-C was confirmed by EFA. D-12-C and its sub-scores demonstrated high level of internal reliability (Cronbach's alpha = 0.88) and moderate level of test-retest reliability. D-12-C total score, physical and affective sub-scores were significantly correlated to SGRQ total score (r s  = 0.59, p < 0.001) and activity sub-score (r s  = 0.38, p = 0.006), SF-36 mental health sub-score (r s  = -0.36, p < 0.001), CAT (r s  = 0.56, p < 0.001), HADS anxiety (r s  = 0.51, p < 0.001) and depression sub-scores (r s  = 0.44, p < 0.001)., Conclusion: D-12-C scale was developed, which demonstrated satisfactory reliability and validity in measuring dyspnoea among COPD patients., (© 2021 The Authors. The Clinical Respiratory Journal published by John Wiley & Sons Ltd.)

Allergic asthma, driven by T helper 2 cell-mediated immune responses to common environmental antigens, remains the most common respiratory disease in children. Perfluorinated chemicals (PFCs) are environmental contaminants of great concern, because of their wide application, persistence in the environment, and bioaccumulation. PFCs associate with immunological disorders including asthma and attenuate immune responses to vaccines. The influence of PFCs on the immunological response to allergens during childhood is unknown. We report here that a major PFC, perfluorooctane sulfonate (PFOS), inactivates house dust mite (HDM) to dampen 5-wk-old, early weaned mice from developing HDM-induced allergic asthma. PFOS further attenuates the asthma protective effect of the microbial product lipopolysaccharide (LPS). We demonstrate that PFOS prevents desensitization of lung epithelia by LPS, thus abolishing the latter's protective effect. A close mechanistic study reveals that PFOS specifically binds the major HDM allergen Der p1 with high affinity as well as the lipid A moiety of LPS, leading to the inactivation of both antigens. Moreover, PFOS at physiological human (nanomolar) concentrations inactivates Der p1 from HDM and LPS in vitro, although higher doses did not cause further inactivation because of possible formation of PFOS aggregates. This PFOS-induced neutralization of LPS has been further validated in primary human cell models and extended to an in vivo bacterial infection mouse model. This study demonstrates that early life exposure of mice to a PFC blunts airway antigen bioactivity to modulate pulmonary inflammatory responses, which may adversely affect early pulmonary health., Competing Interests: The authors declare no competing interest.

Objective: To review the airway microbiome in chronic obstructive pulmonary disease (COPD), bronchiectasis and bronchiectasis-COPD overlap (BCO)., Data Source and Study Selection: Relevant studies were selected from PubMed, Google scholar, EMBASE and Web of Science. All studies involving human microbiomes, published in the English language, and using the search terms "COPD", "Chronic Obstructive Pulmonary Disease", "Bronchiectasis", "BCO" or "Bronchiectasis and COPD overlap", AND "microbiome", "mycobiome" or "metagenomics" were included., Results: Despite variability in sampling methods and specimen types used, microbiome composition remains relatively comparable in COPD and bronchiectasis with prominence of Proteobacteria, Firmicutes and Bacteroidetes. Alterations to airway microbiomes occur in association to disease severity and/or exacerbations in COPD and bronchiectasis. Decreased alpha diversity and Haemophilus-predominant microbiomes are associated with poorer survival in COPD, while, in bronchiectasis, Pseudomonas-predominant microbiomes demonstrate high exacerbation frequency and greater symptom burden while Aspergillus-dominant mycobiome profiles associate with exacerbations. The role of the microbiome in BCO remains understudied., Conclusion: Use of next-generation sequencing has revolutionised our detection and understanding of the airway microbiome in chronic respiratory diseases such as COPD and bronchiectasis. Targeted amplicon sequencing reveals important associations between the respiratory microbiome and disease outcome while metagenomics may elucidate functional pathways. How best to apply this information into patient care, monitoring and treatment, however, remains challenging and necessitates further study., (© 2020 John Wiley & Sons Ltd.)

Impaired mobility often co-occurs with depression. However, there is no systematic review evidence as to whether mobility impairments precede the onset of depression. The objective of this systematic review and meta-analysis was to evaluate whether mobility impairment could predict incident depression. A systematic search of cohort studies were performed in MEDLINE, EMBASE, CINAHL and PsycINFO. The target population was people with no depressive symptoms at baseline and follow-up for depression or depressive symptoms of at least three months. Of 1061 identified abstracts, 13 studies met the review eligibility criteria. The majority of included studies (8 out of 13) were of high methodological quality. Follow-up periods ranged from 12 months to 16 years. Gait speed was the most consistently reported mobility measure. Participants with slow gait speed were at higher risk of developing depressive symptoms (pooled OR = 1.93, 95%CI: 1.54 to 2.42, 11 studies). This review shows that slow gait speed is predictive of the onset of depressive symptoms. Systematic review registration number: CRD42020153791., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Neutrophil is of the most abundant number in human immune system. During acute influenza virus infection, neutrophils are already active in the early phase of inflammation - a time in which clinical biopsy or autopsy material is not readily available. However, the role of neutrophil in virus infection is not well understood. Here, we studied the role of neutrophil in host defense during influenza A virus infection, specifically assessing if it contributes to the differential pathogenesis in H5N1 disease., Methods: Neutrophils were freshly isolated from healthy volunteers and subjected to direct influenza H1N1 and H5N1 virus infection in vitro. The ability of the naïve neutrophils to infiltrate from the basolateral to the apical phase of the influenza virus infected alveolar epithelium was assessed. The viral replication, innate immune responses and Neutrophil extracellular trap (NET) formation of neutrophils upon influenza virus infection were evaluated., Results: Our results demonstrated that influenza virus infected alveolar epithelium allowed neutrophil transmigration. Significantly more neutrophils migrated across the H5N1 influenza virus infected the epithelium than the counterpart infected by the seasonal influenza H1N1 virus infected. Neutrophils were equally susceptible to H5N1 and H1N1 virus infection with similar viral gene transcription. Productive replication was observed in H5N1 infected neutrophils. H5N1 induced higher cytokine and chemokine gene transcription than H1N1 infected neutrophils, including TNF-α, IFN-β, CXCL10, MIP-1α and IL-8. This inferred a more intense inflammatory response posed by H5N1 than H1N1 virus. Strikingly, NADPH oxidase-independent NET formation was only observed in H1N1 infected neutrophils at 6 hpi while no NET formation was observed upon H5N1 infection., Conclusion: Our data is the first to demonstrate that NET formation is abrogated in H5N1 influenza virus infection and might contribute to the severity of H5N1 disease.

Background: Prior studies illustrate the presence and clinical importance of detecting Aspergillus species in the airways of patients with chronic respiratory disease. Despite this, a low fungal biomass and the presence of PCR inhibitors limits the usefulness of quantitative PCR (qPCR) for accurate absolute quantification of Aspergillus in specimens from the human airway. Droplet digital PCR (ddPCR) however, presents an alternative methodology allowing higher sensitivity and accuracy of such quantification but remains to be evaluated in head-to-head fashion using specimens from the human airway. Here, we implement a standard duplex TaqMan PCR protocol, and assess if ddPCR is superior in quantifying airway Aspergillus when compared to standard qPCR., Methods: The molecular approaches of qPCR and ddPCR were applied to DNA fungal extracts in n = 20 sputum specimens obtained from non-diseased ( n = 4), chronic obstructive pulmonary disease (COPD; n = 8) and non-cystic fibrosis bronchiectasis ( n = 8) patients where Aspergillus status was known. DNA was extracted and qPCR and ddPCR performed on all specimens with appropriate controls and head-to-head comparisons performed., Results: Standard qPCR and ddPCR were both able to detect, even at low abundance, Aspergillus species ( Aspergillus fumigatus - A. fumigatus and Aspergillus terreus - A. terreus ) from specimens known to contain the respective fungi. Importantly, however, ddPCR was superior for the detection of A. terreus particularly when present at very low abundance and demonstrates greater resistance to PCR inhibition compared to qPCR., Conclusion: ddPCR has greater sensitivity for A. terreus detection from respiratory specimens, and is more resistant to PCR inhibition, important attributes considering the importance of A. terreus species in chronic respiratory disease states such as bronchiectasis.

Background: While a number of studies have investigated knee symptoms among elite athletes, few have directly compared the association between engagement in different sports and knee symptoms among young adults in the general population. The current study aimed to investigate the relation between sports participation hours, type/ number of sports engaged, self-rated competitiveness and knee symptoms among undergraduates., Methods: Undergraduates were invited to participate in a self-administered online survey through invitation emails. Respondents were instructed to provide demographic information (e.g., age, gender, sports participation hours, types of engaged sports, self-rated competitiveness in sports and anxiety level etc.) and to report knee symptoms (current, the last 7 days, the last 12 months, and lifetime). Multiple logistic regressions were conducted to investigate the association between sports participation and current knee symptoms., Results: Of 17,552 invitees, 3744 responded to the survey. Valid data from 3053 respondents was used for analysis. Forty-four percent of the respondents engaged in sports regularly (≥once per week). Running, cross-training and swimming were the most frequently participated sports among the respondents. The current prevalence rate of knee symptoms was 6.4%. Hours spent participating in combat sports, soccer, yoga, and basketball participation hours were significantly associated with current knee symptoms. Respondents who rated themselves as "competitive" demonstrated a higher risk of having current knee symptoms than "recreational" players. Number of engaged sports was not associated with current knee symptoms among undergraduates., Conclusions: Certain sports types were associated with current knee symptoms. Compared to self-rated "recreational" players, self-rated "competitive" players were more likely to have current knee symptoms. Students should take preventive measures to minimize their risk of developing knee symptoms, especially when participating in combat sports, soccer, yoga, and basketball, or engaging in sports at a highly competitive level., Competing Interests: Competing interestsA co-author of this manuscript, Dr. Arnold YL Wong, is a member of the editorial board of BMC Musculoskeletal Disorders., (© The Author(s) 2020.)

Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited., Competing Interests: Conflict of interest: C.H.T. Bui has nothing to disclose. Conflict of interest: M.M.T. Ng has nothing to disclose. Conflict of interest: M.C. Cheung has nothing to disclose. Conflict of interest: K-C. Ng has nothing to disclose. Conflict of interest: M.P.K. Chan has nothing to disclose. Conflict of interest: L.L.Y. Chan has nothing to disclose. Conflict of interest: J.H.M. Fong has nothing to disclose. Conflict of interest: J.M. Nicholls has nothing to disclose. Conflict of interest: J.S.M. Peiris reports grants from the Research Grants Council of the Hong Kong SAR and the US National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study. Conflict of interest: R.W.Y Chan reports grants from the Research Fund Secretariat, Food and Health Bureau, Hong Kong Special Administrative Region, during the conduct of the study. Conflict of interest: M.C.W. Chan reports grants from the Research Grants Council of the Hong Kong SAR and the US National Institute of Allergy and Infectious Diseases (NIAID), during the conduct of the study., (Copyright ©ERS 2019.)

Background: Highly pathogenic avian influenza (HPAI)-H7N9 virus arising from low pathogenic avian influenza (LPAI)-H7N9 virus with polybasic amino acid substitutions in the hemagglutinin was detected in 2017., Methods: We compared the tropism, replication competence, and cytokine induction of HPAI-H7N9, LPAI-H7N9, and HPAI-H5N1 in ex vivo human respiratory tract explants, in vitro culture of human alveolar epithelial cells (AECs) and pulmonary microvascular endothelial cells (HMVEC-L)., Results: Replication competence of HPAI- and LPAI-H7N9 were comparable in ex vivo cultures of bronchus and lung. HPAI-H7N9 predominantly infected AECs, whereas limited infection was observed in bronchus. The reduced tropism of HPAI-H7N9 in bronchial epithelium may explain the lack of human-to-human transmission despite a number of mammalian adaptation markers. Apical and basolateral release of virus was observed only in HPAI-H7N9- and H5N1-infected AECs regardless of infection route. HPAI-H7N9, but not LPAI-H7N9 efficiently replicated in HMVEC-L., Conclusions: Our findings demonstrate that a HPAI-H7N9 virus efficiently replicating in ex vivo cultures of human bronchus and lung. The HPAI-H7N9 was more efficient at replicating in human AECs and HMVEC-L than LPAI-H7N9 implying that endothelial tropism may involve in pathogenesis of HPAI-H7N9 disease., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Impact of percutaneous coronary interventions (PCI) on health-related quality of life (HRQOL) is important but under-reported in elderly patients., Objectives: To evaluate long-term health status in elderly patients who underwent PCI., Methods: Consecutive patients who underwent PCI at a university-affiliated hospital from September 2009 to June 2012 were prospectively enrolled with HRQOL assessment at baseline (up to 2 weeks before PCI) and at 6-, 12-, and 36-month follow-up using the EuroQol five-dimensional questionnaire descriptive profile and visual analogue scale (VAS). Minimally important benefit (MIB) in HRQOL was defined as greater than half an SD improvement in the baseline VAS score., Results: Of 1957 patients, 49.9%, 29.1%, and 21.0% were aged younger than 65 years, 65 to 74 years, and 75 years and older, respectively. Mean VAS scores at baseline (50.1 ± 20.5 vs. 51.6 ± 20.5 vs. 52.6 ± 21.8; P = 0.09) and at 36 months (72.9 ± 14.0 vs. 72.8 ± 16.1 vs. 72.0 ± 14.8; P = 0.77) were similar between the three age groups, respectively. MIB at 36 months was observed in 65.7%, 61.9%, and 61.2% of patients in each age group, respectively. Proportion of patients aged 75 years and older reporting problems in pain/discomfort and self-care reduced from 91.2% and 24.8% at baseline to 41.4% and 10.1% at 36 months, respectively (both P < 0.01). Independent predictors of MIB in HRQOL at 36 months in patients 75 years and older included poor baseline HRQOL, MIB at 6 months, and presentation with myocardial infarction (all P < 0.01)., Conclusions: Elderly patients experienced sustained long-term improvement in quality of life comparable with younger patients after PCI. Our findings suggest that age per se should not deter against revascularization because of sustained benefit in HRQOL., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

H9N2 viruses are the most widespread influenza viruses in poultry in Asia. We evaluated the infection and tropism of human and avian H9 influenza virus in the human respiratory tract using ex vivo respiratory organ culture. H9 viruses infected the upper and lower respiratory tract and the majority of H9 viruses had a decreased ability to release virus from the bronchus rather than the lung. This may be attributed to a weak neuraminidase (NA) cleavage of carbon-6-linked sialic acid (Sia) rather than carbon-3-linked Sia. The modified cleavage of N-acetlylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) by NA in H9 virus replication was observed by reverse genetics, and recombinant H9N2 viruses with amino acids (38KQ) deleted in the NA stalk, and changing the amino acid at position 431 from Proline-to-Lysine. Using recombinant H9 viruses previously evaluated in the ferret, we found that viruses which replicated well in the ferret did not replicate to the same extent in the human ex vivo cultures. The existing risk assessment models for H9N2 viruses in ferrets may not always have a strong correlation with the replication in the human upper respiratory tract. The inclusion of the human ex vivo cultures would further strengthen the future risk-assessment strategies.