Gait differences between COPD and healthy controls: systematic review and meta-analysis.

BACKGROUND: Despite the importance of gait as a determinant of falls, disability and mortality in older people, understanding of gait impairment in COPD is limited. This study aimed to identify differences in gait characteristics during supervised walking tests between people with COPD and healthy controls. METHODS: We searched 11 electronic databases, supplemented by Google Scholar searches and manual collation of references, in November 2019 and updated the search in July 2021. Record screening and information extraction were performed independently by one reviewer and checked for accuracy by a second. Meta-analyses were performed in studies not considered at a high risk of bias. RESULTS: Searches yielded 21 085 unique records, of which 25 were included in the systematic review (including 1015 people with COPD and 2229 healthy controls). Gait speed was assessed in 17 studies (usual speed: 12; fast speed: three; both speeds: two), step length in nine, step duration in seven, cadence in six, and step width in five. Five studies were considered at a high risk of bias. Low-quality evidence indicated that people with COPD walk more slowly than healthy controls at their usual speed (mean difference (MD) -19 cm·s-1, 95% CI -28 to -11 cm·s-1) and at a fast speed (MD -30 cm·s-1, 95% CI -47 to -13 cm·s-1). Alterations in other gait characteristics were not statistically significant. CONCLUSION: Low-quality evidence shows that people with COPD walk more slowly than healthy controls, which could contribute to an increased falls risk. The evidence for alterations in spatial and temporal components of gait was inconclusive. Gait impairment appears to be an important but understudied area in COPD.

Real-world walking cadence in people with COPD.

Introduction: The clinical validity of real-world walking cadence in people with COPD is unsettled. Our objective was to assess the levels, variability and association with clinically relevant COPD characteristics and outcomes of real-world walking cadence. Methods: We assessed walking cadence (steps per minute during walking bouts longer than 10 s) from 7 days' accelerometer data in 593 individuals with COPD from five European countries, and clinical and functional characteristics from validated questionnaires and standardised tests. Severe exacerbations during a 12-month follow-up were recorded from patient reports and medical registries. Results: Participants were mostly male (80%) and had mean±sd age of 68±8 years, post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57±19% predicted and walked 6880±3926 steps·day-1. Mean walking cadence was 88±9 steps·min-1, followed a normal distribution and was highly stable within-person (intraclass correlation coefficient 0.92, 95% CI 0.90-0.93). After adjusting for age, sex, height and number of walking bouts in fractional polynomial or linear regressions, walking cadence was positively associated with FEV1, 6-min walk distance, physical activity (steps·day-1, time in moderate-to-vigorous physical activity, vector magnitude units, walking time, intensity during locomotion), physical activity experience and health-related quality of life and negatively associated with breathlessness and depression (all p<0.05). These associations remained after further adjustment for daily steps. In negative binomial regression adjusted for multiple confounders, walking cadence related to lower number of severe exacerbations during follow-up (incidence rate ratio 0.94 per step·min-1, 95% CI 0.91-0.99, p=0.009). Conclusions: Higher real-world walking cadence is associated with better COPD status and lower severe exacerbations risk, which makes it attractive as a future prognostic marker and clinical outcome.

Efficacy of a digital lifestyle intervention on health-related QUAlity of life in non-small cell LUng CAncer survivors following inpatient rehabilitation: protocol of the QUALUCA Swiss multicentre randomised controlled trial.

INTRODUCTION: Non-small cell lung cancer (NSCLC) survivors suffer from impaired physical and psychological functioning and reduced health-related quality of life (HRQoL) that persist after active treatment ends. Sustaining rehabilitation benefits, promoting a healthy lifestyle and facilitating self-management at home require a multifaceted aftercare programme. We aim to investigate the effect of a 12-week digital lifestyle intervention on HRQoL and lifestyle-related outcomes in NSCLC survivors after completion of inpatient rehabilitation. METHODS AND ANALYSIS: QUAlity of life in LUng CAncer Survivors (QUALUCA) is a multicentre randomised controlled trial that follows a hybrid type 1 design. We randomly allocate participants in a 1:1 ratio to the intervention group (digital lifestyle intervention) or the control group (standard care) using block randomisation stratified by tumour stage and study site. Four accredited Swiss inpatient rehabilitation centres recruit participants. Key inclusion criteria are a diagnosis of NSCLC, an estimated life expectancy of ≥6 months and access to a smartphone or tablet. The 12-week intervention comprises physical activity, nutrition and breathing/relaxation, delivered through a mobile application (app). The primary outcome is the change in HRQoL from baseline (1 week after rehabilitation) to follow-up (3 months after baseline), assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Secondary outcomes include body mass index, self-reported physical activity, exercise capacity, risk of low protein intake, appetite, psychological distress, cancer-related fatigue, enablement and self-rated health. Explanatory outcomes in the intervention group include app usability, acceptability, appropriateness, and feasibility of the intervention, experiences and satisfaction with the intervention, and app usage data. We aim to enrol 88 participants. For the main statistical analysis, we will use analysis of covariance, adjusted for baseline measures, stratification variables, age and sex. ETHICS AND DISSEMINATION: The Ethics Committees of the Canton of Zurich (lead), the Canton of Bern and Northwest and Central Switzerland approved the study (2023-00245). We will disseminate study results to researchers, health professionals, study participants and relevant organisations, and through publications in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05819346.

A guide for a student-led doctoral-level qualitative methods short course in epidemiology: faculty and student perspectives.

Qualitative research and mixed methods are core competencies for epidemiologists. In response to the shortage of guidance on graduate course development, we wrote a course development guide aimed at faculty and students designing similar courses in epidemiology curricula. The guide combines established educational theory with faculty and student experiences from a recent introductory course for epidemiology and biostatistics doctoral students at the University of Zurich and Swiss Federal Institute of Technology, Zurich. We propose a student-centred course with inverse classroom teaching and practice exercises with faculty input. Integration of student input during the course development process helps align the course syllabus with student needs. The proposed course comprises six sessions that cover learning outcomes in comprehension, knowledge, application, analysis, synthesis and evaluation. Following an introductory session, the students engage in face-to-face interviews, focus group interviews, observational methods, analysis and how qualitative and quantitative methods are integrated in mixed methods. Furthermore, the course covers interviewer safety, research ethics, quality in qualitative research and a practice session focused on the use of interview hardware, including video and audio recorders. The student-led teaching characteristic of the course allows for an immersive and reflective teaching-learning environment. After implementation of the course and learning from faculty and student perspectives, we propose these additional foci: a student project to apply learned knowledge to a case study; integration in mixed-methods; and providing faculty a larger space to cover theory and field anecdotes.

Violence against healthcare professionals in intensive care units: a systematic review and meta-analysis of frequency, risk factors, interventions, and preventive measures.

BACKGROUND: To assess the frequency, risk factors, consequences, and prevention of violence against healthcare workers in intensive care units. METHODS: PubMed, Scopus, Google Scholar, EMBASE, Cochrane, and Web of Science were searched for studies on violence against healthcare workers in adult intensive care units. Risk factors, patient characteristics, and implications for healthcare workers were collected. Study quality, bias, and level of evidence were assessed using established tools. RESULTS: Seventy-five studies with 139,533 healthcare workers from 32 countries were included. The overall median frequency of violence was 51% (IQR 37-75%). Up to 97% of healthcare workers experienced verbal violence, and up to 82% were victims of physical violence. Meta-analysis of frequency revealed an average frequency of 31% (95% CI 22-41%) for physical violence, 57% for verbal violence (95% CI 48-66%), and 12% for sexual violence (95% CI 4-23%). Heterogeneity was high according to the I2 statistics. Patients were the most common perpetrators (median 56%), followed by visitors (median 22%). Twenty-two studies reported increased risk ratios of up to 2.3 or odds ratios of up to 22.9 for healthcare workers in the ICU compared to other healthcare workers. Risk factors for experiencing violence included young age, less work experience, and being a nurse. Patients who exhibited violent behavior were often male, older, and physically impaired by drugs. Violence was underreported in up to 80% of cases and associated with higher burnout rates, increased anxiety, and higher turnover intentions. Overall the level of evidence was low. CONCLUSIONS: Workplace violence is frequent and underreported in intensive care units, with potential serious consequences for healthcare workers, calling for heightened awareness, screening, and preventive measures. The potential risk factors for violence should be further investigated. SYSTEMATIC REVIEW REGISTRATION: The protocol for this review was registered with Prospero on January 15, 2023 (ID CRD42023388449).

Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II-III colorectal cancer from the SCOT and QUASAR 2 trials: a retrospective analysis.

BACKGROUND: Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. METHODS: We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II-III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. FINDINGS: After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68-0·79], p=2·5 × 10-16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64-0·78], p=1·5 × 10-13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84-0·96], p=1·5 × 10-4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63-0·78], p=5·1 × 10-11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29-2·20], p=1·3 × 10-4; low vs high 2·58 [1·91-3·49], p=7·9 × 10-10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73-0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17-2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89-1·88], p=0·17). INTERPRETATION: Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. FUNDING: Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

Electronic Nicotine-Delivery Systems for Smoking Cessation.

BACKGROUND: Electronic nicotine-delivery systems - also called e-cigarettes - are used by some tobacco smokers to assist with quitting. Evidence regarding the efficacy and safety of these systems is needed. METHODS: In this open-label, controlled trial, we randomly assigned adults who were smoking at least five tobacco cigarettes per day and who wanted to set a quit date to an intervention group, which received free e-cigarettes and e-liquids, standard-of-care smoking-cessation counseling, and optional (not free) nicotine-replacement therapy, or to a control group, which received standard counseling and a voucher, which they could use for any purpose, including nicotine-replacement therapy. The primary outcome was biochemically validated, continuous abstinence from smoking at 6 months. Secondary outcomes included participant-reported abstinence from tobacco and from any nicotine (including smoking, e-cigarettes, and nicotine-replacement therapy) at 6 months, respiratory symptoms, and serious adverse events. RESULTS: A total of 1246 participants underwent randomization; 622 participants were assigned to the intervention group, and 624 to the control group. The percentage of participants with validated continuous abstinence from tobacco smoking was 28.9% in the intervention group and 16.3% in the control group (relative risk, 1.77; 95% confidence interval, 1.43 to 2.20). The percentage of participants who abstained from smoking in the 7 days before the 6-month visit was 59.6% in the intervention group and 38.5% in the control group, but the percentage who abstained from any nicotine use was 20.1% in the intervention group and 33.7% in the control group. Serious adverse events occurred in 25 participants (4.0%) in the intervention group and in 31 (5.0%) in the control group; adverse events occurred in 272 participants (43.7%) and 229 participants (36.7%), respectively. CONCLUSIONS: The addition of e-cigarettes to standard smoking-cessation counseling resulted in greater abstinence from tobacco use among smokers than smoking-cessation counseling alone. (Funded by the Swiss National Science Foundation and others; ESTxENDS ClinicalTrials.gov number, NCT03589989.).

Concurrence of seizures and peri-ictal delirium in the critically ill - its frequency, associated characteristics, and outcomes.

BACKGROUND: To assess the frequency, clinical features, and outcome of peri-ictal delirium in adult patients experiencing seizures during intensive care. METHODS: This observational study was conducted at a Swiss intensive care unit from 2015 to 2020. Patients aged ≥ 18 years with seizures were categorized as peri-ictal delirious (Intensive Care Delirium Screening Checklist [i.e., ICDSC] ≥ 4) or not (i.e., ICDSC < 4) within 24 h of seizures. The frequency of peri-ictal delirium and in-hospital death were defined as the primary endpoints. Illness severity and treatment characteristics between delirious and non-delirious patients were secondary endpoints. Logistic regression was used to compare in-hospital death and differences regarding clinical characteristics between delirious and non-delirious patients. RESULTS: 48% of 200 patients had peri-ictal delirium for a median of 3 days. Delirious patients were older (median age 69 vs. 62 years, p = 0.002), had lower Simplified Acute Physiology Scores II (SAPS II; median 43 vs. 54, p = 0.013), received neuroleptics more frequently (31 vs. 5%, p < 0.001), were mechanically ventilated less often (56% vs. 73%, p = 0.013) and shorter (median 3 vs. 5 days, p = 0.011), and had decreased odds for in-hospital death with delirium (OR = 0.41, 95% CI 0.20-0.84) in multivariable analyses. CONCLUSIONS: Delirium emerged in every second patient experiencing seizures and was associated with lower SAPS II, shorter mechanical ventilation, and better outcomes, contradicting assumptions that altered cerebral function, from seizures and delirium, are linked to unfavorable outcomes.

Investigating the prognostic value of digital mobility outcomes in patients with chronic obstructive pulmonary disease: a systematic literature review and meta-analysis.

BACKGROUND: Reduced mobility is a central feature of COPD. Assessment of mobility outcomes that can be measured digitally (digital mobility outcomes (DMOs)) in daily life such as gait speed and steps per day is increasingly possible using devices such as pedometers and accelerometers, but the predictive value of these measures remains unclear in relation to key outcomes such as hospital admission and survival. METHODS: We conducted a systematic review, nested within a larger scoping review by the MOBILISE-D consortium, addressing DMOs in a range of chronic conditions. Qualitative and quantitative analysis considering steps per day and gait speed and their association with clinical outcomes in COPD patients was performed. RESULTS: 21 studies (6076 participants) were included. Nine studies evaluated steps per day and 11 evaluated a measure reflecting gait speed in daily life. Negative associations were demonstrated between mortality risk and steps per day (per 1000 steps) (hazard ratio (HR) 0.81, 95% CI 0.75-0.88, p<0.001), gait speed (<0.80 m·s-1) (HR 3.55, 95% CI 1.72-7.36, p<0.001) and gait speed (per 1.0 m·s-1) (HR 7.55, 95% CI 1.11-51.3, p=0.04). Fewer steps per day (per 1000) and slow gait speed (<0.80 m·s-1) were also associated with increased healthcare utilisation (HR 0.80, 95% CI 0.72-0.88, p<0.001; OR 3.36, 95% CI 1.42-7.94, p=0.01, respectively). Available evidence was of low-moderate quality with few studies eligible for meta-analysis. CONCLUSION: Daily step count and gait speed are negatively associated with mortality risk and other important outcomes in people with COPD and therefore may have value as prognostic indicators in clinical trials, but the quantity and quality of evidence is limited. Larger studies with consistent methodologies are called for.

Interplay of Digital Proximity App Use and SARS-CoV-2 Vaccine Uptake in Switzerland: Analysis of Two Population-Based Cohort Studies.

Objectives: Our study aims to evaluate developments in vaccine uptake and digital proximity tracing app use in a localized context of the SARS-CoV-2 pandemic. Methods: We report findings from two population-based longitudinal cohorts in Switzerland from January to December 2021. Failure time analyses and Cox proportional hazards regression models were conducted to assess vaccine uptake and digital proximity tracing app (SwissCovid) uninstalling outcomes. Results: We observed a dichotomy of individuals who did not use the SwissCovid app and did not get vaccinated, and who used the SwissCovid app and got vaccinated during the study period. Increased vaccine uptake was observed with SwissCovid app use (aHR, 1.51; 95% CI: 1.40-1.62 [CI-DFU]; aHR, 1.79; 95% CI: 1.62-1.99 [CSM]) compared to SwissCovid app non-use. Decreased SwissCovid uninstallation risk was observed for participants who got vaccinated (aHR, 0.55; 95% CI: 0.38-0.81 [CI-DFU]; aHR, 0.45; 95% CI: 0.27-0.78 [CSM]) compared to participants who did not get vaccinated. Conclusion: In evolving epidemic contexts, these findings underscore the need for communication strategies as well as flexible digital proximity tracing app adjustments that accommodate different preventive measures and their anticipated interactions.

Needs assessment in community-dwelling older adults toward digital interventions to promote physical activity: Cross-sectional survey study.

Background: Tackling physical inactivity represents a key global public health challenge. Strategies to increase physical activity (PA) are therefore warranted. Despite the rising availability of digital interventions (DIs), which offer tremendous potential for PA promotion, there has been inadequate attention to the special needs of older adults. Objective: The aim was to investigate community-dwelling older adults' needs, requirements, and preferences toward DIs to promote PA. Methods: The target population of this cross-sectional study was community-dwelling older adults (≥60 years old) within German-speaking Switzerland. Potential respondents were informed about the study and sent a link to a self-developed and self-administered online survey by our cooperating institutions. Results: Overall, 922 respondents who completed the online survey were included in the final analysis. The mean age of the sample was 72 years (SD 6.4, range 60-98). The preferred delivery mode of DIs to promote PA was a website (428/922, 46.4%) and 80.3% (740/922) preferred video-based structures. Most respondents expressed the need for personal access, personal goals, personal messages, and a personal contact in case of problems or questions (585/817, 71.6%; 546/811, 67.3%; 536/822, 65.2%; 536/822, 65.2%). Memory training, psychological wellbeing, and nutrition were mainly rated as relevant additional content of DIs to promote PA (690/849, 81.2%; 661/845, 78.2%, 619/849, 72.9%). Conclusion: Community-dwelling older adults may be willing to use DIs to promote PA in the long term, but this study identified particular needs and requirements in terms of design, technological realization, delivery mode, support, and individualization/personalization among the sample. Our results can inform future developments of DIs to promote PA specifically tailored to older adults. However, caution is warranted in interpreting the findings due to the sample's high PA and education levels.

Associations of multilingualism and language proficiency with cognitive functioning: epidemiological evidence from the SwissDEM study in community dwelling older adults and long-term care residents.

BACKGROUND: We explored whether number of languages spoken and language proficiency are associated with cognitive performance among older adults living in the community and in long-term care (LTC) in Switzerland. METHODS: Among study participants, 664 lived in the community in the Canton of Zurich (Mean age = 72.97 years; SD = 6.08), 386 lived in the community in Ticino (Mean age = 76.24 years; SD = 6.66), and 176 resided in LTC in Ticino (Mean age = 87.61 years; SD = 6.45). We recorded sociodemographic variables, number of languages spoken, language proficiency, and assessed overall cognitive performance, immediate and delayed memory, and verbal fluency with standardized tests. We used adjusted regression models. RESULTS: A higher number of spoken languages was positively associated with overall cognitive performance, verbal fluency and immediate and delayed memory performance in community-dwelling older adults in the Cantons of Ticino and Zurich, (all p values ≤ 0.012;), but not in in older adults living in LTC homes (all p values ≥ 0.35). Higher language proficiency was associated with better memory performance among individuals living in the community in Ticino (p value = 0.003), and to better performance in verbal fluency and memory tasks in Zurich (p values ≤ 0.002). Among LTC residents, proficiency levels were not associated with cognitive performance. CONCLUSIONS: Multilingualism and greater language proficiency were associated with better cognitive functioning in community-dwelling but not in institutionalized older adults. Multilingualism may contribute to cognitive reserve, as well as protect and delay cognitive decline in late life.

Accounting for intensity variation in image analysis of large-scale multiplexed clinical trial datasets.

Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre-analytical heterogeneity. This study reports an analytical approach to the largest multi-parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan-cytokeratin, and DAPI by mIF. TMA slides were multi-spectrally imaged and analysed by cell-based and pixel-based marker analysis. We developed an adaptive thresholding method to account for inter- and intra-slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter- and intra-slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single-plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell-based and pixel-based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF-stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.

Changes in Healthcare Utilization During the COVID-19 Pandemic and Potential Causes-A Cohort Study From Switzerland.

Objectives: To describe the frequency of and reasons for changes in healthcare utilization in those requiring ongoing treatment, and to assess characteristics associated with change, during the second wave of the pandemic. Methods: Corona Immunitas e-cohort study (age ≥20 years) participants completed monthly questionnaires. We compared participants reporting a change in healthcare utilization with those who did not using descriptive and bivariate statistics. We explored characteristics associated with the number of changes using negative binomial regression. Results: The study included 3,190 participants from nine research sites. One-fifth reported requiring regular treatment. Among these, 14% reported a change in healthcare utilization, defined as events in which participants reported that they changed their ongoing treatment, irrespective of the reason. Reasons for change were medication changes and side-effects, specifically for hypertension, or pulmonary embolism treatment. Females were more likely to report changes [Incidence Rate Ratio (IRR) = 2.15, p = 0.002]. Those with hypertension were least likely to report changes [IRR = 0.35, p = 0.019]. Conclusion: Few of those requiring regular treatment reported changes in healthcare utilization. Continuity of care for females and chronic diseases besides hypertension must be emphasized.

Laboratory and free-living gait performance in adults with COPD and healthy controls.

Background: Gait characteristics are important risk factors for falls, hospitalisations and mortality in older adults, but the impact of COPD on gait performance remains unclear. We aimed to identify differences in gait characteristics between adults with COPD and healthy age-matched controls during 1) laboratory tests that included complex movements and obstacles, 2) simulated daily-life activities (supervised) and 3) free-living daily-life activities (unsupervised). Methods: This case-control study used a multi-sensor wearable system (INDIP) to obtain seven gait characteristics for each walking bout performed by adults with mild-to-severe COPD (n=17; forced expiratory volume in 1 s 57±19% predicted) and controls (n=20) during laboratory tests, and during simulated and free-living daily-life activities. Gait characteristics were compared between adults with COPD and healthy controls for all walking bouts combined, and for shorter (≤30 s) and longer (>30 s) walking bouts separately. Results: Slower walking speed (-11 cm·s-1, 95% CI: -20 to -3) and lower cadence (-6.6 steps·min-1, 95% CI: -12.3 to -0.9) were recorded in adults with COPD compared to healthy controls during longer (>30 s) free-living walking bouts, but not during shorter (≤30 s) walking bouts in either laboratory or free-living settings. Double support duration and gait variability measures were generally comparable between the two groups. Conclusion: Gait impairment of adults with mild-to-severe COPD mainly manifests during relatively long walking bouts (>30 s) in free-living conditions. Future research should determine the underlying mechanism(s) of this impairment to facilitate the development of interventions that can improve free-living gait performance in adults with COPD.

Development of hybrid immunity during a period of high incidence of Omicron infections.

BACKGROUND: Seroprevalence and the proportion of people with neutralizing activity (functional immunity) against SARS-CoV-2 variants were high in early 2022. In this prospective, population- based, multi-region cohort study, we assessed the development of functional and hybrid immunity (induced by vaccination and infection) in the general population during this period of high incidence of infections with Omicron variants. METHODS: We randomly selected and assessed individuals aged ≥16 years from the general population in southern (n = 739) and north-eastern (n = 964) Switzerland in March 2022. We assessed them again in June/July 2022, supplemented with a random sample from western (n = 850) Switzerland. We measured SARS-CoV-2 specific IgG antibodies and SARS-CoV-2 neutralizing antibodies against three variants (ancestral strain, Delta, Omicron). RESULTS: Seroprevalence remained stable from March 2022 (97.6%, n = 1894) to June/July 2022 (98.4%, n = 2553). In June/July, the percentage of individuals with neutralizing capacity against ancestral strain was 94.2%, against Delta 90.8% and against Omicron 84.9%, and 50.6% developed hybrid immunity. Individuals with hybrid immunity had highest median levels of anti-spike IgG antibodies titres [4518 World Health Organization units per millilitre (WHO U/mL)] compared with those with only vaccine- (4304 WHO U/mL) or infection- (269 WHO U/mL) induced immunity, and highest neutralization capacity against ancestral strain (hybrid: 99.8%, vaccinated: 98%, infected: 47.5%), Delta (hybrid: 99%, vaccinated: 92.2%, infected: 38.7%) and Omicron (hybrid: 96.4%, vaccinated: 79.5%, infected: 47.5%). CONCLUSIONS: This first study on functional and hybrid immunity in the Swiss general population after Omicron waves showed that SARS-CoV-2 has become endemic. The high levels of antibodies and neutralization support the emerging recommendations of some countries where booster vaccinations are still strongly recommended for vulnerable persons but less so for the general population.

Nicotinamide N-methyltransferase sustains a core epigenetic program that promotes metastatic colonization in breast cancer.

Metastatic colonization of distant organs accounts for over 90% of deaths related to solid cancers, yet the molecular determinants of metastasis remain poorly understood. Here, we unveil a mechanism of colonization in the aggressive basal-like subtype of breast cancer that is driven by the NAD+ metabolic enzyme nicotinamide N-methyltransferase (NNMT). We demonstrate that NNMT imprints a basal genetic program into cancer cells, enhancing their plasticity. In line, NNMT expression is associated with poor clinical outcomes in patients with breast cancer. Accordingly, ablation of NNMT dramatically suppresses metastasis formation in pre-clinical mouse models. Mechanistically, NNMT depletion results in a methyl overflow that increases histone H3K9 trimethylation (H3K9me3) and DNA methylation at the promoters of PR/SET Domain-5 (PRDM5) and extracellular matrix-related genes. PRDM5 emerged in this study as a pro-metastatic gene acting via induction of cancer-cell intrinsic transcription of collagens. Depletion of PRDM5 in tumor cells decreases COL1A1 deposition and impairs metastatic colonization of the lungs. These findings reveal a critical activity of the NNMT-PRDM5-COL1A1 axis for cancer cell plasticity and metastasis in basal-like breast cancer.

Factors Associated With COVID-19 Non-Vaccination in Switzerland: A Nationwide Study.

Objectives: We compared socio-demographic characteristics, health-related variables, vaccination-related beliefs and attitudes, vaccination acceptance, and personality traits of individuals who vaccinated against COVID-19 and who did not vaccinate by December 2021. Methods: This cross-sectional study used data of 10,642 adult participants from the Corona Immunitas eCohort, an age-stratified random sample of the population of several cantons in Switzerland. We used multivariable logistic regression models to explore associations of vaccination status with socio-demographic, health, and behavioral factors. Results: Non-vaccinated individuals represented 12.4% of the sample. Compared to vaccinated individuals, non-vaccinated individuals were more likely to be younger, healthier, employed, have lower income, not worried about their health, have previously tested positive for SARS-CoV-2 infection, express lower vaccination acceptance, and/or report higher conscientiousness. Among non-vaccinated individuals, 19.9% and 21.3% had low confidence in the safety and effectiveness of SARS-CoV-2 vaccine, respectively. However, 29.1% and 26.7% of individuals with concerns about vaccine effectiveness and side effects at baseline, respectively vaccinated during the study period. Conclusion: In addition to known socio-demographic and health-related factors, non-vaccination was associated with concerns regarding vaccine safety and effectiveness.

Longitudinal humoral and cell-mediated immune responses in a population-based cohort in Zurich, Switzerland between March and June 2022 - evidence for protection against Omicron SARS-CoV-2 infection by neutralizing antibodies and spike-specific T-cell responses.

OBJECTIVES: The correlate(s) of protection against SARS-CoV-2 remain incompletely defined. Additional information regarding the combinations of antibody and T cell-mediated immunity which can protect against (re)infection is needed. METHODS: We conducted a population-based, longitudinal cohort study including 1044 individuals of varying SARS-CoV-2 vaccination and infection statuses. We assessed spike (S)- and nucleocapsid (N)-immunoglobulin(Ig)G and wildtype, Delta, and Omicron-neutralizing antibody (N-Ab) activity. In a subset of 328 individuals, we evaluated S, membrane (M), and N-specific T cells. Three months later, we reassessed Ab (n = 964) and T cell (n = 141) responses and evaluated factors associated with protection from (re)infection. RESULTS: At the study start, >98% of participants were S-IgG seropositive. N-IgG and M/N-T-cell responses increased over time, indicating viral (re)exposure, despite existing S-IgG. Compared to N-IgG, M/N-T cells were a more sensitive measure of viral exposure. High N-IgG titers, Omicron-N-Ab activity, and S-specific-T-cell responses were all associated with a reduced likelihood of (re)infection over time. CONCLUSION: Population-level SARS-CoV-2 immunity is S-IgG-dominated, but heterogeneous. M/N-T-cell responses can distinguish previous infection from vaccination, and monitoring a combination of N-IgG, Omicron-N-Ab, and S-T-cell responses may help estimate protection against SARS-CoV-2 (re)infection.

Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study.

OBJECTIVE: To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection. DESIGN: Population based, longitudinal cohort. SETTING: General population of canton of Zurich, Switzerland. PARTICIPANTS: 1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection. MAIN OUTCOME MEASURES: Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection. RESULTS: 22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)). CONCLUSIONS: Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials. REGISTRATIONS: ISRCTN18181860, .