Systemic impairment in relation to disease burden in patients with moderate COPD eligible for a lifestyle program. Findings from the INTERCOM trial

Carel R van Wetering1, Floortje E van Nooten2, Stijn J M Mol3, Martine Hoogendoorn2, Maureen P M H Rutten-van Mölken2, Annemie M Schols41Department of Physiotherapy, Máxima Medical Centre, Veldhoven, The Netherlands; 2Institute for Medical Technology Assessment, Erasmus Medical Centre, Rotterdam, The Netherlands; 3Department of Respiratory Medicine, Máxima Medical Centre, Veldhoven, The Netherlands; 4Department of Respiratory Medicine, Maastricht University, Maastricht, The NetherlandsIntroduction: In contrast with the frequency distribution of chronic obstructive pulmonary disease (COPD) stages in the population, in which the majority of the patients is classified as GOLD 2, much less information is available on the prevalence and implications of systemic manifestations in less severe patients relative to GOLD 3 and 4.Aim: To characterize local and systemic impairment in relation to disease burden in a group of GOLD 2 COPD patients (n = 127, forced expiratory volume in one second (SD): 67 (11)% pred) that were eligible for the Interdisciplinary Community-based COPD management (INTERCOM) trial.Methods: Patients were included for this lifestyle program based on a peak exercise capacity (Wmax) <70% of predicted. Metabolic and ventilatory response to incremental cycle ergometry, 6 minute walking distance (6MWD), constant work rate test (CWR), lung function, maximal inspiratory pressure (Pimax), quadriceps force (QF), quadriceps average power (QP) (isokinetic dynamometry), handgrip force (HGF) and body composition were measured. Quality of life (QoL) was assessed by the St. George’s Respiratory Questionnaire (SGRQ) and dyspnea by the modified Medical Research Council (MRC) dyspnea scale. Exacerbations and COPD-associated hospital admissions in 12 months prior to the start of the study were recorded. Burden of disease was defined in terms of exercise capacity, QoL, hospitalization, and exacerbation frequency. GOLD 2 patients were compared with reference values and with GOLD 3 patients who were also included in the trial.Results: HGF (77.7 (18.8) % pred) and Pimax (67.1 (22.5)% pred) were impaired in GOLD 2, while QF (93.5 (22.5)% pred) was only modestly decreased. Depletion of FFM was present in 15% of weight stable GOLD 2 patients while only 2% had experienced recent involuntary weight loss. In contrast to Wmax, submaximal exercise capacity, muscle function, and body composition were not significantly different between GOLD 2 and 3 subgroups. Body mass index and fat-free mass index were significantly lower in smokers compared to ex-smokers. In multivariate analysis, QF and diffusing capacity (DLco) were independently associated with Wmax and 6 MWD in GOLD 2 while only 6 MWD was identified as an independent determinant of health-related QoL. HGF was an independent predictor of hospitalization.Conclusions: This study shows that also in patients with moderate COPD, eligible for a lifestyle program based on a decreased exercise capacity, systemic impairment is an important determinant of disease burden and that smoking affects body composition.Keywords: COPD, systemic impairment, lifestyle, pulmonary rehabilitatio

Dual-Wavelength Imaging of Tumor Progression by Activatable and Targeting Near-Infrared Fluorescent Probes in a Bioluminescent Breast Cancer Model

Bioluminescence imaging (BLI) has shown its appeal as a sensitive technique for in vivo whole body optical imaging. However, the development of injectable tumor-specific near-infrared fluorescent (NIRF) probes makes fluorescence imaging (FLI) a promising alternative to BLI in situations where BLI cannot be used or is unwanted (e.g., spontaneous transgenic tumor models, or syngeneic mice to study immune effects)

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis

Objective Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults.Design Systematic review.Eligibility Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease.Data source PubMed and Embase (1 January 2020–28 September 2022).Risk of bias Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies.Data analysis Meta-analyses for each eligible drug were performed if ≥2 similar study designs were available.Results In all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I2=48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I2=96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies.Conclusions Results from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection.PROSPERO registration number CRD42021292797

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic:systematic review and meta-analysis

OBJECTIVE: Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults.DESIGN: Systematic review.ELIGIBILITY: Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease.DATA SOURCE: PubMed and Embase (1 January 2020-28 September 2022).RISK OF BIAS: Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies.DATA ANALYSIS: Meta-analyses for each eligible drug were performed if ≥2 similar study designs were available.RESULTS: In all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I 2=48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I 2=96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies. CONCLUSIONS: Results from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection.PROSPERO REGISTRATION NUMBER: CRD42021292797.</p

4T1-luc2 tumor growth curve indicated by BLI and FLI.

<p>During tumor progression, from day 4 to day 18, there was a steady increase in both BLI and FLI signal intensities.</p

TBRs of 4T1-luc2 tumors exploiting four different NIRF probes.

<p>The TBRs, measured on the final day of the experiment, for ProSense680, IRDye 800CW 2-DG, MMPSense680 and IRDye 800CW EGF ranged from 2.29±0.38 to 4.02±0.24.</p

Schematic representation of the localization of the signal intensity areas used to calculate TBRs.

<p>TBRs were calculated by dividing the mean fluorescence intensity of four areas, of the same size, located inside the tumor region (1–4) by the mean fluorescence intensity of four areas located approximately 5 mm outside the tumor region (background fluorescence) (5–8).</p

<i>In vitro</i> tumor cell detection limit studies.

<p>4T1-luc2 cells were seeded in 96-well plates with various initial densities (39 to 2×10⁴ cells per well). The next day, cells were used for BLI measurement or incubated with either Prosense680 or with IRDye 800CW EGF and then used for FLI measurements. Statistic significance was calculated by determining the difference between optical signals from wells with and without cells. The star indicates the first significant difference. * = P<0.05; *** = P<0.0001.</p

Immunohistological and fluorescent analysis of tumor sections.

<p>The upper panels display sections stained with antibodies against EGFR (A), GLUT-1 (B), MMP-9 (C) and CathepsinB (D). The lower panels show the corresponding sections with FLI signals from animals injected with IRDye 800CW EGF (E), IRDye 800CW 2-DG (F), MMPSense680 (G) or ProSense680 (H). Scale bar = 2 mm.</p