Background Long-term health sequelae of COVID-19 may be multiple but have thus far not been systematically studied. Methods All patients discharged after COVID-19 from the Radboud university medical centre, Nijmegen, The Netherlands, were consecutively invited to a multidisciplinary outpatient facility. Also, non-admitted patients with mild disease but with symptoms persisting >6 weeks could be referred by general practitioners. Patients underwent a standardized assessment including measurements of lung function, chest CT/X-ray, 6-minute walking test, body composition, and questionnaires on mental, cognitive, health status and quality of life (QoL). Results 124 patients (age 59±14 years, 60% male) were included; 27 with mild, 51 with moderate, 26 with severe and 20 with critical disease. Lung diffusion capacity was below lower limit of normal in 42% of discharged patients. Ninety-nine percent of discharged patients had reduced ground-glass opacification on repeat CT imaging, and normal chest X-rays were found in 93% of patients with mild diseases. Residual pulmonary parenchymal abnormalities were present in 91% of discharged patients, and correlated with reduced lung diffusion capacity. Twenty-two percent had low exercise capacity, 19% low fat-free mass index, and problems in mental and/or cognitive function were found in 36% of the patients. Health status was generally poor, particularly in the domains functional impairment (64%), fatigue (69%) and QoL (72%). Conclusions This comprehensive health assessment revealed severe problems in several health domains in a substantial number of ex-COVID-19 patients. Longer follow-up studies are warranted to elucidate natural trajectories and to find predictors of complicated long-term trajectories of recovery.

Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results.

IntroductionInspiratory muscle training (IMT) has been applied during pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD). However, it remains unclear if the addition of IMT to a general exercise training programme leads to additional clinically relevant improvements in patients with COPD. In this study, we will investigate whether the addition of IMT to a general exercise training programme improves 6 min walking distance, health-related quality of life, daily physical activity and inspiratory muscle function in patients with COPD with inspiratory muscle weakness.Methods and analysisPatients with COPD (n=170) with inspiratory muscle weakness (Pi,max <60 cm H2O or <50%pred) will be recruited to a multicentre randomised placebo controlled trial of IMT and allocated into one of the two groups. Patients in both groups will follow a 3 month general exercise training programme, in combination with home-based IMT. IMT will be performed with a recently developed device (POWERbreathe KH1). This device applies an inspiratory load that is provided by an electronically controlled valve (variable flow resistive load). The intervention group (n=85) will undertake an IMT programme at a high intensity (≥50% of their Pi,max), whereas the placebo group (n=85) will undertake IMT at a low training intensity (≤10% of Pi,max). Total daily IMT time for both groups will be 21 min (6 cycles of 30 breaths). Improvement in the 6 min walking distance will be the primary outcome. Inspiratory muscle function, health-related quality of life and daily physical activity will be assessed as secondary outcomes.Ethics and disseminationEthics approval has been obtained from relevant centre committees and the study has been registered in a publicly accessible clinical trial database. The results will be easily interpretable and should immediately be communicated to healthcare providers, patients and the general public.ResultsThis can be incorporated into evidence-based treatment recommendations for clinical practice.ClinicalTrials.govNCT01397396.

ABSTRACT:The application of sandwich-cultured rat hepatocytes for the identification of the hepatic intrinsic clearance of compounds with widely varying extraction ratios was investigated. We previously showed the applicability of this in vitro system, in combination with a model describing molecular diffusion, hepatocyte/medium partition, and nonsaturated metabolism, which resulted in a successful identification of this parameter for tolbutamide. This approach is further validated using the compounds 7-ethoxycoumarin and warfarin, covering a 100-fold range of extraction ratios. Clearance of these two substrates could be reliably determined, but only if the depletion of the parent compound in medium as well as in the hepatocyte sandwich was measured. Sensitivity analyses showed that the time course of depletion of the parent compound in medium, especially for warfarin, is insensitive to the partition and diffusion parameter values, whereas depletion in the hepatocyte sandwich was far more sensitive. When varying the volumes of collagen in the sandwich culture, it appears that the most reliable kinetic parameters could be obtained by fitting the data with the smaller collagen volume and that these parameters obtained from fitting to data of the larger volumes generally cannot be verified satisfactorily with the data of the smaller volumes. The values of hepatic clearance that were obtained after extrapolation of the intrinsic clearance to the hepatic clearance from blood were comparable within a factor of 2 to hepatic clearance data in the literature. This indicates that this sandwich culture and modeling system can be applied for the identification of the hepatic intrinsic clearance rate of the total range from low to high clearance compounds.Predicting the kinetic parameters of compounds in vivo using data from in vitro experiments is a fast developing area of research (Obach, 1999;Haenen et al., 2002;Lau et al., 2002;. Intrinsic clearance, which is the key parameter enabling in vitro-in vivo extrapolation, can be determined from various in vitro models, which include microsomes, liver slices, and isolated hepatocytes (including hepatocyte suspensions and plated hepatocytes) (Cross and Bayliss, 2000). A major disadvantage of these models is their short-term use, because of declining enzyme activities and viability (Berthiaume et al., 1996;Berry et al., 1997).Recently, we have successfully developed the alternative approach of using sandwich-cultured rat hepatocytes in determining the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide (Treijtel et al., 2004). The sandwich culture is a long-term in vitro system allowing for long incubation periods. Besides prolonged cell viability, other advantages of this system are cellular morphology comparable to the in vivo situation, including cellular polarity, physiological levels of protein secretion, development of an extensive bile canalicular network, and expression of drug transporter proteins. Furthermore, the most important phase I enzyme a...

After two years, a significant increase in MPH-induced DH in COPD patients was demonstrated, which was not accompanied by a decline in FEV(1). It might be that DH is a sensitive measure to track consequences of changes in airflow obstruction.