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Survivors of severe COVID-19 related respiratory failure may experience durable functional impairments. We aimed at investigating health-related quality of life (HR-QoL), physical functioning, fatigue, and cognitive outcomes in COVID-19 patients who received invasive mechanical ventilation (IMV). Case-series, prospective, observational cohort study at 18 months from hospital discharge. Patients referring to the Intensive Care Unit (ICU) of Humanitas Research Hospital (Milan, Italy) were recruited if they needed IMV due to COVID-19 related respiratory failure. After 18 months, these patients underwent the 6-min walking test (6MWT), the Italian version of the 5-level EQ-5D questionnaire (EQ-5D-5L), the Functional Assessment of Chronic Illness Therapy – Fatigue questionnaire (FACIT-F), the Trail Making Test-B (TMT-B) and the Montreal Cognitive Assessment-BLIND test (MoCA-BLIND). 105 patients were studied. The population's age was 60 ± 10 years on average, with a median Frailty Scale of 2 (Hodgson et al., 2017; Carenzo et al., 2021a [2,3]). EQ-VAS was 80 [70–90] out of 100, walked distance was 406 [331–465] meters, corresponding to about 74 ± 19,1% of the predicted value. FACIT-F score was 43 [36–49] out of 52, and MoCa-BLIND score was 19 (DeSalvo et al., 2006; von Elm et al., 2008; Herdman et al., 2011; Scalone et al., 2015 [16-20]) out of 22. The median TMT-B time was 90 [62–120] seconds. We found a possible age and gender specific effect on HR-QoL and fatigue. After 18 months from ICU discharge, survivors of severe COVID-19 respiratory failure experience a moderate reduction in HR-QoL, and a severe reduction in physical functioning. Fatigue prevalence is higher in younger patients and in females. Finally, cognitive impairment was present at a low frequency. •ICU COVID-19 survivors face cognitive, physical and mental health issues, emphasizing the need for targeted interventions.•18 months post-ICU discharge survivors show moderate reductions in quality of life.•At 18 months post-ICU discharge, survivors show fatigue, mild cognitive decline, and moderate to severe physical limitations.

Spinal cord injury (SCI) affects millions of people worldwide. One of the main challenges of rehabilitation strategies is re-training and enhancing the plasticity of the spinal circuitry that was preserved or rebuilt after the injury. The serotonergic system appears to be crucial in these processes, since recent studies have reported the capability of serotonergic (5-HT) axons for axonal sprouting and regeneration in response to central nervous system (CNS) trauma or neurodegeneration. We took advantage of tryptophan hydroxylase 2 knockout (TPH2 KO) rats, lacking serotonin specifically in the brain and spinal cord, to study the role of the serotonergic system in the recovery of sensorimotor function after SCI. In the present work, we compared the rate of sensorimotor recovery of TPH2 KO and wild-type (WT) female rats after SCI (lateral hemisection at the T8 spinal level). SCI caused severe motor impairments in the ipsilateral left hindlimb, the most pronounced in the first week after the hemisection with gradual functional recovery during the following 3 weeks. The results demonstrate that TPH2 KO rats have less potential to recover motor functions since the degree of sensorimotor deficit in the tapered beam walking test (TBW) and ladder walking test (LW) was significantly higher in the TPH2 KO group in comparison to the WT animals in the 3rd and 4th weeks after SCI. The recovery dynamics of the hindlimb muscle tone and voluntary movements was in agreement with the restoration of motor performance in TBW and LW. Compound muscle action potential analysis in the gastrocnemius (GM) and tibialis (TA) muscles of both hindlimbs after electrical stimulation of the sciatic nerve or lumbar region (L5–L6) of the spinal cord indicated slower recovery of sensorimotor pathways in the TPH2 KO group versus their WT counterparts. In general, the observed results confirm the significance of central serotonergic mechanisms in the recovery of sensorimotor functions in rats and the relevance of the TPH2 KO rat model in studying the role of the 5-HT system in neurorehabilitation.

Introduction Long COVID‐19 illness is a severely disabling disease with shortness of breath, weakness and fatigue as leading symptoms, resulting in poor quality of life and substantial delay in return to work. No specific respiratory therapy has been validated for patients with long COVID. The intermittent hypoxia–hyperoxia training (IHHT) is a respiratory therapeutic modality to improve exercise performance via controlled respiratory conditioning. The purpose of the present study is to investigate the therapeutic effect of IHHT on functional and symptomatic recovery of patients with long COVID syndrome. Methods A prospective, controlled, open‐treatment interventional study was conducted in patients with long COVID who were admitted to an inpatient rehabilitation programme. Patients were assigned nonrandomized to receive IHHT in addition to the standardized rehabilitation programme (IHHT group) or standard rehabilitation alone (control group). The IHHT group received supervised sessions of intermittent hypoxic (10–12% O2) and hyperoxic (30–35% O2) breathing three times per week throughout the rehabilitation period. Primary endpoint was improved walking distance in a 6‐min walk test (6MWT) between study groups. Secondary endpoints were change in stair climbing power, dyspnoea (Borg dyspnoea Scale), fatigue assessment scale (FAS) and change in health‐related quality of life (HRQoL) assessed by patient global assessment (PGA), EQ‐5D analogue scale and the MEDIAN Corona Recovery Score (MCRS). Further assessments included maximum handgrip strength, nine hole peg test, timed up‐and‐go, respiratory function and functional ambulation category (FAC), serum analyses and safety of the intervention. Results A total of 145 patients were included in the study (74% female, mean age 53 ± 12 years) and assigned to IHHT (n = 70) or standard care (n = 75). The 6MWT distance improved 2.8‐fold in the IHHT group compared to the control group (91.7 ± 50.1 m vs. 32.6 ± 54.2 m, ANCOVA p < 0.001). Stair climbing power improved 3.7‐fold in the IHHT group compared to controls (−1.91 ± 2.23 s vs. −0.51 ± 1.93 s, p < 0.001). Secondary endpoints on dyspnoea, fatigue and HRQoL (PGA, EQ‐5D and MCRS) improved significantly in the IHHT group compared to controls. The IHHT group exhibited a significant decrease in blood pressure, heart rate and increase in haemoglobin levels that was not observed in the control group. No adverse events were observed. Conclusion Respiratory treatment with IHHT in addition to a multidisciplinary rehabilitation programme improves functional capacity, symptomatic status and quality of life in patients with disabling long COVID. IHHT has been demonstrated to be safe, well tolerated and feasible to be integrated in an inpatient rehabilitation programme to improve outcome in long COVID.

Field-based walking tests are well-established outcome measures in clinical research trials and in the evaluation of routine clinical services, including pulmonary rehabilitation. Despite widespread use, there has been little attention to, or reporting of, the quality assurance of these tests. Physical activity monitoring has become increasingly popular and data from activity monitors could be used for quality assurance of field-based walking tests. We provide examples in this article of data-driven insights possible with this approach, using data from waist-worn accelerometry, for the incremental shuttle walking test (ISWT), endurance shuttle walk test (ESWT) and six-minute walk test (6MWT). Given the multitude of devices to measure physical activity and the range metrics to describe physical activity, we also comment on some of the technical considerations to using activity monitors for walking test quality assurance. Data-driven approaches to quality assurance are already commonplace for other outcome measures in clinical respiratory trials, but little is known about this approach for field-based walking tests. The application of physical activity monitoring may be extended to other field-based exercise tests and additional rehabilitation services. This may be more challenging for self-paced walking tests such as the 6MWT. Future work should apply this approach to research trials and service evaluations to explore the impact of field-based walking test quality on performance (e.g. distance on the ISWT or time achieved for the ESWT), responsiveness to interventions (e.g. pulmonary rehabilitation) and effectiveness of training procedures (e.g. remote training for multi-site trials).

A simplified 4‐strata risk stratification approach based on three variables is widespread in pulmonary arterial hypertension (PAH) at follow‐up. This study aimed to assess the impact of replacing the 6‐min walk test (6MWT) with the peak 02 uptake evaluated by the cardiopulmonary exercise test (CPET) on risk stratification by this scale. We included 180 prevalent patients with PAH from two reference hospitals in Spain, followed up between 2006 and 2022. Patients were included if all the variables of interest were available within a 3‐month period on the Spanish Registry of Pulmonary Arterial Hypertension (REHAP): functional class (FC); NT‐proBNP; 6MWT; and CPET. The original 4‐strata model (NT‐proBNP, 6MWT, FC) identified most patients at low or intermediate‐low risk (36.7% and 51.1%, respectively). Notably, the modified scale (NT‐proBNP, CPET, FC) improved the identification of patients at intermediate‐high risk up to 18.9%, and at high risk up to 1.1% in comparison with the previous 12.2% and 0.0% in the original scale. This new model increased the number of patients correctly classified into higher‐risk strata (positive NRI of 0.06), as well as classified more patients without events in lower‐risk strata (negative NRI of 0.04). The proposed score showed a slightly superior prognostic capacity compared with the original model (Harrel's C‐index 0.717 vs. 0.709). Using O2 uptake instead of distance walked in the 6MWT improves the identification of high‐risk patients using the 4‐strata scale. This change could have relevant prognostic implications and lead to changes in the specific treatment of PAH.

Background Low cardiopulmonary fitness, measured by oxygen uptake peak (VO 2pk ), is associated with postoperative complications and mortality. Obese people have difficulty in performing the cardiopulmonary exercise test, which requires maximal exertion. The incremental shuttle walking test (ISWT) and 6-min walking test (6MWT) have been used to assess cardiorespiratory capacity, mortality, and complications in the postoperative phase. However, the physiological response elicited by these tests in obese people is unknown. This study analyzed and compared cardiopulmonary fitness (oxygen uptake [VO 2 ] and CO 2 output [VCO 2 ]) in the ISWT and 6MWT in obese adults using a telemetry system. Methods Fifteen obese patients (10 women; mean age 39.4 ± 10.1 years; mean body mass index 43.5 ± 6.8 kg/m 2 ) with normal forced vital capacity (% FVC 93.7) performed the 6MWT and ISWT in the field in this cross-sectional study. Metabolic (VO 2pk , VCO 2 ) and respiratory (minute ventilation; VE) variables were recorded using telemetry. Results Obese patients performed the ISWT with an incremental and exponential cardiopulmonary response, with higher VO 2pk (15.4 ± 2.9 ml/kg/min), VCO 2 (1.7 ± 0.7 l/min), and VE (51.4 ± 21.3 l/min) than the 6MWT (VO 2pk  = 13.2 ± 2.59 ml/kg/min, VCO 2  = 1.4 ± 0.6 l/min; VE = 41.2 ± 16.6 l/min (all p  < 0.01). They also demonstrated more effort intensity, assessed by VO 2 , ( p  = 0.006) and heart rate ( p  = 0.04) in the ISWT than the 6MWT. In the 6MWT, patients showed a fast rise in ventilatory and metabolic response, reaching a plateau. Conclusion The ISWT test generated superior metabolic and ventilatory stress than the 6MWT and may be more suitable for assessing cardiopulmonary fitness than self-paced tests.

During pulmonary rehabilitation (PR), patients receive individually tailored walking exercise training. The personalised nature of exercise prescription is a fundamental component of PR. Despite this, the measurement of physical activity (PA) has been limited to a ‘one size fits all’ approach and can be challenging to translate into clinically meaningful or real-world units, such as cadence. This discrepancy may partly explain the inconsistent evidence for the impact of PR on PA. It may also provide an opportunity to standardise PA assessment in the context of chronic respiratory disease (CRD) and PR, where field-based walking tests are routine measures. This technical note provides an example of how to develop personalised PA intensity thresholds, calibrated against an individual’s performance on the Incremental Shuttle Walking Test (ISWT; maximal) and Endurance Shuttle Walk Test (ESWT; sub-maximal). These are externally paced tests, with each level (speed) of the tests denoting a specific speed (intensity); ranging 1.8 km/h (ISWT Level 1) to 8.5 km/h (ISWT Level 12). From the ESWT, it becomes possible to evaluate adherence to each individual’s walking exercise prescription. Future research should explore this approach and its responsiveness to PR. It may be possible to extend this methodology with the inclusion of physiological parameters (e.g., heart rate, calorimetry, and oxygen consumption) to derive relative intensity markers (e.g. moderate-to-vigorous), accounting for individual differences in exercise capacity, under the same paradigm as PR exercise prescription.

In pulmonary arterial hypertension (PAH) patients it is essential to perform a prognostic assessment to optimize the treatment. The aim of this study is to evaluate the risk stratification concordance assessed with different exercise test variables in a cohort of PAH patients. A retrospective analysis was performed using patient data registered in the PAH unit. Only those patients in whom the mean time elapsed between the 6‐min walking test (6MWT) and the cardiopulmonary exercise test (CPET) was a maximum of 6 months were selected. A total of 140 records from 40 patients were finally analyzed. When it came to assessing the concordance between the two exercise tests in the guidelines (CPET and 6MWT), up to 84.3% of the records did not coincide in terms of the risk stratification. Exclusively considering the CPET parameters, most of the records (75%) failed to include all three variables in the same risk category. When analyzing the VO2 alone, up to 40.7% of the tests yielded different risk classifications depending on whether the parameter was expressed. In conclusion, there is a low concordance between the two proposed exercise tests. These results should be a call for reflection on whether the cut‐off points set for the exercise tests proposed for the current risk stratification are adequate to achieve a correct risk stratification or whether they require an appropriate revision.

Six-minute walking test distance (6MWD) and body mass index, obstruction, dyspnea and exercise (BODE) index are measures of functional status in COPD patients, but require space, time and patient's compliance. Exhaled volatile organic compounds (VOCs) analysis via electronic nose is a quick and easy method that has already been used to discriminate COPD phenotypes. The aim of this study is to evaluate whether VOCs analysis can predict functional status and its variation over time in COPD patients. A monocentric prospective study with 1 year of follow-up was carried out. All patients underwent pulmonary function tests, arterial gas analysis, bioimpedance analysis, 6-minute walking test, and VOCs collection. Exhaled breath was collected with Pneumopipe and analyzed using BIONOTE electronic nose. Outcomes prediction was performed by -fold cross-validated partial least square discriminant analysis: accuracy, sensitivity and specificity as well as Cohen's kappa for agreement were calculated. We enrolled 63 patients, 60.3% men, with a mean age of 71 (SD: 8) years, median BODE index of 1 (interquartile range: 0-3) and mean 6MWD normalized by squared height (n6MWD) of 133.5 (SD: 42) m/m . The BIONOTE predicted baseline BODE score (dichotomized as BODE score <3 or ≥3) with an accuracy of 86% and quartiles of n6MWD with an accuracy of 79%. n6MWD decline more than the median value after 1 year was predicted with an accuracy of 86% by BIONOTE, 52% by Global Initiative for Chronic Obstructive Lung Disease (GOLD) class and 78% by combined BIONOTE and GOLD class. Exhaled VOCs analysis identifies classes of BODE and n6MWD quartiles, and outperforms GOLD classification in predicting n6MWD variation.

Many studies have shown that fibronectin type III domain-containing protein 5 (FDNC5) and brain-derived neurotrophic factor (BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia; however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion (pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16-20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions (based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities (based on the spatial learning scores from the Morris water maze test 16-19 days after operation), and memory abilities (based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF (r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China (approval Nos. 20160858A232, 20160860A234) on February 24, 2016.