The Non-Paced 3-Minute Sit-to-Stand Test: Feasibility and Clinical Relevance for Pulmonary Rehabilitation Assessment.

Pulmonary rehabilitation (PR) improves health-related quality-of-life (HRQoL) in individuals with chronic obstructive pulmonary disease (COPD), notably by increasing exercise tolerance. Easy-to-implement sit-to-stand tests can facilitate the assessment of exercise tolerance in routine practice. This retrospective study conducted in a real-life setting was designed to describe the non-paced 3-min sit-to-stand test (3-STST) and to evaluate its relationship with HRQoL (VQ11 questionnaire) to identify the determinants of 3-STST performance and to analyze the evolution of 3-STST performance and HRQoL over the course of a community-based PR program. Seventy-one COPD patients (age 69 ± 10 years old; 51% with GOLD spirometric stages III-IV) were included. Mean ± SD 3-STST performance at the initial PR assessment was 43 ± 15 repetitions. This performance was significantly associated with HRQoL and other indicators of clinical severity (lung function, dyspnea, and functional capacities). During the multivariate analysis, younger age, exertional dyspnea with mMRC ≤ 1, and better HRQoL were significantly associated with better 3-STST performance. From the initial to second PR assessment, changes in 3-STST performance were significantly associated with changes in HRQoL. This study provides evidence that the non-paced 3-STST is feasible and might be clinically relevant in the assessment of patients with COPD referred for community-based PR. This test deserves to be prospectively validated.

Respiratory rehabilitation for Covid-19 related persistent dyspnoea: A one-year experience.

BACKGROUND: Growing consideration is emerging regarding the burden of persisting sequelae after SARS-CoV-2 infection. Out-patients exhibiting long Covid may benefit from ambulatory rehabilitation which is, to date, poorly documented. METHODS: A longitudinal follow-up over a one-year period was conducted in two ambulatory rehabilitation structures in order to describe the characteristics of real-life patients referred with Covid-19 sequelae and their evolution over the course of rehabilitation. RESULTS: 39 consecutive patients were included from April 1st, 2020 to April 1st, 2021. Patients were middle-aged (48 ± 15yr), without comorbidities, and mostly mild to moderate SARS-CoV-2 infection (25(64%) not requiring hospitalisation). Rehabilitation referral was considered with a median delay of 73[34-178] days after disease onset. Most prevalent symptoms were dyspnoea (n = 35(90%)) and fatigue (n = 30(77%)). Hyperventilation syndrome was highly frequent (n = 12(34%)). 29(74%) patients presented with prolonged functional sequelae, which was associated with younger age (43 ± 14 vs. 50 ± 10yr; p = 0.002), greater prevalence of hyperventilation syndrome (n = 12(41%) vs. 0(0%); p = 0.255) and poorer quality of life (VQ-11; 31 ± 10 vs. 23 ± 9; p = 0.030). Over the course of rehabilitation, exertional dyspnoea, 6-min walking distance, 3-min sit-to-stand test, hyperventilation syndrome prevalence and quality of life significantly improved. CONCLUSION: Hyperventilation is frequent in long Covid and may explain persistent dyspnoea as well as altered quality of life. Our data support screening of hyperventilation syndrome and functional impairment in mild Covid-19 out-patients as both of these components may improve with ambulatory rehabilitation.

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction-mimicking pharmacological inhibition-strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.