Safety and Efficacy of Pulmonary Rehabilitation for Long COVID Patients Experiencing Long-Lasting Symptoms.

Due to the high prevalence and persistence of long COVID, it is important to evaluate the safety and efficacy of pulmonary rehabilitation (PR) for patients who experience long-lasting symptoms more than six months after initial COVID-19 onset. Enrolled patients were admitted for a four-week in-patient-PR due to long COVID symptoms (n = 47). The safety of PR was confirmed by the absence of adverse events. Symptom-related outcomes were evaluated pre- and post-PR with significant score changes for: 6 min walking distance (61 [28 to 103] m), quality of life (mental Short Form-12: 10 [6 to 13], and physical: 9 [6 to 12]), Montreal Cognitive Assessment (1 [0 to 3]), fatigue (MFI-20: -19 [-28 to -8]), dyspnea (DYSPNEA-12: -7 [-9 to -2] and mMRC; -1 [-1 to 0]), Nijmegen questionnaire (-8 [-11 to -5]), anxiety and depression (HADS:-4 [-5 to -2] and -2 [-4 to -1], respectively) and posttraumatic stress disorder checklist scale (-8 [-12 to -4]). At the individual level, the percentage of symptomatic patients for each outcome decreased, with a high response rate, and the number of persistent symptoms per patient was reduced from six at PR initiation to three at the end of the program. Our results show that in-PR is safe and efficient at decreasing long-lasting symptoms experienced by long COVID patients at more than six months after initial disease onset.

High Prevalence of Non-Responders Based on Quadriceps Force after Pulmonary Rehabilitation in COPD.

Pulmonary rehabilitation (PR) in patients with COPD improves quality of life, dyspnea, and exercise tolerance. However, 30 to 50% of patients are "non-responders" (NRs) according to considered variables. Surprisingly, peripheral muscle force is never taken into account to attest the efficacy of PR, despite its major importance. Thus, we aimed to estimate the prevalence of force in NRs, their characteristics, and predictors of non-response. In total, 62 COPD patients were included in this retrospective study (May 2019 to December 2020). They underwent inpatient PR, and their quadriceps isometric maximal force (QMVC) was assessed. The PR program followed international guidelines. Patients with a QMVC increase <7.5 N·m were classified as an NR. COPD patients showed a mean improvement in QMVC after PR (10.08 ± 12.97 N·m; p < 0.001). However, 50% of patients were NRs. NRs had lower pre-PR values for body mass, height, body mass index, PaO2, and QMVC. Non-response can be predicted by low QMVC, high PaCO2, and gender (when male). This model has a sensitivity of 74% and specificity of 81%. The study highlights the considerable number of NRs and potential risk factors for non-response. To systematize the effects, it may be interesting to implement blood gas correction and/or optimize the programs to enhance peripheral and central effects.

Time-Course of Changes in Multidimensional Fatigue and Functional Exercise Capacity and Their Associations during a Short Inpatient Pulmonary Rehabilitation Program.

This study aimed to assess the time-course of changes in multidimensional fatigue and functional exercise capacity and their associations during an inpatient pulmonary rehabilitation (PR) program. Seventy COPD patients from three centres were enrolled for a four-week PR program and were evaluated before (T0) and at the end of each week (T1, T2, T3, and T4). Weekly change in multidimensional fatigue was assessed by the multidimensional inventory questionnaire (MFI-20) and functional exercise capacity by the 6-minute walking distance (6MWD). Reaction time (RT) and heart rate variability (HRV) were also assessed as complementary markers of fatigue. HRV did not change during the study (all p > 0.05). MFI-20 score and RT decreased during the first part of the program (p < 0.001) and levelled off at T2 (all p > 0.05 compared with each preceding time). While 6MWD improved by almost 70% during the first part of the PR, it continued to increase, albeit at a greatly reduced pace, between T2 and T4 (p < 0.05). In parallel, a negative association was found between MFI-20 score and 6MWD at each evaluation time (r ranged from 0.43 to 0.71), with a significantly stronger T3 correlation compared with the other time periods (all p < 0.05). The strengthening of the association between fatigue and functional exercise capacity at T3, which occurred concomitantly with the slowdown of functional exercise capacity improvement, is consistent with a role for fatigue in the limitation of performance changes during PR. The limitation of fatigue during PR is thus an interesting aspect to improve the magnitude of performance changes.

Effectiveness comparison of inpatient vs. outpatient pulmonary rehabilitation: a systematic review.

BACKGROUND: Pulmonary rehabilitation (PR) is the cornerstone of nonpharmacological treatments in chronic respiratory disease (CRD) management. PR can be performed in different settings, the most frequent of which are inpatient (inPR) and outpatient (outPR) management. In the literature, these two distinct modalities are generally considered to be the same intervention. Yet, they differ in terms of the length of stay, social support, and the time the patient is not in their normal environment, and the presumed absence of differences in terms of efficacy has never been established. PURPOSE: To identify studies that directly compared the effects of inPR and outPR on patients with all types of CRDs through a systematic review and to synthesize the evidence regarding the effectiveness comparison of both modalities. METHODS: A literature search was performed on PubMed, Web of Science, and Cochrane Library on 24 March 2022. The inclusion criteria were: articles with adults with chronic respiratory disease and comparing inPR versus outPR in at least one PR outcome. RESULTS: Seven hundred thirty-six articles were retrieved from the databases. Six retrospective articles met the inclusion criteria. A best-evidence synthesis (BES) was carried out. Eight outcomes could be found in the included papers. For healthcare burden and refusals, no data could be extracted, and thus no BES was performed. For the eight remaining outcomes, two results were in favor of inPR with moderate evidence (HRQoL and psychological status), three were in favor of no difference between inPR and outPR with moderate or limited evidence (muscle strength, dropouts/adherence, and survival status), and three led to conflicting results (exercise tolerance, dyspnea, and economic costs). CONCLUSION: With the current state of knowledge, the majority of the studies converge towards an absence of differences between inPR and outPR or in favor of inPR for seven out of eight outcomes, albeit with moderate, limited, or conflicting evidence. The greater effectiveness of inPR for some outcomes will have to be confirmed in a well-designed RCT in order to orient public health policies in terms of the development of PR with the best evidence-based medicine approach. TRIAL REGISTRATION: PROSPERO: CRD42020166546 .

Standardization of the assessment process within telerehabilitation in chronic diseases: a scoping meta-review.

BACKGROUND: Telerehabilitation (TR) interventions are receiving increasing attention. They have been evaluated in various scientific areas through systematic reviews. However, there is a lack of data on how to standardize assessment and report on their domains to guide researchers across studies and bring together the best evidence to assess TR for chronic diseases. AIMS AND OBJECTIVES: The aim of this study was to identify domains of assessment in TR and to qualitatively and quantitatively analyze how and when they are examined to gain an overview of assessment in chronic disease. METHODS: A scoping meta-review was carried out on 9 databases and gray literature from 2009 to 2019. The keyword search strategy was based on "telerehabilitation", "evaluation", "chronic disease" and their synonyms. All articles were subjected to qualitative analysis using the Health Technology Assessment (HTA) Core Model prior to further analysis and narrative synthesis. RESULTS: Among the 7412 identified articles, 80 studies met the inclusion criteria and addressed at least one of the noncommunicable diseases (NCD) categories of cardiovascular disease (cardiovascular accidents), cancer, chronic respiratory disease, diabetes, and obesity. Regarding the domains of assessment, the most frequently occurring were "social aspect" (n = 63, 79%) (e.g., effects on behavioral changes) and "clinical efficacy" (n = 53, 66%), and the least frequently occurring was "safety aspects" (n = 2, 3%). We also identified the phases of TR in which the assessment was conducted and found that it most commonly occurred in the pilot study and randomized trial phases and least commonly occurred in the design, pretest, and post-implementation phases. CONCLUSIONS: Through the HTA model, this scoping meta-review highlighted 10 assessment domains which have not been studied with the same degree of interest in the recent literature. We showed that each of these assessment domains could appear at different phases of TR development and proposed a new cross-disciplinary and comprehensive method for assessing TR interventions. Future studies will benefit from approaches that leverage the best evidence regarding the assessment of TR, and it will be interesting to extend this assessment framework to other chronic diseases.

Association between long-term oxygen therapy provided outside the guidelines and mortality in patients with COPD.

INTRODUCTION: Hypoxaemia is a frequent complication of chronic obstructive pulmonary disease (COPD). To prevent its consequences, supplemental oxygen therapy is recommended by international respiratory societies. However, despite clear recommendations, some patients receive long-term oxygen therapy (LTOT), while they do not meet prescription criteria. While evidence suggests that acute oxygen supply at high oxygenation targets increases COPD mortality, its chronic effects on COPD mortality remain unclear. Thus, the study will aim to evaluate through a systematic review and individual patient data meta-analysis (IPD-MA), the association of LTOT prescription outside the guidelines on survival over time in COPD. METHODS: Systematic review and IPD-MA will be conducted according to Preferred Reporting Items for a Systematic Review and Meta-Analyses IPD guidelines. Electronic databases (PubMed, Web of Science, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, OpenGrey and BioRxiv/MedRxix) will be scanned to identify relevant studies (cohort of stable COPD with arterial oxygen tension data available, with indication of LTOT filled out at the moment of the study and with a survival follow-up). The anticipated search dates are January-February 2022. The main outcome will be the association between LTOT and time to all-cause mortality according to hypoxaemia severity, after controlling for potential covariates and all available clinical characteristics. Quantitative data at the level of the individual patient will be used in a one-step approach to develop and validate a prognostic model with a Cox regression analysis. The one-step IPD-MA will be conducted to study the association and the moderators of association between supplemental oxygen therapy and mortality. Multilevel survival analyses using Cox-mixed effects models will be performed. ETHICS AND DISSEMINATION: As a protocol for a systematic review, a formal ethics committee review is not required. Only studies with institutional approval from an ethics committee and anonymised IPD will be included. Results will be disseminated through peer-reviewed publications and presentations in conferences. PROSPERO REGISTRATION NUMBER: CRD42020209823.

The role of personality traits in inpatient pulmonary rehabilitation response in patients with chronic obstructive pulmonary disease.

BACKGROUND: The effectiveness of pulmonary rehabilitation (PR) is a critical issue for chronic obstructive pulmonary disease (COPD) patients. However, PR response is marked by a strong heterogeneity, partially unexplained to date. We hypothesized that personality traits defined by the Five-Factor Model could modulate the effect of inpatient-PR. OBJECTIVE: The aim was to assess the associations between these five personality traits and PR outcomes. METHODS: 74 persons with COPD admitted for a 5-week inpatient PR program had a personality assessment at the start of the program (T1). Exercise capacity, quality of life, sensory and affective dyspnea dimensions were assessed at T1 and at the end of the program (T2). Their evolution was evaluated using the delta score between T2 and T1. PR response was defined using the minimal clinically important change score for each of them. A composite response was established distinguishing the poor responders' group, made of patients who responded to 0, 1 or 2 parameters and the good responders' group, with patients who responded on 3 or 4 indicators. RESULTS: Logistic regressions analyses highlighted that those with a high level of openness [OR = 0.36, 95% CI = 0.15-0.74, p < 0.01] were less likely to respond on quality of life, controlling for socio-demographic factors and the severity of the disease. CONCLUSION: This study shows that the investigation of the personality constitutes an interesting perspective for better understanding the interindividual differences observed between patients in the PR response. Tailoring clinical intervention to the patient's personality could be a promising prospect for optimizing PR effectiveness.

Is bilateral corticospinal connectivity impaired in patients with chronic obstructive pulmonary disease?

KEY POINTS: During moderate and high levels of quadriceps force production, the ipsilateral motor cortex is concomitantly activated with the contralateral motor cortex throughout the corpus callosum to generate the motor command. Chronic obstructive pulmonary disease (COPD) patients display a structurally impaired corpus callosum that may explain the reduced motor command in this population, which in turn contributes to COPD-related muscle weakness of the knee extensors. The study aimed to determine whether bilateral connectivity was impaired and ipsilateral activation was lowered during unilateral strength production of the knee extensors. Our results indicate impaired bilateral connectivity but preserved ipsilateral activation in patients during unilateral isometric contractions of 50% of maximum voluntary strength. The preservation of ipsilateral activation during force production despite impaired bilateral connectivity is consistent with a reorganization of bilateral motor network function that drives unilateral strength production. ABSTRACT: The contralateral primary motor cortex (M1) is not the only brain area implicated in motor command generation. During moderate and high levels of quadriceps force production, the ipsilateral M1 is concomitantly activated. Such activation is mediated by the corpus callosum, the main component of bilateral connectivity. Structural damage to the corpus callosum has been observed in chronic obstructive pulmonary disease (COPD) patients, which might reduce ipsilateral activation and contribute to the lower motor command associated with COPD muscle weakness. We thus aimed to determine whether bilateral connectivity and ipsilateral activation were impaired in COPD. Twenty-two COPD patients and 21 healthy age-matched controls were evaluated by transcranial magnetic stimulation, at rest and during 50% of maximal voluntary isometric contraction (MVIC) of the dominant vastus lateralis muscle. Bilateral connectivity was determined by the ipsilateral silent period (iSP) during 50% MVIC. Ipsilateral activation was determined as the increase in ipsilateral excitability from rest to 50% MVIC. As expected, COPD patients had significantly lower MVIC (-25%, p = 0.03). These patients also showed a significantly lower iSP (-53%, p < 0.001) compared to controls. The ipsilateral excitability was increased in patients and controls (×2.5 and ×3.5, respectively, p < 0.001) but not differently between groups (p = 0.84). Despite impaired bilateral connectivity in COPD, ipsilateral activation was not increased. Reorganization in the patients' interhemispheric pathways could explain the preserved ipsilateral activation.

Specific motor cortex hypoexcitability and hypoactivation in COPD patients with peripheral muscle weakness.

BACKGROUND: Peripheral muscle weakness can be caused by both peripheral muscle and neural alterations. Although peripheral alterations cannot totally explain peripheral muscle weakness in COPD, the existence of an activation deficit remains controversial. The heterogeneity of muscle weakness (between 32 and 57% of COPD patients) is generally not controlled in studies and could explain this discrepancy. This study aimed to specifically compare voluntary and stimulated activation levels in COPD patients with and without muscle weakness. METHODS: Twenty-two patients with quadriceps weakness (COPDMW), 18 patients with preserved quadriceps strength (COPDNoMW) and 20 controls were recruited. Voluntary activation was measured through peripheral nerve (VAperipheral) and transcranial magnetic (VAcortical) stimulation. Corticospinal and spinal excitability (MEP/Mmax and Hmax/Mmax) and corticospinal inhibition (silent period duration) were assessed during maximal voluntary quadriceps contractions. RESULTS: COPDMW exhibited lower VAcortical and lower MEP/Mmax compared with COPDNoMW (p < 0.05). Hmax/Mmax was not significantly different between groups (p = 0.25). Silent period duration was longer in the two groups of COPD patients compared with controls (p < 0.01). Interestingly, there were no significant differences between all COPD patients taken together and controls regarding VAcortical and MEP/Mmax. CONCLUSIONS: COPD patients with muscle weakness have reduced voluntary activation without altered spinal excitability. Corticospinal inhibition is higher in COPD regardless of muscle weakness. Therefore, reduced cortical excitability and a voluntary activation deficit from the motor cortex are the most likely cortical mechanisms implicated in COPD muscle weakness. The mechanisms responsible for cortical impairment and possible therapeutic interventions need to be addressed.

Psychoactive medications in chronic obstructive pulmonary disease patients: From prevalence to effects on motor command and strength.

INTRODUCTION: In chronic-obstructive pulmonary disease (COPD) patients, the peripheral muscle weakness is partly due to reduced motor command. The psychoactive medications, which are often prescribed in COPD, are mainly inhibitory and thus may contribute to motor command reduction. The aims were to characterize and quantify the use of these drugs and determine their effects on cortical excitability and inhibition and thus on motor command and muscle weakness in these patients. METHODS: First, a prevalence study was conducted on 421 COPD patients. Second, cortical excitability, inhibition and voluntary activation were assessed in 40 patients (15 under psychoactive medications vs. 25 controls) by transcranial magnetic stimulation of the rectus femoris. Quadriceps maximal isometric strength was also assessed. RESULTS: About 48% of the patients were taking psychoactive medication. Benzodiazepines (21%) and antidepressants (13.5%) were the most prescribed. Patients with medications tended to be younger and isolated (p < 0.05). They also showed impaired cortical inhibition and decreased cortical excitability (+36%, p = 0.02). Voluntary activation was reduced (-3.6%, p = 0.04) but quadriceps strength was comparable between groups. CONCLUSIONS: Psychoactive medications are prevalent in COPD patients. Patients under these medications exhibited brain impairment and reduced motor command. Paradoxically, voluntary strength was unaltered.

Synthesis and Antiviral Evaluation of Carbocyclic Nucleoside Analogs of Nucleoside Reverse Transcriptase Translocation Inhibitor MK-8591 (4'-Ethynyl-2-fluoro-2'-deoxyadenosine).

MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4'-Ethynyl-G derivative (±)-29 displayed a promising IC50 of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC50 of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC50 of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.

Impact of Chronic Obstructive Pulmonary Disease on Cognitive and Motor Performances in Dual-Task Walking.

When two tasks are performed simultaneously, they compete for attentional resources, resulting in a performance decrement in one or both tasks. Patients with attention disorders have a reduced ability to perform several tasks simultaneously (e.g., talking while walking), which increases the fall risk and frailty. This study assessed the cognitive and motor performances of patients with COPD and healthy controls within a dual-task walking paradigm. A subobjective was to assess the impact of a pulmonary rehabilitation program on the dual-task performances in COPD. Twenty-five patients with COPD and 20 controls performed a cognitive task (subtraction) and a 15-m walking test separately (single-task; ST) and jointly (dual-task; DT). In addition, a subsample of 10 patients performed the same evaluations 5 weeks later after a pulmonary rehabilitation program following current recommendations. Cognitive and gait performances in ST showed no differences between patients with COPD and controls (all p > 0.05). However, COPD patients exhibited a greater increase in gait variability than controls in DT (4.07 ± 1.46% vs. 2.17 ± 0.7%, p < 0.001). The pulmonary rehabilitation program had no effect on the dual-task impairment for the subsample of patients (p = 0.87). This study provides evidence of insufficient attentional resources to successfully deal with DT in patients with COPD, and this was expressed through an exaggerated increase in gait variability in DT walking. Given the high risk of falls and disability associated with altered gait variability, dual-task training interventions should be considered in pulmonary rehabilitation programs.

The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-ß-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.

Discovery of the Aryl-phospho-indole IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor.

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.

Brain Damage and Motor Cortex Impairment in Chronic Obstructive Pulmonary Disease: Implication of Nonrapid Eye Movement Sleep Desaturation.

STUDY OBJECTIVES: Nonrapid eye movement (NREM) sleep desaturation may cause neuronal damage due to the withdrawal of cerebrovascular reactivity. The current study (1) assessed the prevalence of NREM sleep desaturation in nonhypoxemic patients with chronic obstructive pulmonary disease (COPD) and (2) compared a biological marker of cerebral lesion and neuromuscular function in patients with and without NREM sleep desaturation. METHODS: One hundred fifteen patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grades 2 and 3), resting PaO2 of 60-80 mmHg, aged between 40 and 80 y, and without sleep apnea (apnea-hypopnea index < 15) had polysomnographic sleep recordings. In addition, twenty-nine patients (substudy) were assessed i) for brain impairment by serum S100B (biological marker of cerebral lesion), and ii) for neuromuscular function via motor cortex activation and excitability and maximal voluntary quadriceps strength measurement. RESULTS: A total of 51.3% patients (n = 59) had NREM sleep desaturation (NREMDes). Serum S100B was higher in the NREMDes patients of the substudy (n = 14): 45.1 [Q1: 37.7, Q3: 62.8] versus 32.9 [Q1: 25.7, Q3: 39.5] pg.ml(-1) (P = 0.028). Motor cortex activation and excitability were lower in NREMDes patients (both P = 0.03), but muscle strength was comparable between groups (P = 0.58). CONCLUSIONS: Over half the nonhypoxemic COPD patients exhibited NREM sleep desaturation associated with higher values of the cerebral lesion biomarker and lower neural drive reaching the quadriceps during maximal voluntary contraction. The lack of muscle strength differences between groups suggests a compensatory mechanism(s). Altogether, the results are consistent with an involvement of NREM sleep desaturation in COPD brain impairment. CLINICAL TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov as NCT01679782.

Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.

Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.

Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease.

We disclose here the synthesis of a series of macrocyclic HCV protease inhibitors, where the homoserine linked together the quinoline P2' motif and the macrocyclic moiety. These compounds exhibit potent inhibitory activity against HCV NS3/4A protease and replicon cell based assay. Their enzymatic and antiviral activities are modulated by substitutions on the quinoline P2' at position 8 by methyl and halogens and by small heterocycles at position 2. The in vitro structure activity relationship (SAR) studies and in vivo pharmacokinetic (PK) evaluations of selected compounds are described herein.

Is nocturnal desaturation a trigger for neuronal damage in chronic obstructive pulmonary disease?

Patients with chronic obstructive pulmonary disease (COPD) present many neurological disorders of unknown origin. Although hypoxemia has long been thought to be responsible, several studies have shown evidence of neuronal damage and dysfunction even in non-hypoxemic patients with COPD. Adaptive mechanisms protect the brain from hypoxia: when arterial oxygen tension (PaO2) decreases, the cerebral blood flow (CBF) increases, ensuring continuously adequate oxygen delivery to the brain. However, this mechanism is abolished during non-rapid eye movement (NREM) sleep. Any drop in PaO2 during NREM sleep is therefore not compensated by increased CBF, causing decreased cerebral oxygen delivery with subsequent brain hypoxia. Patients with may therefore be exposed to neuronal damage during this critical time. This mechanism is of vital importance for patients with COPD because of the potentially deleterious cortical effects. Nocturnal desaturation is quite frequent in COPD and affects approximately one out of two patients who are not hypoxemic during wakefulness. Although the prevalence of NREM sleep desaturation has never been specifically assessed in COPD, current data suggest that at least half of the nocturnal desaturation in desaturating patients occurs during NREM sleep. This review presents the rationale for the hypothesis that nocturnal desaturation during NREM sleep promotes neuronal damage and dysfunction in COPD.

Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.

Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic ß-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).