Revised European guidelines for the accreditation of sleep medicine centres.

The accreditation of sleep centres aims to ensure high-quality diagnosis and management of sleep centres. European accreditation standards were introduced in 2006, and were aimed at centres offering inpatient polysomnography and vigilance tests (Mean Sleep Latency Test and Maintenance of Wakefulness Test). Since then, the practice of sleep medicine has evolved, with greater use of ambulatory polysomnography and polygraphy. As a result, in many sleep centres, actual clinical practice, although of a high standard, is no longer in accordance with the published guidelines. The current criteria have been revised with the introduction of level-based criteria. Level 1 and 2 centres offer full diagnostic testing in a laboratory-based setting. Level 1 practices will usually be university affiliated, and have a full teaching and active research role. Level 3 and 4 practices may offer both inpatient and ambulatory testing. Level 3 practices perform polysomnography, while level 4 practices (usually monodisciplinary and focussed on sleep apnea) perform polygraphy only. The role of the medical and paramedical team, training, appropriate equipment, patient care pathways and patient management according to national/European recommendations is underlined for accreditation at each level. It is anticipated that the guidelines will be reviewed and if necessary revised after 4 years.

Melatonin secretion and sleep disorders in patients with spinal cord injuries.

STUDY DESIGN: Prospective observational study. OBJECTIVES: To evaluate melatonin secretion, daytime sleepiness and sleep disorders in patients with spinal cord injuries (SCI), and their association with lesion level. SETTING: Specialized neuro rehabilitation hospital in France METHODS: Prospective observational study of patients aged over 18 hospitalized in for spinal cord injury. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PQSI), daytime sleepiness with the Epworth Sleepiness scale (ESS), and melatonin secretion by 24 h urinary dosage of 6-sulphatoxy-melatonin. RESULTS: 213 patients were screened, 21 patients were included: 17 complete (AIS A) and 4 lesions (AIS B), 76% of traumatic origin with 12 tetraplegic and 9 paraplegic, mean 10 (range 0.5-40) years after injury. Mean age was 46.8 ± 14.7 years, mean BMI 23.56 ± 4.1 and men outnumbered women (15 vs 6). Melatonin secretion was analyzed by 24 h secretion and by secretion profile. Comparing retained vs abolished secretion, only 23% (4/17) of patients with a lesion above T8 retained melatonin secretion, compared to 80% (4/5) with a lesion below T8 (p = 0.022). Non significant differences were found in secretion profile in patients who retained secretion: no patient with a lesion above T8 had a normal secretion profile compared to 50% with a lesion below T8 and in the impact of partial vs total lesions above T8 in whom 17% (2/12) of complete ASIA-A lesions and 50% (2/4) of incomplete lesions retained secretion. CONCLUSION: Lesions of the spinal cord above T8 are strongly associated with abolition of melatonin secretion.

[Sleep in a performance artist: Eight days and seven nights sitting inside a metal sculpture]. / Le sommeil d'un performeur de l'extrême. Dormir huit jours et sept nuits, assis, sans bouger, enfermé dans une sculpture.

Sleep in extreme situations has been little studied. The artist Abraham Poincheval (AP) is known for his performances in confined spaces. For his show at the Perrotin Gallery in Paris, he was enclosed for 8days and 7nights in a metal sculpture of his body in a seated position, with his head facing a work by Hans Hartung at the end of a cone system placed in front of his eyes which occluded all other visual stimuli. The interior of the metal structure was not padded and there was no head support. His sleep and internal temperature were continuously recorded using polysomnography (Grael, Compumedics) and an orally swallowed temperature sensitive capsule (Bodycap) with temperature sampling every 2min. AP slept an average of 355.1min/24h, composed of light slow-wave sleep (N1: 47.1min, N2: 192.2min), deep slow-wave sleep (N3: 100.4min), and REM sleep 4,3 % (15.4min). Sleep, although mostly nocturnal, was split into periods of no more than 20min. Deep sleep was therefore remarkably resistant to the uncomfortable experimental conditions, while REM sleep was markedly impaired, lasting only a few short minutes and followed by rapid awakening. This is probably due to the head position within the sculpture which was unsupported, so REM sleep with its inherent muscle atonia led to involuntary head flexion and was impossible to sustain for long. The thermal minimum was between 5:17 a.m. and 6:35 a.m. The amplitude of the core temperature decreased by more than 30 % between the beginning and the end of the protocol. Despite the immobility induced by the confined experimental conditions, there was no desynchronization of circadian rhythms. The sleep time was surprisingly long given the conditions, and slow-wave sleep was relatively preserved with an amount typically found in normal subjects while REM sleep was markedly impaired. Slow-wave sleep is clearly preserved underlying its central role in physical and mental homeostasis. REM sleep is clearly more fragile. The reduction in REM sleep linked to position has been found in a study of sleep in the sitting position in airplanes where loss of muscle tonus in the neck fragments REM sleep. Techniques for selective REM sleep deprivation also use muscle atonia: one of the initial techniques of selective REM sleep deprivation relied on muscle atonia in REM causing a cat to fall from a small perch into water. In man, the lack of head support is clearly a source of REM fragmentation. However in the case of this study, we cannot exclude an effect of other factors, notably the meditative techniques used by the performer to maintain attention on the painting, described as a dream state punctuated by visual hallucinations. Surprisingly, despite physical isolation within the sculpture, AP's biological rhythms remained stable. However, the conditions were not those of complete isolation: noise, the presence of the public in the gallery who occasionally talked to AP through the sculpture, and variations in light during the day were all temporal cues. In addition, a heatwave during the performance raised the temperature in the room with reduced total sleep time on the hottest night. Although the phase of the circadian rhythm measured by the internal temperature did not change, the amplitude fell which is compatible with reduced physical activity. In conclusion, under physically constraining and uncomfortable sleep conditions, deep sleep is maintained while REM sleep is starkly reduced. From a homeostatic point of view, this means that over a short period of time, in a survival situation, energy recovery through deep slow-wave sleep takes priority over REM sleep.

Eco-anxiety: An adaptive behavior or a mental disorder? Results of a psychometric study.

OBJECTIVE: Eco-anxiety is a complex construct that has been created to grasp the psychological impact of the consequences of global warming. The concept needs a reliably valid questionnaire to better evaluate its impact on the risk of anxiety and depressive disorders. The Eco-Anxiety Questionnaire (EAQ-22) evaluates two dimensions: 'habitual ecological anxiety' and 'distress related to eco-anxiety'. However, a version in French, one of the world's widely spoken languages, was until now lacking. We aimed to translate and validate the French EAQ-22 and to evaluate the prevalence of the level of the two dimensions of eco-anxiety and the relationship with anxiety and depressive symptoms in a representative adult sample of the French general population. METHODS: This study was performed under the auspices of the Institut national du sommeil et de la vigilance (INSV). Participants (18-65 years) were recruited by an institute specialized in conducting online surveys of representative population samples (quota sampling). Two native French speakers and two native English speakers performed a forward-backward translation of the questionnaire. The Hospital Anxiety and Depression scale (HAD) was administered to assess anxiety (HAD-A) and depressive (HAD-D) symptoms and for external validity. Internal structural validity and external validity were analysed. RESULTS: Evaluation was performed on 1004 participants: mean age 43.47 years (SD=13.41, range: [19-66]); 54.1% (n=543) women. Using the HAD, 312 (31.1%) patients had current clinically significant anxiety symptoms (HAD-A>10) and 150 (14.9%) had current clinically significant depressive symptoms (HAD-D>10). Cronbach's alpha coefficient was 0.934, indicating very good internal consistency. Correlation between EAQ-22 and HAD scores was low (r[1004]=0.209, P<0.001), 'habitual ecological anxiety' was correlated less with HAD-A and HAD-D than 'distress related to eco-anxiety', indicating good external validity. CONCLUSION: This study validates the French EAQ-22 and paves the way for using the EAQ-22 as a global tool for assessing eco-anxiety. Further prospective studies are now required to better evaluate the impact of eco-anxiety on the occurrence of anxiety and depressive disorder.

Self-administered non-invasive vagus nerve stimulation therapy for severe pharmacoresistant restless legs syndrome: outcomes at 6 months.

Severe pharmacoresistant restless legs syndrome (RLS) is difficult to manage and a source of suffering to patients. We studied the effectiveness at 6 months of an innovative treatment: transauricular vagus nerve stimulation (taVNS) in the left cymba concha in a case series of 15 patients, 53% male, mean (SD) age 62.7 (12.3) years with severe pharmacoresistant RLS (mean [SD] International Restless Legs Rating Scale [IRLS] score of 31.9 [2.9]) at baseline. Following an 8-week non-randomised hospital-based study with eight 1-h sessions of taVNS, patients were trained to administer taVNS at home and were followed up for 6 months. The primary outcome measure was the IRLS score, secondary outcome measures were quality of life, mood disorders using the Hospital Anxiety and Depression scale (HAD) subscales for depression (HADD) and anxiety (HADA). At the 6-month follow-up 13/15 patients continued to use weekly taVNS. Symptom severity decreased (mean [SD] IRLS score 22.2 [9.32] at 6 months, p = 0.0005). Four of the 15 patients had an IRLS score of <20 at 6 months and two an IRLS score of 5. Quality of life significantly improved compared to baseline (mean [SD] score at baseline 49.3 [18.1] versus 65.66 [22.58] at 6 months, p = 0.0005) as did anxiety and depression symptoms (mean [SD] HADA score at baseline 8.9 [5.4] versus 7.53 [4.42] at 6 months, p = 0.029; and HADD score at baseline 5.2 [4.5] versus 4.73 [4.44] at 6 months, p = 0.03). Treatment was well tolerated, and no adverse events were reported. Our case series shows a potential role for self-administered taVNS in patients with severe pharmacoresistant RLS. Randomised controlled trials are needed to confirm the utility of taVNS.

Adherence to continuous positive airway pressure therapy in patients with spinal cord injury and obstructive sleep apnea: trajectories and predictors.

PURPOSE: To identify specific determinants of non-adherence or cessation of continuous positive airway pressure (CPAP) therapy in a population of patients with spinal cord injuries (SCI). METHODS: Retrospective analysis of data from patients with SCI who underwent a full night supervised polysomnography between 2015 and 2021 and presented with moderate to severe obstructive sleep apnea (OSA) and for whom CPAP was indicated. Adherence was studied at 1, 6, and 12 months. Univariate and multivariate analyses were performed to identify factors associated with non-adherence (< 4 h per night or CPAP cessation). Factors studied were demographic and disease-related data and both subjective and objective sleep parameters. RESULTS: A total of 60 patients were included (40% cervical SCI). In univariate analysis, the only predictive parameters of non-adherence observed at 1, 6, and 12 months were the average use of CPAP on the 1st night (p = 0.02) and over the 1st week (p ≤ 0.001). A complete lesion (AIS-A) was predictive of non-adherence at 1 and 6 months (p = 0.02 at 6 months), while mask leakage was associated with non-adherence at 12 months (p = 0.02). Upper limb autonomy and the presence of family caregivers did not appear to be protective. In multivariate analysis, only the average use in the first week remained predictive of adherence (> 4 h) in the short, medium and long term. CONCLUSION: In patients with SCI and OSA, the 1st week of CPAP treatment seems to be determinant of short-, medium-, and long-term CPAP adherence. Support for SCI patients from the start of treatment is essential and may help avoid treatment failures.

Noninvasive Vagus Nerve Stimulation: A New Therapeutic Approach for Pharmacoresistant Restless Legs Syndrome.

AIMS: This work aimed to study the effect of noninvasive vagus nerve stimulation on severe restless legs syndrome (RLS) resistant to pharmacotherapy. MATERIALS AND METHODS: Patients with severe pharmacoresistant RLS were recruited from a tertiary care sleep center. Intervention was one-hour weekly sessions of transauricular vagus nerve stimulation (tVNS) in the left cymba concha, for eight weeks. The primary outcome measure was the score on the International Restless Legs Rating Scale (IRLS); secondary outcome measures were quality of life (Restless Legs Syndrome Quality of Life scale [RLSQOL]), mood disorders using the Hospital Anxiety and Depression scale subscale for depression (HADD) and Hospital Anxiety and Depression scale subscale for anxiety (HADA), and objective sleep latency, sleep duration, efficiency, and leg movement time measured by actigraphy. RESULTS: Fifteen patients, 53% male, aged mean 62.7 ± 12.3 years with severe RLS, reduced quality of life, and symptoms of anxiety and depression, were included. The IRLS improved from baseline to session eight: IRLS 31.9 ± 2.9 vs 24.6 ± 5.9 p = 0.0003. Of these participants, 27% (4/15) had a total response with a decrease below an IRLS score of 20; 40% (6/15) a partial response with an improvement in the IRLS > 5 but an IRLS above 20; and 33% (5/15) were nonresponders. After tVNS, quality of life improved (RLSQOL 49.3 ± 18.1 vs 80.0 ± 19.6 p = 0.0005), as did anxiety (HADA 8.9 ± 5.4 vs 6.2 ± 5.0 p = 0.001) and depression (HADD 5.2 ± 4.5 vs 4.0 ± 4.0 p = 0.01). No significant change was found in actigraphic outcome measures. CONCLUSIONS: In this pilot study, tVNS improved the symptoms of RLS in 66% of participants (10/15) with severe pharmacoresistant RLS, with concomitant improvements in quality of life and mood. Randomized controlled trials evaluating therapeutic efficacy of tVNS in RLS are needed to confirm these promising findings.

Gendered Expectations: the Impact of Gender, Evaluation Language, and Clinical Setting on Resident Trainee Assessment of Faculty Performance.

BACKGROUND: Gender inequity is pervasive in academic medicine. Factors contributing to these gender disparities must be examined. A significant body of literature indicates men and women are assessed differently in teaching evaluations. However, limited data exist on how faculty gender affects resident evaluation of faculty performance based on the skill being assessed or the clinical practice settings in which the trainee-faculty interaction occurs. OBJECTIVE: Evaluate for gender-based differences in the assessment of general internal medicine (GIM) faculty physicians by trainees in inpatient and outpatient settings. DESIGN: Retrospective cohort study SUBJECTS: Inpatient and outpatient GIM faculty physicians in an Internal Medicine residency training program from July 1, 2015, to December 31, 2018. MAIN MEASURES: Faculty scores on trainee teaching evaluations including overall teaching ability and Accreditation Council for Graduate Medical Education (ACGME) competencies (medical knowledge [MK], patient care [PC], professionalism [PROF], interpersonal and communication skills [ICS], practice-based learning and improvement [PBLI], and systems-based practice [SBP]) based on the institutional faculty assessment form. KEY RESULTS: In total, 3581 evaluations by 445 trainees (55.1% men, 44.9% women) assessing 161 GIM faculty physicians (50.3% men, 49.7% women) were included. Male faculty were rated higher in overall teaching ability (male=4.69 vs. female=4.63, p=0.003) and in four of the six ACGME competencies (MK, PROF, PBLI, and SBP) based on our institutional evaluation form. In the inpatient setting, male faculty were rated more favorably for overall teaching (male = 4.70, female = 4.53, p=<0.001) and across all ACGME competencies. The only observed gender difference in the outpatient setting favored female faculty in PC (male = 4.65, female = 4.71, p=0.01). CONCLUSIONS: Male and female GIM faculty performance was assessed differently by trainees. Gender-based differences were impacted by the setting of evaluation, with the greatest difference by gender noted in the inpatient setting.

Why is it so hard to enact responsible change?: Scientists need to work more closely with other social groups to implement sustainable innovation.

Science is key to developing sustainable products and solutions. But scientists also need to work more with governments, industry and society to help implement those solutions.

Recommendations for environmental risk assessment of gene drive applications for malaria vector control.

Building on an exercise that identified potential harms from simulated investigational releases of a population suppression gene drive for malaria vector control, a series of online workshops identified nine recommendations to advance future environmental risk assessment of gene drive applications.

Dealing with uncertainty in clinical reasoning: A threshold model and the roles of experience and task framing.

INTRODUCTION: Uncertainty is integral to clinical practice and clinical reasoning but has proven difficult to study and model. Little is known about how clinicians manage uncertainty. According to evidence-based medicine theory, clinicians should utilise new information to reduce uncertainty until reaching action thresholds for further information gathering or treatment. We examined the impact of experience and task framing on uncertainty thresholds and the extent to which these thresholds guided clinical decisions. Finally, we sought to determine the impact of framing by having participants provide threshold responses as a range or as specific numbers. METHODS: One hundred sixty-eight fourth-year medical students, 93 residents and 72 faculty were presented a case of viral pneumonia with a suspected superimposed bacterial infection. Participants identified their testing and treatment thresholds with either a specific number or an inter-threshold range of probabilities that would compel them to test further. Afterwards, they were told the patient had a 20% pre-test probability of a superimposed infection and asked whether they would treat the patient with antibiotics, order additional testing or neither. Responses were compared with their previously stated threshold values to assess decision-making consistency. RESULTS: Testing thresholds were 15.8%, 20.6% and 25.8%, treatment thresholds were 78.5%, 71.6% and 73.4% and threshold spans (difference between testing and treatment thresholds) were 62.7, 51 and 47.6 for students, residents and faculty, respectively. Sixty-four percent of respondents made judgements consistent with their thresholds, 28% escalated their decision (doing more than their thresholds predicted) and 7.6% de-escalated their decision (doing less than their thresholds predicted). Framing had an impact on both faculty and resident decisions and a larger impact on students. DISCUSSION: These findings help us understand how clinical reasoning and threshold determinations vary with clinical experience. As uncertainty can lead to unnecessary testing and cognitive discomfort, examining decision thresholds helps us ascertain how diagnostic and treatment decisions are made.

Gene Drives in the U.K., U.S., and Australian Press (2015-2019): How a New Focus on Responsibility Is Shaping Science Communication.

Gene drive is a controversial biotechnology for pest control. Despite a commitment from gene drive researchers to responsibility and the key role of the media in debates about science and technology, little research has been conducted on media reporting of gene drive. We employ metaphor and discourse analysis to explore how responsibility is reflected in the coverage of this technology in the U.S., U.K., and Australian press. The findings reveal a rhetorical strategy of trust-building by evoking the moral attributes of gene drive researchers. We discuss the implications of these findings for the communication of new technologies.

A video polysomnographic study of spontaneous smiling during sleep in newborns.

The objective of the present study was to confirm the link between spontaneous smiling and active sleep in newborns, and to identify the role of the cortex in the generation of spontaneous smiles. A total of 12 healthy newborns born at term and three infants with major congenital abnormalities (two with hydranencephaly and one with a left hemispherectomy) were evaluated by video and polysomnography during a 3-hr sleep period. Smiles were graded and their association with isolated rapid eye movements and grouped rapid eye movements was analysed. In all, 383 smiles were recorded of which 377 occurred during active sleep. Smiles were shown to be significantly associated with active sleep (p < .0001) and with grouped rapid eye movements (p < .0001). Bilateral smiles were more frequent than asymmetrical smiles. Among asymmetrical smiles, left-sided smiles were more frequent than right-sided smiles (p < .0001). Maternal stimulation during active sleep did not increase smiles. Smiling was absent during active sleep only in the infant with total hydranencephaly in whom nearly all cortical tissue was absent. In conclusion, smiling occurs in healthy newborns, almost exclusively in active sleep and is associated with grouped rapid eye movements. In infants with major congenital abnormalities, smiling is abolished only when nearly all of the cerebral cortex is absent. These results support the hypothesis of the role of active sleep in the stimulation of neuronal circuits responsible for spontaneous smiling and emphasise the importance of cortical areas in newborn smiling.

Ugandan stakeholder hopes and concerns about gene drive mosquitoes for malaria control: new directions for gene drive risk governance.

BACKGROUND: The African Union's High-Level Panel on Emerging Technologies identified gene drive mosquitoes as a priority technology for malaria elimination. The first field trials are expected in 5-10 years in Uganda, Mali or Burkina Faso. In preparation, regional and international actors are developing risk governance guidelines which will delineate the framework for identifying and evaluating risks. Scientists and bioethicists have called for African stakeholder involvement in these developments, arguing the knowledge and perspectives of those people living in malaria-afflicted countries is currently missing. However, few African stakeholders have been involved to date, leaving a knowledge gap about the local social-cultural as well as ecological context in which gene drive mosquitoes will be tested and deployed. This study investigates and analyses Ugandan stakeholders' hopes and concerns about gene drive mosquitoes for malaria control and explores the new directions needed for risk governance. METHODS: This qualitative study draws on 19 in-depth semi-structured interviews with Ugandan stakeholders in 2019. It explores their hopes for the technology and the risks they believed pertinent. Coding began at a workshop and continued through thematic analysis. RESULTS: Participants' hopes and concerns for gene drive mosquitoes to address malaria fell into three themes: (1) ability of gene drive mosquitoes to prevent malaria infection; (2) impacts of gene drive testing and deployment; and, (3) governance. Stakeholder hopes fell almost exclusively into the first theme while concerns were spread across all three. The study demonstrates that local stakeholders are able and willing to contribute relevant and important knowledge to the development of risk frameworks. CONCLUSIONS: International processes can provide high-level guidelines, but risk decision-making must be grounded in the local context if it is to be robust, meaningful and legitimate. Decisions about whether or not to release gene drive mosquitoes as part of a malaria control programme will need to consider the assessment of both the risks and the benefits of gene drive mosquitoes within a particular social, political, ecological, and technological context. Just as with risks, benefits-and importantly, the conditions that are necessary to realize them-must be identified and debated in Uganda and its neighbouring countries.

Population pharmacokinetic model of blood THC and its metabolites in chronic and occasional cannabis users and relationship with on-site oral fluid testing.

AIMS: To develop a population pharmacokinetic (PP) model of delta-9-tetrahydrocannabinol (THC) and its metabolites in blood and to determine the relationship between blood THC pharmacokinetics and results of on-site oral fluid (OF) testing in chronic (CC) and occasional (OC) cannabis users. METHODS: Fifteen CC (1-2 joints/day) and 15 OC (1-2 joints/week) aged 18-34 years were included, genotyped for their CYP2C9 polymorphisms. Twelve measurements of blood THC, 11-OH-THC and THC-COOH were carried out during the 24-hour period after controlled cross-over random inhalation of placebo, 10 mg or 30 mg of THC. OF tests (DrugWipe® 5S) were performed up to 6 hours and then stopped after two successive negative results. The blood concentrations and their relationship to OF testing results were analysed using a PP approach with NONMEM® and R. RESULTS: A three-compartment model described the pharmacokinetics of THC, with zero-order absorption, and a two-compartment model the metabolites. The fraction of THC converted to 11-OH-THC was 0.27 and the fraction of 11-OH-THC to THC-COOH was 0.86. Smoking 30 mg of THC decreased the THC bioavailability to 0.68 compared to 10 mg. CC showed a 2.41 greater bioavailability than OC, leading to higher Cmax and AUC for the three compounds for the same dose. The best model describing the probability of a positive OF test included THC blood concentration and the group as covariate: for a similar THC blood concentration, a CC was less likely to be positive than an OC. CONCLUSION: OC are more likely to screen positive than CC for a similar blood concentration.

Blue-Enriched White Light Therapy Reduces Fatigue in Survivors of Severe Traumatic Brain Injury: A Randomized Controlled Trial.

OBJECTIVE: Fatigue is one of the disabling sequelae of traumatic brain injury (TBI), with repercussions on quality of life, rehabilitation, and professional reintegration. Research is needed on effective interventions. We evaluated efficacy of blue-enriched white light (BWL) therapy on fatigue of patients with severe TBI. SETTING: Physical Medicine and Rehabilitation and Physiology departments of University hospitals. PARTICIPANTS: Adult patients with fatigue symptoms following severe TBI, Fatigue Severity Scale (FSS) score 4 or more, Epworth Sleepiness Scale (ESS) score 10 or more, and/or Pittsburgh Sleep Quality Index (PSQI]) more than 5 were randomly assigned to one of 2 parallel groups: a BWL therapy group, with 30-minute exposure to waking white light enriched with blue for 4 weeks, and a group without light therapy (N-BWL), no light. DESIGN: Randomized controlled trial. ClinicalTrials.gov number: NCT02420275. MAIN MEASURES: The primary outcome measure was the response of the FSS to 4 weeks of treatment. In addition, we assessed latency change of the P300 component of event-related potentials before and after therapy. RESULTS: Significant improvement in the FSS score (P = .026) was found in the BWL group compared with the N-BWL group. CONCLUSION: BWL phototherapy reduces fatigue in patients with severe TBI.

Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: a population-based analysis.

Delayed lymphocyte and T-cell immune reconstitution following bendamustine-rituximab (BR) for indolent non-Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population-based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33-92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m2 (range 140-1440 mg/m2 ). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow-up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 109 /l) and CD4+ recovery (≥0·2 × 109 /l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m2 (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2-0·8), end-of-treatment ALC ≤0·4 × 109 /l (HR 0·53; 95% CI: 0·3-0·9) and CD4+ <0·1 × 109 /l 1-year post-BR (HR 0·03; 95% CI: 0·008-0·15) were covariables for delayed CD4+ recovery. ALC-recovery ≥1 × 109 /l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4-6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.

Effect of Smoked Cannabis on Vigilance and Accident Risk Using Simulated Driving in Occasional and Chronic Users and the Pharmacokinetic-Pharmacodynamic Relationship.

BACKGROUND: The pharmacokinetic-pharmacodynamic relationship between whole blood δ-9-tetrahydrocannabinol (THC) and driving risk is poorly understood. METHODS: Fifteen chronic cannabis consumers (1-2 joints/day; CC) and 15 occasional cannabis consumers (1-2 joints/week; OC) of 18 to 34 years of age were included. A pharmacokinetic study was conducted with 12 blood samplings over a 24-h period before and after controlled random inhalation of placebo or 10 mg or 30 mg of THC. THC and metabolites were quantified using LC-MS/MS. Effects on reaction time by psychomotor vigilance tests and driving performance through a York driving simulator were evaluated 7 times. A pharmacokinetic-pharmacodynamic analysis was performed using R software. RESULTS: Whole blood peak THC was 2 times higher in CC than in OC for a same dose and occurred 5 min after the end of consumption. THC remained detectable only in CC after 24 h. Despite standardized consumption, CC consumed more available THC from each cigarette regardless of dose. Maximal effect for reaction time was dose- and group-dependent and only group-dependent for driving performance, both being decreased and more marked in OC than in CC. These effects were maximal around 5 h after administration, and the duration was longer in OC than in CC. A significant pharmacokinetic-pharmacodynamic relationship was observed only between T max for blood THC and the duration effect on mean reciprocal reaction time. CONCLUSIONS: Inhalation from cannabis joints leads to a rapid increase in blood THC with a delayed decrease in vigilance and driving performance, more pronounced and lasting longer in OC than in CC. ClinicalTrials.gov Identifier: NCT02061020.