PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.

Mutations of PAK3, a p21-activated kinase, are associated in humans with cognitive deficits suggestive of defective cortical circuits and with frequent brain structural abnormalities. Most human variants no longer exhibit kinase activity. Since GABAergic interneurons express PAK3 as they migrate within the cortex, we here examined the role of PAK3 kinase activity in the regulation of cortical interneuron migration. During the embryonic development, cortical interneurons migrate a long distance tangentially and then re-orient radially to settle in the cortical plate, where they contribute to cortical circuits. We showed that interneurons expressing a constitutively kinase active PAK3 variant (PAK3-ca) extended shorter leading processes and exhibited unstable polarity. In the upper cortical layers, they entered the cortical plate and extended radially oriented processes. In the deep cortical layers, they exhibited erratic non-processive migration movements and accumulated in the deep pathway. Pharmacological inhibition of PAK3 kinase inhibited the radial migration switch of interneurons to the cortical plate and reduced their accumulation in the deep cortical layers. Interneurons expressing a kinase dead PAK3 variant (PAK3-kd) developed branched leading processes, maintained the same polarity during migration and exhibited processive and tangentially oriented movements in the cortex. These results reveal that PAK3 kinase activity, by promoting leading process shortening and cell polarity changes, inhibits the tangential processive migration of interneurons and favors their radial re- orientation and targeting to the cortical plate. They suggest that patients expressing PAK3 variants with impaired kinase activity likely present alterations in the cortical targeting of their GABAergic interneurons.

Major depressive disorder with hypersomnolence complaint: A comparison study with non-depressed individuals examining objective biomarkers.

BACKGROUND: Hypersomnolence is common in major depressive disorder (MDD), associated with more severe episodes, suicide and antidepressant resistance. Nevertheless, few studies used polysomnography (PSG) and multiple sleep latency test (MSLT) to characterize these patients. In this context, we compared patients visiting a sleep center for hypersomnolence complaint with MDD (HSC/MDD+) and without MDD (HSC/MDD-). METHODS: HSC/MDD+ and HSC/MDD- groups were defined according to DSM-5 criteria and CES-D scale, and had a 30 h-PSG with ad libitum-sleep and PSG followed by MLST. RESULTS: HSC/MDD+ had an increased self-declared total sleep time (sTST) of about 10 h30 similar to HSC/MDD- (630.8 ± 17.3 min-vs-616.5 ± 18.1 min, respectively, p = 0.39). Nevertheless, their objective TST (oTST) on ad libitum PSG was significantly longer and about 10 h50 (648.6 ± 23.9 min-vs-587.4 ± 19.0 min, respectively, p = 0.038). HSC/MDD+ also significantly better estimated their sleep duration, with a lower difference between their sTST and oTST compared to HSC/MDD- (10.0 ± 1.7 %-vs-17.4 ± 2.1 %, respectively, p = 0.009) and confirmed significantly more frequently the hypersomnia diagnosis -i.e. oTST>10H- (82.6 ± 8.1 %-vs-54.6 ± 10.9 %, respectively, p = 0.046). Using the Kupfer index (KI), we confirmed a reduced REM sleep latency in patients MDD/HSC+ (15.2 ± 10.0 %-vs-2.3 ± 2.3 %, respectively, p = 0.039). Both groups had comparable increased diurnal sleepiness assessed with the Epworth scale (14.1 ± 1.1-vs-14.8 ± 1.1, respectively, p = 0.65). HSC/MDD+ had less MSLT sleep latency <8 min (9.1 ± 5.1 %-vs-27.3 ± 6.8 %, respectively, p = 0.048). LIMITATIONS: Retrospective cross-sectional study. CONCLUSIONS: HSC/MDD+ accurately estimated their sleep duration, objectively confirmed hypersomnia and may specifically had a decreased Kupfer index.

Images: "Too much heat for my non-24-hour sleep-wake disorder!" A case report.

The non-24-hour sleep-wake disorder (N24SWD) is a rare condition, sometimes associated with blindness or with suprachiasmatic nuclei lesions, resulting in a free-running rhythm or hypernycthemeral syndrome. Synchronizers, such as light, when light perception remains, melatonin, food intakes, physical activity, social interactions, and temperature, play a key role in the treatment of N24SWD. In this report, we describe a case illustrating the impact of outdoor temperature in a 34-year-old man with N24SWD effectively treated through a combination of chronotherapy interventions. During 3 consecutive heat waves, he experienced a recurrence of his natural 25.5-hour free-running rhythm, with a consistent bedtime phase delay caused by temperature, resulting in the discontinuation of chronotherapy. After these heat waves, he was able again to resynchronize his rhythms with the combination of chronotherapeutics. This case report highlights that patients with N24SWD may be particularly at risk of relapse during heat waves, with direct implications for monitoring and reinforcing chronotherapies. CITATION: Garrivet J, d'Ortho M-P, Frija-Masson J, et al. "Too much heat for my non-24-hour sleep-wake disorder!" A case report. J Clin Sleep Med. 2024;20(2):329-333.

The nightmare severity index (NSI): A short new multidimensional tool for assessing nightmares.

This psychometric pilot study aims to evaluate a new multidimensional simple scale, named the nightmare severity index (NSI) - close to the existing insomnia (ISI) and hypersomnia (HSI) severity indexes. The NSI encompasses all main dimensions of nightmare disorder, evaluating four subdimensions: frequency, emotional impact, diurnal impact, and nocturnal impact of nightmares. The NSI was completed by a total of 102 patients. The majority of the population consisted of women (64%) and outpatient individuals (76%) diagnosed with mood disorders such as depression (31%) and bipolar disorder (41%). Comorbidity with post-traumatic stress disorder (PTSD) was prevalent (44%), and psychotropic medications were commonly used (47%). Internal validity analyses indicated that the NSI was well suited for exploratory factor analysis. All items demonstrated satisfactory correlations with the factors, and the questionnaire exhibited good internal consistency (Cronbach's alpha >0.7). Higher NSI scores were observed among individuals experiencing nightmare symptoms considering the DSM-5/ICSD-3 criteria. In summary, the NSI proves to be a promising and valuable tool for clinical practice, demonstrating good acceptability, internal validity, and the ability to assess nightmare severity.

Effects of smoking on sleep architecture and ventilatory parameters including apneas: Results of the Tab-OSA study.

Background: The interaction between smoking and sleep seems appears to be bidirectional, but few studies evaluated the impact of smoking and its cessation on objective sleep parameters. In this context, this new study aimed to assess the impact of smoking and its cessation on sleep architecture and on ventilatory sleep parameters, particularly the presence of sleep apnea syndrome (apnea-hypopnea index (AHI)≥15). Methods: Patients hospitalized for polysomnographic sleep exploration were compared according to their smoking status: active smokers (AS), former smokers (FS), non-smokers (NoNi). Psychiatric and non-psychiatric co-morbidities and treatment or substance use were taken into account in the analyses. Results: A total of 170 participants were included (N = 37 FS, 39 AS, 86 NoNi). A significant decrease in the mean nocturnal O2 saturation was observed for FS and AS compared to NoNi. No differences were found regarding AHI. Regarding sleep architecture, we observed a significant decrease in the slow wave sleep duration for AS compared to NoNi, and interestingly not between FS and NoNi. Conclusion: This study suggests that current smokers suffer from alterations in both sleep architecture and ventilatory parameters, the later appears to persist even after smoking cessation.

Prevalence, treatment and determinants of obstructive sleep apnoea and its symptoms in a population-based French cohort.

Background: Obstructive sleep apnoea (OSA) is associated with increased morbidity and mortality. Although the disorder has been well studied in selected high-risk populations, few data exist on its prevalence in the general population. We aimed to assess the prevalence and determinants of OSA in France. Methods: Data from participants of the French population-based CONSTANCES cohort aged 18-69 years at inclusion and being treated for sleep apnoea or screened for OSA in 2017 using the Berlin Questionnaire were analysed. Weighted analyses were performed to provide recent and representative results in the general population. Results: Among 20 151 participants, the prevalence of treated sleep apnoea was 3.5% (95% CI 3.0-3.9%). The prevalence of untreated subjects with a positive Berlin Questionnaire was 18.1% (95% CI 17.3-19.2%) for a total weighted prevalence of treated sleep apnoea or high risk of OSA of 20.9% (95% CI 20.0-21.9%). Regarding prevalence of OSA symptoms, it was 37.2% (95% CI 36.1-38.3%) for severe snoring and 14.6% (95% CI 13.8-15.5%) for hypersomnolence. In multivariable logistic regression analysis, male sex, age, previous cardiovascular events, smoking, low educational level, low physical activity and depressive symptoms were associated with having either treated sleep apnoea or a positive Berlin Questionnaire. Conclusion: In this large French population-based cohort, one in five participants had a high likelihood of OSA, whereas only 3.5% were treated for the disorder, suggesting major underdiagnosis in the general population. OSA diagnosis should be considered more often in people with risk factors such as depressive symptoms as well as unhealthy behaviours and socioeconomic conditions.

Continuous positive airway pressure as an accurate marker for non-24-hour sleep-wake rhythm disorder.

Non-24-h sleep-wake rhythm disorder is quite rare in sighted patients and frequently associated with psychiatric disorders. We report the case of a 46-year-old man with autism spectrum disorder (ASD) and agoraphobia who had been referred for a suspicion of obstructive sleep apnea syndrome (OSAS). Polysomnography and arterial blood gas confirmed moderate OSAS associated with hypoventilation. Continuous positive airway pressure (CPAP) was started on fixed mode with excellent results. At follow-up, his CPAP report data revealed an irregular sleep-wake rhythm with a progressive offset of sleep schedule and wake time delayed from 1 h from day to day. Melatonin (or agonist) is efficacious and safe for long-term treatment in ASD and circadian rhythm sleep-wake disorder (CRSWD) with light therapy and wakefulness promoting medication. This case underlines the importance to sensitise psychiatrists to sleep and CRSWD, and also that CPAP data offer a possible objective alternative to sleep diary.

Effect of lockdown on sleep-wake rhythm and alcohol use.

The global covid-19 pandemic has imposed radical changes in daily lives. This study reflects upon sociodemographic and clinical characteristics (sleep-wake rhythm, psychiatric symptoms, and alcohol use behavior) during the full lockdown, comparing individuals who increased their alcohol use (iAU), those who maintained a stable use (sAU), and those who did not consume alcohol (AnoU). Participants were recruited via e-mails and they were required to complete an online survey that included questionnaires, during the last week of the full lockdown. The iAU group, compared to the sAU group, presented more disturbed sleep (PSQI; p < .001), more severe insomnia (ISI; p < .001), shorter sleep duration (p < .001), longer sleep latency (p < .001), and less regular sleep-wake schedules (p = .005). They also reported more anxiety (HAD-A; p = .009), more depressive symptoms (HAD-D: p = .006) and more psychotraumatic symptoms (PCL-5: p = .018). Moreover, the sAU group, compared to AnoU, showed better quality of sleep (PSQI; p = .002) and less severe anxiety symptoms (HAD-A; p = .014). Maintaining a stable use was also related to a better quality of life associated with bigger homes with more frequent outdoors living spaces and higher monthly incomes. Individuals who increased their alcohol consumption during the Covid-19 lockdown exhibited more sleep and circadian rhythm disturbances, as well as more (severe) psychiatric symptoms.

Factors associated with insomnia symptoms: A cross-sectional study during a Covid-19 fully restrictive lockdown.

Insomnia is the most frequent sleep disorder and a public health concern that increased during the Covid 19 pandemic. Fully restrictive lockdowns during Covid are interesting periods to examine the impact of environmental and behavioural changes on the emergence of insomnia symptoms. In this cross-sectional study we aimed to (1) determine the main factors associated with insomnia symptoms during a Covid-19 fully restrictive lockdown examining the associated daily life alterations and (2) create a predictive model of insomnia symptoms. We used the data drawn from the "Covid-RythmE" study that reached volunteers from the general French population through an online survey during the last 2 weeks of the 2 month full lockdown. Associations with insomnia symptoms were tested and significant associations were entered in a Backward Stepwise Logistic Regression (BSLR) to assess the best combination to classify individuals with or without insomnia symptoms. From the 1624 participants, 50.64% suffered from mild to severe insomnia symptoms as assessed by the ISI. The best combination for explaining insomnia symptoms with 74.26% of accuracy included: age (OR = 1.15), females (OR = 1.26), smaller home sizes (OR = 0.77), environmental noises (OR = 1.59), anxiety symptoms (OR = 1.24), depressive symptoms (OR = 1.15), regularity of sleep-wake schedules (OR = 1.25), exposure to screen during the morning (OR = 1.13), and LED light during the evening (OR = 1.17). Thus, lifestyle schedule and exposure to natural synchronizers such as light, are primordial in considering in insomnia physiopathology, prevention and treatment, as well as the associated mental health status.

Biosensors for the Rapid Detection of Cardiovascular Biomarkers of Vital Interest: Needs, Analysis and Perspectives.

We have previously surveyed a panel of 508 physicians from around the world about which biomarkers would be relevant if obtained in a very short time frame, corresponding to emergency situations (life-threatening or not). The biomarkers that emerged from this study were markers of cardiovascular disease: troponin, D-dimers, and brain natriuretic peptide (BNP). Cardiovascular disease is a group of disorders affecting the heart and blood vessels. At the intersection of medicine, basic research and engineering, biosensors that address the need for rapid biological analysis could find a place of choice in the hospital or primary care ecosystem. Rapid, reliable, and inexpensive analysis with a multi-marker approach, including machine learning analysis for patient risk analysis, could meet the demand of medical teams. The objective of this opinion review, proposed by a multidisciplinary team of experts (physicians, biologists, market access experts, and engineers), is to present cases where a rapid biological response is indeed valuable, to provide a short overview of current biosensor technologies for cardiac biomarkers designed for a short result time, and to discuss existing market access issues.

Golgi Dysfunctions in Ciliopathies.

The Golgi apparatus (GA) is essential for intracellular sorting, trafficking and the targeting of proteins to specific cellular compartments. Anatomically, the GA spreads all over the cell but is also particularly enriched close to the base of the primary cilium. This peculiar organelle protrudes at the surface of almost all cells and fulfills many cellular functions, in particular during development, when a dysfunction of the primary cilium can lead to disorders called ciliopathies. While ciliopathies caused by loss of ciliated proteins have been extensively documented, several studies suggest that alterations of GA and GA-associated proteins can also affect ciliogenesis. Here, we aim to discuss how the loss-of-function of genes coding these proteins induces ciliary defects and results in ciliopathies.

Non-canonical glutamine transamination sustains efferocytosis by coupling redox buffering to oxidative phosphorylation.

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.

Narcolepsy Type 1: A Remitting Disease? An Unusual Case Report.

We describe the case of a male patient who was diagnosed with narcolepsy type 1 on the basis of sleep and wake symptoms, and the results of investigations including video-polysomnography, multiple sleep latency test, human leukocyte antigen status and orexin level in cerebrospinal fluid. During the first years after disease onset, the patient did not show any significant improvement despite treatment with a variety of stimulant and anti-cataplectic drugs. However, spontaneous remission of disease occurred after 15 years.

Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia.

Increased blood fibrocytes are associated with a poor prognosis in fibrotic lung diseases. We aimed to determine whether the percentage of circulating fibrocytes could be predictive of severity and prognosis during coronavirus disease 2019 (COVID-19) pneumonia. Blood fibrocytes were quantified by flow cytometry as CD45+/CD15-/CD34+/collagen-1+ cells in patients hospitalized for COVID-19 pneumonia. In a subgroup of patients admitted in an intensive care unit (ICU), fibrocytes were quantified in blood and bronchoalveolar lavage (BAL). Serum amyloid P (SAP), transforming growth factor-ß1 (TGF-ß1), CXCL12, CCL2, and FGF2 concentrations were measured. We included 57 patients in the hospitalized group (median age = 59 yr [23-87]) and 16 individuals as healthy controls. The median percentage of circulating fibrocytes was higher in the patients compared with the controls (3.6% [0.2-9.2] vs. 2.1% [0.9-5.1], P = 0.04). Blood fibrocyte count was lower in the six patients who died compared with the survivors (1.6% [0.2-4.4] vs. 3.7% [0.6-9.2], P = 0.02). Initial fibrocyte count was higher in patients showing a complete lung computed tomography (CT) resolution at 3 mo. Circulating fibrocyte count was decreased in the ICU group (0.8% [0.1-2.0]), whereas BAL fibrocyte count was 6.7% (2.2-15.4). Serum SAP and TGF-ß1 concentrations were increased in hospitalized patients. SAP was also increased in ICU patients. CXCL12 and CCL2 were increased in ICU patients and negatively correlated with circulating fibrocyte count. We conclude that circulating fibrocytes were increased in patients hospitalized for COVID-19 pneumonia, and a lower fibrocyte count was associated with an increased risk of death and a slower resolution of lung CT opacities.

Residual ground glass opacities three months after Covid-19 pneumonia correlate to alteration of respiratory function: The post Covid M3 study.

INTRODUCTION: Lung function in survivors of SARS-Co-V2 pneumonia is poorly known, but concern over the possibility of sequelae exists. METHODS: Retrospective study on survivors with confirmed infection and pneumonia on chest-CT. Correlations between PFT and residual radiologic anomalies at three months taking into account initial clinical and radiological severity and steroid use during acute phase. RESULTS: 137 patients (69 men, median age 59 (Q1 50; Q3 68), BMI 27.5 kg/m2 (25.1; 31.7)) were assessed. Only 32.9% had normal PFT, 75 had altered DLCO. Median (Q1; Q3) values were: VC 79 (66; 92) % pred, FEV1 81 (68; 89), TLC 78 (67; 85), DLCO 60 (44; 72), and KCO 89 (77; 105). Ground glass opacities (GGO) were present in 103 patients (75%), reticulations in 42 (30%), and fibrosis in 18 (13%). There were significantly lower FEV1 (p = 0.0089), FVC (p = 0.0010), TLC (p < 0.0001) and DLCO (p < 0.0001) for patients with GGO, lower TLC (p = 0.0913) and DLCO (p = 0.0181) between patients with reticulations and lower FVC (p = 0.0618), TLC (p = 0.0742) DLCO (p = 0.002) and KCO (p = 0.0114) between patients with fibrosis. Patients with initial ≥50% lung involvement had significantly lower FEV1 (p = 0.0019), FVC (p = 0.0033), TLC (p = 0.0028) and DLCO (p = 0.0003) compared to patients with ≤10%. There was no difference in PFT and residual CT lesions between patients who received steroids and those who did not. CONCLUSION: The majority of patients have altered PFT at three months, even in patients with mild initial disease, with significantly lower function in patients with residual CT lesions. Steroids do not seem to modify functional and radiological recovery. Long-term follow-up is needed.

Alteration of Diffusion Capacity After SARS-CoV-2 Infection: A Pathophysiological Approach.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has affected millions of people worldwide, and pneumonia affects 90% of patients. This raises the possibility of millions of people with altered lung function. Few data exist to date on pulmonary function after SARS-CoV-2 infection, but alteration of diffusion capacity of CO (D LCO) is the most frequently described abnormality. First, we present original data on lung function at 3 months after SARS-CoV-2 infection and discuss the effect of using European Coal and Steel Community (ECSC) or Global Lung Function Initiative (GLI) reference equations to diagnose diffusion capacity. Second, we review existing data on D LCO alteration after SARS-CoV-2 infection and discuss the implication of restrictive disorder in D LCO alteration. Last, we discuss the pathophysiology of D LCO alteration and try to disentangle vascular damage and fibrosis.

Accuracy of Smart Scales on Weight and Body Composition: Observational Study.

BACKGROUND: Smart scales are increasingly used at home by patients to monitor their body weight and body composition, but scale accuracy has not often been documented. OBJECTIVE: The goal of the research was to determine the accuracy of 3 commercially available smart scales for weight and body composition compared with dual x-ray absorptiometry (DEXA) as the gold standard. METHODS: We designed a cross-sectional study in consecutive patients evaluated for DEXA in a physiology unit in a tertiary hospital in France. There were no exclusion criteria except patient declining to participate. Patients were weighed with one smart scale immediately after DEXA. Three scales were compared (scale 1: Body Partner [Téfal], scale 2: DietPack [Terraillon], and scale 3: Body Cardio [Nokia Withings]). We determined absolute error between the gold standard values obtained from DEXA and the smart scales for body mass, fat mass, and lean mass. RESULTS: The sample for analysis included 53, 52, and 48 patients for each of the 3 tested smart scales, respectively. The median absolute error for body weight was 0.3 kg (interquartile range [IQR] -0.1, 0.7), 0 kg (IQR -0.4, 0.3), and 0.25 kg (IQR -0.10, 0.52), respectively. For fat mass, absolute errors were -2.2 kg (IQR -5.8, 1.3), -4.4 kg (IQR -6.6, 0), and -3.7 kg (IQR -8.0, 0.28), respectively. For muscular mass, absolute errors were -2.2 kg (IQR -5.8, 1.3), -4.4 kg (IQR -6.6, 0), and -3.65 kg (IQR -8.03, 0.28), respectively. Factors associated with fat mass measurement error were weight for scales 1 and 2 (P=.03 and P<.001, respectively), BMI for scales 1 and 2 (P=.034 and P<.001, respectively), body fat for scale 1 (P<.001), and muscular and bone mass for scale 2 (P<.001 for both). Factors associated with muscular mass error were weight and BMI for scale 1 (P<.001 and P=.004, respectively), body fat for scales 1 and 2 (P<.001 for both), and muscular and bone mass for scale 2 (P<.001 and P=.002, respectively). CONCLUSIONS: Smart scales are not accurate for body composition and should not replace DEXA in patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03803098; https://clinicaltrials.gov/ct2/show/NCT03803098.

Knowledge self-monitoring, efficiency, and determinants of self-confidence statement in multiple choice questions in medical students.

BACKGROUND: Multiple-choice question (MCQ) tests are commonly used to evaluate medical students, but they do not assess self-confidence nor penalize lucky guess or harmful behaviors. Based on a scoring method according to the appropriateness of confidence in answers, the study aimed at assessing knowledge self-monitoring and efficiency, and the determinants of self-confidence. METHODS: A cross-sectional study of 842 s- and third-year medical students who were asked to state their level of confidence (A: very confident, B: moderately confident and C: not confident) during 12 tests (106,806 events). A bonus was applied if the level of confidence matched with the correctness of the answer, and a penalty was applied in the case of inappropriate confidence. RESULTS: Level A was selected more appropriately by the top 20% students whereas level C was selected more appropriately by the lower 20% students. Efficiency of higher-performing students was higher when correct (among correct answers, rate of A statement), but worse when incorrect compared to the bottom 20% students (among incorrect answers, rate of C statement). B and C statements were independently associated with female and male gender, respectively (OR for male vs female = 0.89 [0.82-0.96], p = 0.004, for level B and 1.15 [1.01-1.32], p = 0.047, for level C). CONCLUSION: While both addressing the gender confidence gap, knowledge self-monitoring might improve awareness of students' knowledge whereas efficiency might evaluate appropriate behavior in clinical practice. These results suggest differential feedback during training in higher versus lower-performing students, and potentially harmful behavior in decision-making during clinical practice in higher-performing students.