Childhood asthma outcomes during the COVID-19 pandemic: Findings from the PeARL multi-national cohort.

BACKGROUND: The interplay between COVID-19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID-19 pandemic on childhood asthma outcomes. METHODS: The PeARL multinational cohort included 1,054 children with asthma and 505 non-asthmatic children aged between 4 and 18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID-19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control. RESULTS: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks, and hospitalizations due to asthma, in comparison with the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits, or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. CONCLUSION: Childhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.

Silent Cerebral Small-Vessel Disease Is Twice as Prevalent in Middle-Aged Individuals With Well-Controlled, Combination Antiretroviral Therapy-Treated Human Immunodeficiency Virus (HIV) Than in HIV-Uninfected Individuals.

Background: Silent cerebral small-vessel disease (CSVD) is defined as white matter hyperintensities, silent brain infarction, or microbleeds. CSVD is responsible for future vascular events, cognitive impairment, frailty, and shorter survival. CSVD prevalence among middle-aged people living with well-controlled human immunodeficiency virus (HIV) infection (PLHIV) is unknown. Methods: The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) EP51 Microvascular Brain Retina and Kidney Study (MicroBREAK; NCT02082574) is a cross-sectional study with prospective enrollment of treated PLHIV, ≥50 years old with viral load controlled for ≥12 months, and frequency age- and sex-matched HIV-uninfected controls (HUCs). It was designed to estimate CSVD prevalence on 3T magnetic resonance imaging (3D fluid-attenuated inversion recovery, transversal T2-weighted gradient-echo imaging and diffusion-weighted imaging), as diagnosed by 2 blinded neuroradiologists. A logistic regression model was used to assess the impact of HIV on CSVD after adjustment for traditional risk factors. Results: Between June 2013 and May 2016, 456 PLHIV and 154 HUCs were recruited. Median age was 56 and 58 years, respectively (P = .001), among whom 84.9% and 77.3%, respectively (P = .030), were men. CSVD was detected in 51.5% of PLHIV and 36.4% of HUCs with an adjusted odds ratio (aOR) of 2.3. The HIV impact differed according to age, with aOR values of 5.3, 3.7, and 1.0 for age groups <54, 54-60, and >60 years, respectively (P = .022). Older age, hypertension, and lower CD4 cell count nadir were independently associated with a higher risk of CSVD among PLHIV. Conclusions: HIV is an independent risk factor for CSVD. Despite sustained immunovirological control, the CSVD prevalence was twice as high among middle-aged PLHIV than HUCs. Clinical Trials Registration: NCT02082574.

Magnetic resonance post-contrast vascular hyperintensities at 3 T: a new highly sensitive sign of vascular occlusion in acute ischaemic stroke.

BACKGROUND: Magnetic resonance imaging (MRI) is the diagnostic cornerstone for precisely identifying acute ischaemic strokes and locating vascular occlusions, especially since mechanical thrombectomy has become a reference treatment. We observed that a post-contrast three-dimensional turbo-spin-echo T1-weighted sequence showed striking post-contrast vascular hyperintensities (PCVH) in ischaemic territories. We aimed to evaluate the prevalence and the meaning of this finding. METHODS: This retrospective single centre study included 130 consecutive patients admitted for acute ischaemic stroke with a 3-T MRI performed in the first 12 h of symptom onset from September 2014 through September 2016. Two neuroradiologists blinded to clinical data analysed the first MRI assessments. The association between PCVH and clinical, radiological and follow-up findings was assessed, as well as inter- and intra-observer agreements. RESULTS: Of 130 patients, 105 (81%) had PCVH in the ischaemic territory. PCVH were associated with the presence of thrombus on susceptibility weighted imaging (p < 0.0001) and vascular occlusions on MR angiography (p < 0.0001). All patients with a visible thrombus had PCVH closely surrounding the clot. PCVH were associated with higher initial (p < 0.01) and follow-up (p < 0.01) National Institutes of Health Stroke Scale score, and higher mRS score (p < 0.05). Thrombectomy was the reference treatment for all patients with arterial occlusions. Inter- and intra-observer agreements for the detection of PCVH were excellent (κ = 0.95 and κ = 0.91, respectively). CONCLUSIONS: PCVH during acute strokes are a striking sensitive and reproducible tool for diagnosing and locating vascular occlusions. It may help triage patients who can benefit from thrombectomy. KEY POINTS: • Post-contrast vascular hyperintensities (PCVH) are a sensitive MR finding in acute stroke • PCVH are strongly associated with the presence and location of arterial occlusions • Inter- and intra-observer agreements for the detection of PCVH are excellent • PCVH are visible even in the case of significant motion artefacts • PCVH may help triage patients who can benefit from mechanical thrombectomy.

Co-Infection of Mosquitoes with Chikungunya and Dengue Viruses Reveals Modulation of the Replication of Both Viruses in Midguts and Salivary Glands of Aedes aegypti Mosquitoes.

Arthropod-borne virus (arbovirus) infections cause several emerging and resurgent infectious diseases in humans and animals. Chikungunya-affected areas often overlap with dengue-endemic areas. Concurrent dengue virus (DENV) and chikungunya virus (CHIKV) infections have been detected in travelers returning from regions of endemicity. CHIKV and DENV co-infected Aedes albopictus have also been collected in the vicinity of co-infected human cases, emphasizing the need to study co-infections in mosquitoes. We thus aimed to study the pathogen-pathogen interaction involved in these co-infections in DENV/CHIKV co-infected Aedes aegypti mosquitoes. In mono-infections, we detected CHIKV antigens as early as 4 days post-virus exposure in both the midgut (MG) and salivary gland (SG), whereas we detected DENV serotype 2 (DENV-2) antigens from day 5 post-virus exposure in MG and day 10 post-virus exposure in SG. Identical infection rates were observed for singly and co-infected mosquitoes, and facilitation of the replication of both viruses at various times post-viral exposure. We observed a higher replication for DENV-2 in SG of co-infected mosquitoes. We showed that mixed CHIKV and DENV infection facilitated viral replication in Ae. aegypti. The outcome of these mixed infections must be further studied to increase our understanding of pathogen-pathogen interactions in host cells.

Physical Sequestration of Bacillus anthracis in the Pulmonary Capillaries in Terminal Infection.

The lung is the terminal target of Bacillus anthracis before death, whatever the route of infection (cutaneous, inhalational, or digestive). During a cutaneous infection in absence of toxins, we observed encapsulated bacteria colonizing the alveolar capillary network, bacteria and hemorrhages in alveolar and bronchiolar spaces, and hypoxic foci in the lung (endothelial cells) and brain (neurons and neuropil). Circulating encapsulated bacteria were as chains of approximately 13 µm in length. Bacteria of such size were immediately trapped within the lung capillary network, but bacteria of shorter length were not. Controlling lung-targeted pathology would be beneficial for anthrax treatment.

Microtubule-associated proteins 1 (MAP1) promote human immunodeficiency virus type I (HIV-1) intracytoplasmic routing to the nucleus.

After cell entry, HIV undergoes rapid transport toward the nucleus using microtubules and microfilaments. Neither the cellular cytoplasmic components nor the viral proteins that interact to mediate transport have yet been identified. Using a yeast two-hybrid screen, we identified four cytoskeletal components as putative interaction partners for HIV-1 p24 capsid protein: MAP1A, MAP1S, CKAP1, and WIRE. Depletion of MAP1A/MAP1S in indicator cell lines and primary human macrophages led to a profound reduction in HIV-1 infectivity as a result of impaired retrograde trafficking, demonstrated by a characteristic accumulation of capsids away from the nuclear membrane, and an overall defect in nuclear import. MAP1A/MAP1S did not impact microtubule network integrity or cell morphology but contributed to microtubule stabilization, which was shown previously to facilitate infection. In addition, we found that MAP1 proteins interact with HIV-1 cores both in vitro and in infected cells and that interaction involves MAP1 light chain LC2. Depletion of MAP1 proteins reduced the association of HIV-1 capsids with both dynamic and stable microtubules, suggesting that MAP1 proteins help tether incoming viral capsids to the microtubular network, thus promoting cytoplasmic trafficking. This work shows for the first time that following entry into target cells, HIV-1 interacts with the cytoskeleton via its p24 capsid protein. Moreover, our results support a role for MAP1 proteins in promoting efficient retrograde trafficking of HIV-1 by stimulating the formation of stable microtubules and mediating the association of HIV-1 cores with microtubules.

Phenotypic clustering: a novel method for microglial morphology analysis.

BACKGROUND: Microglial cells are tissue-resident macrophages of the central nervous system. They are extremely dynamic, sensitive to their microenvironment and present a characteristic complex and heterogeneous morphology and distribution within the brain tissue. Many experimental clues highlight a strong link between their morphology and their function in response to aggression. However, due to their complex "dendritic-like" aspect that constitutes the major pool of murine microglial cells and their dense network, precise and powerful morphological studies are not easy to realize and complicate correlation with molecular or clinical parameters. METHODS: Using the knock-in mouse model CX3CR1(GFP/+), we developed a 3D automated confocal tissue imaging system coupled with morphological modelling of many thousands of microglial cells revealing precise and quantitative assessment of major cell features: cell density, cell body area, cytoplasm area and number of primary, secondary and tertiary processes. We determined two morphological criteria that are the complexity index (CI) and the covered environment area (CEA) allowing an innovative approach lying in (i) an accurate and objective study of morphological changes in healthy or pathological condition, (ii) an in situ mapping of the microglial distribution in different neuroanatomical regions and (iii) a study of the clustering of numerous cells, allowing us to discriminate different sub-populations. RESULTS: Our results on more than 20,000 cells by condition confirm at baseline a regional heterogeneity of the microglial distribution and phenotype that persists after induction of neuroinflammation by systemic injection of lipopolysaccharide (LPS). Using clustering analysis, we highlight that, at resting state, microglial cells are distributed in four microglial sub-populations defined by their CI and CEA with a regional pattern and a specific behaviour after challenge. CONCLUSIONS: Our results counteract the classical view of a homogenous regional resting state of the microglial cells within the brain. Microglial cells are distributed in different defined sub-populations that present specific behaviour after pathological challenge, allowing postulating for a cellular and functional specialization. Moreover, this new experimental approach will provide a support not only to neuropathological diagnosis but also to study microglial function in various disease models while reducing the number of animals needed to approach the international ethical statements.

Shigella impairs T lymphocyte dynamics in vivo.

The Gram-negative enteroinvasive bacterium Shigella flexneri is responsible for the endemic form of bacillary dysentery, an acute rectocolitis in humans. S. flexneri uses a type III secretion system to inject effector proteins into host cells, thus diverting cellular functions to its own benefit. Protective immunity to reinfection requires several rounds of infection to be elicited and is short-lasting, suggesting that S. flexneri interferes with the priming of specific immunity. Considering the key role played by T-lymphocyte trafficking in priming of adaptive immunity, we investigated the impact of S. flexneri on T-cell dynamics in vivo. By using two-photon microscopy to visualize bacterium-T-cell cross-talks in the lymph nodes, where the adaptive immunity is initiated, we provide evidence that S. flexneri, via its type III secretion system, impairs the migration pattern of CD4(+) T cells independently of cognate recognition of bacterial antigens. We show that bacterial invasion of CD4(+) T lymphocytes occurs in vivo, and results in cell migration arrest. In the absence of invasion, CD4(+) T-cell migration parameters are also dramatically altered. Signals resulting from S. flexneri interactions with subcapsular sinus macrophages and dendritic cells, and recruitment of polymorphonuclear cells are likely to contribute to this phenomenon. These findings indicate that S. flexneri targets T lymphocytes in vivo and highlight the role of type III effector secretion in modulating host adaptive immune responses.

Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by CAG expansion in the huntingtin gene, which adds a homopolymeric tract of polyglutamine (polyQ) to the encoded protein leading to the formation of toxic aggregates. Despite rapidly accumulating evidences supporting a role for intercellular transmission of protein aggregates, little is known about whether and how huntingtin (Htt) misfolding progresses through the brain. It has been recently reported that synthetic polyQ peptides and recombinant fragments of mutant Htt are readily internalized in cell cultures and able to seed polymerization of a reporter wild-type Htt. However, there is no direct evidence of aggregate transfer between cells and the mechanism has not been explored. By expressing recombinant fragments of mutant Htt in neuronal cells and in primary neurons, we found that aggregated fragments formed within one cell spontaneously transfer to neighbors in cell culture. We demonstrate that the intercellular spreading of the aggregates requires cell-cell contact and does not occur upon aggregate secretion. Interestingly, we found that the expression of mutant, but not wild-type Htt fragments, increases the number of tunneling nanotubes, which in turn provide an efficient mechanism of transfer.

Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis.

OBJECTIVE: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation. METHODS: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared. RESULTS: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients. CONCLUSIONS: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.

Virulent Shigella flexneri affects secretion, expression, and glycosylation of gel-forming mucins in mucus-producing cells.

Mucin glycoproteins are secreted in large amounts by the intestinal epithelium and constitute an efficient component of innate immune defenses to promote homeostasis and protect against enteric pathogens. In this study, our objective was to investigate how the bacterial enteropathogen Shigella flexneri, which causes bacillary dysentery, copes with the mucin defense barrier. We report that upon in vitro infection of mucin-producing polarized human intestinal epithelial cells, virulent S. flexneri manipulates the secretion of gel-forming mucins. This phenomenon, which is triggered only by virulent strains, results in accumulation of mucins at the cell apical surface, leading to the appearance of a gel-like structure that favors access of bacteria to the cell surface and the subsequent invasion process. We identify MUC5AC, a gel-forming mucin, as a component of this structure. Formation of this gel does not depend on modifications of electrolyte concentrations, induction of trefoil factor expression, endoplasmic reticulum stress, or response to unfolded proteins. In addition, transcriptional and biochemical analyses of infected cells reveal modulations of mucin gene expression and modifications of mucin glycosylation patterns, both of which are induced by virulent bacteria in a type III secretion system-dependent manner. Thus, S. flexneri has developed a dedicated strategy to alter the mucus barrier by targeting key elements of the gel-forming capacity of mucins: gene transcription, protein glycosylation, and secretion.

Newly visualized fibrillar collagen scaffolds dictate Entamoeba histolytica invasion route in the human colon.

The extracellular matrix (ECM) and its role in the outcome of infectious diseases have been poorly investigated. In this study, we determined the impact of the collagen fibres architecture on the invasive process of the enteric parasite Entamoeba histolytica. The behaviour of E. histolytica wild-type and silenced for the cysteine protease A5 (CP-A5) were compared on a three-dimensional collagen matrix and within human colon fragments for fibrillar collagen cleavage and migration. The interstitial collagen fibres within the connective tissue of the human colon, visualized by multiphoton and second harmonic generation signals imaging, presented a dense scaffold at the subepithelial level and a loose meshwork within the chorion. To penetrate the tissue, E. histolytica migrated on the dense scaffold that remained intact, reached the crypt of Lieberkhün, migrated along and then disorganized the loose scaffold to escape into the mucosa. Interestingly, in vitro, CP-A5 was not required for collagenase activity and migration through the matrix but was necessary within the tissue environment for collagen meshwork remodelling and subsequent invasion. The data point out that further step of invasion relay with ECM destruction that requires human components induced or activated in the presence of CP-A5.

Factors associated with the time to recover adequate nutrition in infants hospitalized for bronchiolitis, a French retrospective study.

BACKGROUND: Inadequate feeding is a frequent reason for hospital referring in infants with bronchiolitis and may leads to unnecessary prolonged hospitalization. Our objective was to identify the factors associated with the time to recover adequate feeding (TRAF) and the hospital length of stay (LOS) in infants hospitalized for bronchiolitis. METHODS: We conducted a single-center retrospective study including infants less than 12 months hospitalized for bronchiolitis at Le Havre Hospital (France) between September 2018 and February 2021. A multivariate logistic regression model was computed to investigate the factors associated with (1) TRAF, and (2) LOS. RESULTS: 268 infants were included to assess the TRAF and 478 infants to assess the LOS. The median age was 3.2 months (1.6-5.4) and the sex ratio M/F was 11/20. The use of accessory muscles, nutritional support, and RR ≥70/min or <30/min or apnea are associated (OR=1.5), from virtually no association (OR=1.0) to a significant positive association (OR=2.6) with the TRAF. Intense use of accessory muscles (OR=3.9; 95% CI 1.6-10.4) and "severe" clinical condition (OR=2.8; 95% CI 1.7-4.8) at admission, O2 supplementation (OR=2.0; 95% CI 1.3-3.1) were significantly related to prolonged LOS in the multivariate analysis. CONCLUSIONS: The clinical severity on admission may be related to the TRAF, ranging from none to significant. Other known factors such as oxygen therapy and the new clinical severity scale proposed by the latest French guidelines appeared to be related to the LOS in this work. Further studies are needed to highlight these factors.

Contribution of the glycolytic flux and hypoxia adaptation to efficient biofilm formation by Candida albicans.

The fungal pathogen Candida albicans forms therapeutically challenging biofilms on biomedical implants. Using a transcript profiling approach genes whose expression is favoured upon biofilm growth compared with planktonic growth have been previously identified. Knock-out mutants for 38 of these genes were constructed, six of which showed a specific defect in biofilm formation. Among these genes, TYE7 that encodes a transcriptional activator of glycolytic genes in planktonic and biofilm growth conditions was identified as being required for the cohesiveness of biofilms. Biofilms formed by the tye7Δ knock-out mutant showed a hyperfilamentous morphology, and growth of this mutant on solid medium under hypoxia was also associated with the production of hyphae. Similar to TYE7 inactivation, inhibition of glycolysis or ATP synthesis using oxalate or an uncoupler, respectively, triggered morphogenesis when a wild-type strain was grown under hypoxia. These treatments also induced the formation of weakly cohesive, hyper-filamentous biofilms by a wild-type strain. Our data indicate that a hypoxic environment is generated within C. albicans biofilms and that continued biofilm development requires a Tye7p-dependent upregulation of glycolytic genes necessary to adapt to hypoxia and prevent uncontrolled hyphal formation. Thus, adaptation to hypoxia is an integral component of biofilm formation in C. albicans.

Oxygen uptake kinetics during treadmill walking in adolescents with clinically stable cystic fibrosis.

BACKGROUND: Oxygen uptake (V̇O2) kinetics have been shown to be slowed in adolescents with cystic fibrosis (CF) during heavy-intensity cycling and maximal exercise testing. OBJECTIVES: This study investigated V̇O2 kinetics in adolescents with CF compared to control adolescents (CON) during a treadmill-walking exercise. METHODS: Eight adolescents with CF and mild-to-moderate pulmonary obstruction (5 girls; 13.1 ± 2.5 years; FEV1 67.8 ± 21.4%) and 18 CON adolescents (10 girls; 13.8 ± 1.8 years) were recruited. Pulmonary gas exchange and ventilation were measured during a single transition of 10 min of treadmill walking and a 5 min seated recovery period. Participant's walking speed was determined during a one-minute self-paced walking task along a 50-m corridor. A six-parameter, non-linear regression model was used to describe the changes in V̇O2 function during the treadmill walking and recovery, with monoexponential curve fitting used to describe the mean response time (MRT1) at the onset of exercise, and the half-life (T1/2V̇O2) at the offset of exercise. V̇O2 baseline and amplitude, minute ventilation and respiratory equivalents were recorded. RESULTS: V̇O2 kinetics were slower in CF group compared to CON group during the treadmill walking with a greater MRT1 (32 ± 14 s vs 21 ± 16 s; p = .04, effect size = 0.75). The T1/2V̇O2 was prolonged during recovery in CF group compared to CON group (86 ± 24 s vs 56 ± 22 s; p = .04, effect size = 1.31). The mean VE/V̇CO2 during exercise was the only parameter significantly greater in CF group compared to CON group (32.9 ± 2.3 vs 29.0 ± 2.4; p < .01, effect size = 1.66). CONCLUSION: V̇O2 kinetics were found to be slowed in adolescents with CF during treadmill walking.

Effects of Exercise Training on Peripheral Muscle Strength in Children and Adolescents with Cystic Fibrosis: A Meta-Analysis.

Background: Exercise training is a cornerstone of care for people with cystic fibrosis (pwCF); it improves exercise capacity and health-related physical fitness, but no meta-analysis has investigated its effects on muscle function in young pwCF. The objective of this meta-analysis was to assess the effects of exercise on peripheral muscle strength in young pwCF. Methods: An electronic search was conducted in four databases (Pubmed, Science Direct, CENTRAL, and PEDRO) from their inception to July 2022. Grey literature databases (OpenGrey, the European Respiratory Society, the American Thoracic Society, and the European Cystic Fibrosis Society) were also consulted. Randomized controlled trials comparing any type of exercise with standard care in young pwCF (5 to 19 years old) were included. Two authors independently selected the relevant studies, extracted the data, assessed the risk of bias (using the Rob2 tool), and rated the quality of the evidence. Results: Ten studies met the inclusion criteria, involving 359 pwCF. Exercise training improved both lower and upper limb muscle strength (SMD 1.67 (95%CI 0.80 to 2.53), I2 = 76%, p < 0.001 and SMD 1.30 (95%CI 0.66 to 1.93), I2 = 62%, p < 0.001, respectively). Improvements were also reported in muscle mass and maximal oxygen consumption. Results regarding physical activity levels were inconclusive. The overall risk of bias for the primary outcome was high. Conclusions: Exercise training may have a positive effect on peripheral muscle strength in young pwCF. The evidence quality is very low and the level of certainty is poor. There is a need for high-quality randomized controlled studies to confirm these results.

Panda Unit, a Mother-Baby Unit Nested in a Neonatal Care Service.

The PANDA unit is a full-time mother-baby hospitalization unit based on an original model of care for vulnerable dyads. It is located within a neonatal unit allowing tripartite care (perinatal psychiatry, neonatology and post-natal care). It thus differs from traditional mother-baby units in its close links with the other perinatal care actors, allowing comprehensive health and mental health care in the immediate post-partum period. Patients admitted to the Panda Unit may have been referred during the antenatal period or taken into care in an emergency if the mother's clinical condition requires it, in the aftermath of childbirth. During their stay, the dyads are evaluated daily by a perinatal psychiatrist. This includes assessment of maternal clinical state, the newborn's development and the quality of mother-infant interactions. During the first 6 months of use, 24 dyads have benefited from PANDA care. Three women among 5 were admitted during the antenatal period and almost one-third were aged under 21. The first primary diagnosis during the antepartum was major depressive disorder, two-fold that of personality disorder or bipolar disorder alone. At the end of PANDA stay, close to 3 women among 4 were back to their home with their child, and an out-of-home placement was mandated for 4 infants. PANDA unit is a step toward continuous and comprehensive integrative care. The mother and baby do not leave the maternity ward, and management of mother, baby, and their interactions can start immediately after birth. Considering the importance of the first months of life in the establishment of fundamental links and bonding, PANDA offers an innovative opportunity for what we hope will be both therapeutic and preventive for at-risk dyads. The detection, and ultimately prevention and management of risk of abuse and neglect is another major challenge that this unit hopes to address from the very beginning.

Toll-like receptor 3 (TLR3) plays a major role in the formation of rabies virus Negri Bodies.

Human neurons express the innate immune response receptor, Toll-like receptor 3 (TLR3). TLR3 levels are increased in pathological conditions such as brain virus infection. Here, we further investigated the production, cellular localisation, and function of neuronal TLR3 during neuronotropic rabies virus (RABV) infection in human neuronal cells. Following RABV infection, TLR3 is not only present in endosomes, as observed in the absence of infection, but also in detergent-resistant perinuclear inclusion bodies. As well as TLR3, these inclusion bodies contain the viral genome and viral proteins (N and P, but not G). The size and composition of inclusion bodies and the absence of a surrounding membrane, as shown by electron microscopy, suggest they correspond to the previously described Negri Bodies (NBs). NBs are not formed in the absence of TLR3, and TLR3(-/-) mice -- in which brain tissue was less severely infected -- had a better survival rate than WT mice. These observations demonstrate that TLR3 is a major molecule involved in the spatial arrangement of RABV-induced NBs and viral replication. This study shows how viruses can exploit cellular proteins and compartmentalisation for their own benefit.

Measurement properties of the one-minute sit-to-stand test in children and adolescents with cystic fibrosis: A multicenter randomized cross-over trial.

BACKGROUND: Functional exercise capacity assessment is recommended in children with cystic fibrosis (CF). The six-minute walk test (6MWT) is a valid evaluation of exercise capacity but can be technically complex. Inversely, the sit-to-stand test (STST) is a simple method to evaluate exercise capacity, and is validated in healthy children and adults with CF. This study aimed to evaluate STST measurement properties in children and adolescents with CF. METHODS: In this multicenter study, children with CF (6 to 18 years) performed two iterations of both the STST and the 6MWT in a randomized order. Criterion validity was determined by assessing correlations between STST repetitions and 6MWT distance (6MWD). Intra-rater reliability, test-retest repeatability, mean bias and limits of agreement were also assessed. Relationships with other outcomes (i.e. respiratory and quadriceps muscle strength) and cardio-respiratory responses were analysed for both tests. RESULTS: Thirty-six children with CF were included (mean age 12.0 ±3.5 years and FEV1 95.8 ±25.0%). On average, 39.6 ±10.5 repetitions were performed during the STST and mean 6MWD was 596.0 ±102.6 meters. STST number of repetitions was significantly correlated with 6MWD (r = 0.48; p<0.01). Both tests had very good intra-rater reliability (ICCSTST = 0.91 (95%CI 0.76-0.96) and ICC6MWT = 0.94 (95%CI 0.85-0.97)), and a significant test-retest learning effect. The number of STST repetitions was not correlated with quadriceps or respiratory muscle strength test, and the STST induced fewer cardio-respiratory responses than the 6MWT. CONCLUSIONS: The STST is an easy-to-use functional test with moderate criterion validity when compared to the 6MWT in children with CF, probably because both tests measure different components of functional exercise capacity. The STST is useful when the 6MWT is unfeasible, however further investigations are required to explore the clinical implications of STST results in children with CF. CLINICAL TRIAL REGISTRATION: NCT03069625.