Exploring the implementation and underlying mechanisms of centralized referral systems to access specialized health services in Quebec.

BACKGROUND: In 2016, Quebec, a Canadian province, implemented a program to improve access to specialized health services (Accès priorisé aux services spécialisés (APSS)), which includes single regional access points for processing requests to such services via primary care (Centre de répartition des demandes de services (CRDS)). Family physicians fill out and submit requests for initial consultations with specialists using a standardized form with predefined prioritization levels according to listed reasons for consultations, which is then sent to the centralized referral system (the CRDS) where consultations with specialists are assigned. We 1) described the APSS-CRDS program in three Quebec regions using logic models; 2) compared similarities and differences in the components and processes of the APSS-CRDS models; and 3) explored contextual factors influencing the models' similarities and differences. METHODS: We relied on a qualitative study to develop logic models of the implemented APSS-CRDS program in three regions. Semi-structured interviews with health administrators (n = 9) were conducted. The interviews were analysed using a framework analysis approach according to the APSS-CRDS's components included in the initially designed program, Mitchell and Lewis (2003)'s logic model framework, and Chaudoir and colleagues (2013)'s framework on contextual factors' influence on an innovation's implementation. RESULTS: Findings show the APSS-CRDS program's regional variability in the implementation of its components, including its structure (centralized/decentralized), human resources involved in implementation and operation, processes to obtain specialists' availability and assess/relay requests, as well as monitoring methods. Variability may be explained by contextual factors' influence, like ministerial and medical associations' involvement, collaborations, the context's implementation readiness, physician practice characteristics, and the program's adaptability. INTERPRETATION: Findings are useful to inform decision-makers on the design of programs like the APSS-CRDS, which aim to improve access to specialists, the essential components for the design of these types of interventions, and how contextual factors may influence program implementation. Variability in program design is important to consider as it may influence anticipated effects, a next step for the research team. Results may also inform stakeholders should they wish to implement similar programs to increase access to specialized health services via primary care.

Acetylene-based frequency stabilization of a laser system for potassium laser cooling.

We demonstrate a laser frequency stabilization technique for laser cooling of potassium atoms, based on saturated absorption spectroscopy in the C-Band optical telecommunication window, using ro-vibrational transitions of the acetylene molecule (12C2H2). We identified and characterized several molecular lines, which allow to address each of the potassium D2 (767 nm) and D1 (770 nm) cooling transitions, thanks to a high-power second harmonic generation (SHG) stage. We successfully used this laser system to cool the 41K isotope of potassium in a 2D-3D Magneto-Optical Traps setup.

Brivaracetam: First Canadian Experience in an Intractable Epilepsy Population.

OBJECTIVE: To evaluate the effectiveness and tolerability of brivaracetam (BRV) in a refractory epilepsy population in an outpatient clinical setting. METHODS: Retrospective medical information system review and self-report questionnaire for all patients treated with BRV until the end of 2017. RESULTS: Thirty-eight patients were included, 73.7% female and mean age 36.2. The mean number of antiepileptic drugs (AEDs) for previous use was 8.9, and for current use was 2.5. Mean seizure frequency in the last 3 months was 12 per month. At 3, 6, 12, and 15 months, the 50% responder rates were 36.1%, 32%, 41.2%, and 45.5%, respectively. Patients took BRV for a median duration of 8.25 months, ranging from 7 days to 60 months. Retention rate was 75.0%, 72.0%, 59.2%, and 47.9% at 3, 6, 12, and 15 months, respectively. Overall, the main reasons for discontinuation were adverse events (AEs) (52.3%), lack of efficacy (35.3%), or both (11.8%). The rate of total AEs was 60.5% according to medical records and 85.7% according to questionnaire, including mostly tiredness, psychiatric, and memory complaints. Psychiatric side effects occurred in 31.6% according to medical records and 47.4% according to questionnaire results, which is higher than previously reported and persisted throughout the study period. CONCLUSIONS: BRV appears to be a useful and safe add-on treatment, even in a very refractory group of patients. In this real-life clinical setting, psychiatric AEs were found at a higher rate than previously published.

Experimental Observation of a Time-Driven Phase Transition in Quantum Chaos.

We report the first experimental observation of the time-driven phase transition in a canonical quantum chaotic system, the quantum kicked rotor. The transition bears a firm analogy to a thermodynamic phase transition, with the time mimicking the temperature and the quantum expectation of the rotor's kinetic energy mimicking the free energy. The transition signals a sudden change in the system's memory behavior: before the critical time, the system undergoes chaotic motion in phase space and its memory of initial states is erased in the course of time; after the critical time, quantum interference enhances the probability for a chaotic trajectory to return to the initial state, and thus the system's memory is recovered.

Return to the Origin as a Probe of Atomic Phase Coherence.

We report on the observation of the coherent enhancement of the return probability ["enhanced return to the origin" (ERO)] in a periodically kicked cold-atom gas. By submitting an atomic wave packet to a pulsed, periodically shifted, laser standing wave, we induce an oscillation of ERO in time that is explained in terms of a periodic, reversible dephasing in the weak-localization interference sequences responsible for ERO. Monitoring the temporal decay of ERO, we exploit its quantum-coherent nature to quantify the decoherence rate of the atomic system.

Experimental Observation of Two-Dimensional Anderson Localization with the Atomic Kicked Rotor.

Dimension 2 is expected to be the lower critical dimension for Anderson localization in a time-reversal-invariant disordered quantum system. Using an atomic quasiperiodic kicked rotor-equivalent to a two-dimensional Anderson-like model-we experimentally study Anderson localization in dimension 2 and we observe localized wave function dynamics. We also show that the localization length depends exponentially on the disorder strength and anisotropy and is in quantitative agreement with the predictions of the self-consistent theory for the 2D Anderson localization.

Proteomic profiling of the TRAF3 interactome network reveals a new role for the ER-to-Golgi transport compartments in innate immunity.

Tumor Necrosis Factor receptor-associated factor-3 (TRAF3) is a central mediator important for inducing type I interferon (IFN) production in response to intracellular double-stranded RNA (dsRNA). Here, we report the identification of Sec16A and p115, two proteins of the ER-to-Golgi vesicular transport system, as novel components of the TRAF3 interactome network. Notably, in non-infected cells, TRAF3 was found associated with markers of the ER-Exit-Sites (ERES), ER-to-Golgi intermediate compartment (ERGIC) and the cis-Golgi apparatus. Upon dsRNA and dsDNA sensing however, the Golgi apparatus fragmented into cytoplasmic punctated structures containing TRAF3 allowing its colocalization and interaction with Mitochondrial AntiViral Signaling (MAVS), the essential mitochondria-bound RIG-I-like Helicase (RLH) adaptor. In contrast, retention of TRAF3 at the ER-to-Golgi vesicular transport system blunted the ability of TRAF3 to interact with MAVS upon viral infection and consequently decreased type I IFN response. Moreover, depletion of Sec16A and p115 led to a drastic disorganization of the Golgi paralleled by the relocalization of TRAF3, which under these conditions was unable to associate with MAVS. Consequently, upon dsRNA and dsDNA sensing, ablation of Sec16A and p115 was found to inhibit IRF3 activation and anti-viral gene expression. Reciprocally, mild overexpression of Sec16A or p115 in Hec1B cells increased the activation of IFNß, ISG56 and NF-κB -dependent promoters following viral infection and ectopic expression of MAVS and Tank-binding kinase-1 (TBK1). In line with these results, TRAF3 was found enriched in immunocomplexes composed of p115, Sec16A and TBK1 upon infection. Hence, we propose a model where dsDNA and dsRNA sensing induces the formation of membrane-bound compartments originating from the Golgi, which mediate the dynamic association of TRAF3 with MAVS leading to an optimal induction of innate immune responses.

Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307.

OBJECTIVE: To evaluate safety, tolerability, seizure frequency, and regional variations in treatment responses with the AMPA antagonist, perampanel, in a large extension study during up to 3 years of treatment. METHODS: Patients ≥ 12 years old with partial-onset seizures despite treatment with 1-3 antiepileptic drugs at baseline completed a perampanel phase III trial and entered extension study 307 (NCT00735397). Patients were titrated to 12 mg/day (or their individual maximum tolerated dose) during the blinded conversion period, followed by open-label maintenance. Exposure, safety (adverse events [AEs], vital signs, weight, electrocardiography [ECG], laboratory values) and seizure outcomes were analyzed; key measures were assessed by geographic regions. RESULTS: Among 1,216 patients, median exposure was 1.5 years (range 1 week to 3.3 years), with >300 patients treated for >2 years. Treatment retention was 58.5% at cutoff. AEs reported in ≥ 10% of patients were dizziness, somnolence, headache, fatigue, irritability, and weight increase. Only dizziness and irritability caused discontinuation in >1% of patients (3.9% and 1.3%, respectively). The only serious AEs reported in >1% of patients were epilepsy-related (convulsion, 3.0%; status epilepticus, 1.1%). No clinically relevant changes in vital signs, ECG or laboratory parameters were seen. After titration/conversion, responder rate and median percentage change from baseline in seizure frequency were stable: 46% for both measures at 9 months (in 980 patients with ≥ 9 months' exposure) and 58% and 60%, respectively, at 2 years (in the 337 patients with 2 years' exposure). Median percentage reduction in frequency of secondarily generalized (SG) seizures ranged from 77% at 9 months (N = 422) to 90% at 2 years (N = 141). Among the 694 patients with maintenance data ≥ 1 year, 5.3% were seizure-free for the entire year. SIGNIFICANCE: No new safety signals emerged during up to 3 years of perampanel exposure in 39 countries. Seizure responses remained stable, with marked reductions, particularly in SG seizures.

Optimisation and validation of a co-manipulated robot for brachytherapy procedure.

BACKGROUND: Low-dose rate brachytherapy is the referent treatment for early-stage prostate cancer and consists in manually inserting radioactive seeds within the organ to destroy tumorous cells. This treatment is inaccurate leading to side effects. Researchers developed robots to improve this technique. Despite ameliorating accuracy, they cannot be clinically used because of size and acceptability. Therefore, a 6-DOF parallel and co-manipulated robot is proposed to meet these requirements. METHODS: To fulfil the application requirements, a compact design was modelled. The robot's optimal dimensions were defined by establishing kinematics and implementing genetic algorithm. The robot's relevance was evaluated by measuring workspace and needle placement errors. RESULTS: The robot fits into a cube of 300 × 300 × 300 mm3 and provides a free-singularity workspace of 55 × 55 × 150 mm3 with a possible end-effector rotation of 15° and a needle placement error <3 mm. CONCLUSION: The results are promising and prove that our robot fulfils the application requirements and presents a beneficial alternative to the manual procedure.

Novel Staufen1 ribonucleoproteins prevent formation of stress granules but favour encapsidation of HIV-1 genomic RNA.

Human immunodeficiency virus type 1 (HIV-1) Gag selects for and mediates genomic RNA (vRNA) encapsidation into progeny virus particles. The host protein, Staufen1 interacts directly with Gag and is found in ribonucleoprotein (RNP) complexes containing vRNA, which provides evidence that Staufen1 plays a role in vRNA selection and encapsidation. In this work, we show that Staufen1, vRNA and Gag are found in the same RNP complex. These cellular and viral factors also colocalize in cells and constitute novel Staufen1 RNPs (SHRNPs) whose assembly is strictly dependent on HIV-1 expression. SHRNPs are distinct from stress granules and processing bodies, are preferentially formed during oxidative stress and are found to be in equilibrium with translating polysomes. Moreover, SHRNPs are stable, and the association between Staufen1 and vRNA was found to be evident in these and other types of RNPs. We demonstrate that following Staufen1 depletion, apparent supraphysiologic-sized SHRNP foci are formed in the cytoplasm and in which Gag, vRNA and the residual Staufen1 accumulate. The depletion of Staufen1 resulted in reduced Gag levels and deregulated the assembly of newly synthesized virions, which were found to contain several-fold increases in vRNA, Staufen1 and other cellular proteins. This work provides new evidence that Staufen1-containing HIV-1 RNPs preferentially form over other cellular silencing foci and are involved in assembly, localization and encapsidation of vRNA.

Experimental test of universality of the Anderson transition.

We experimentally test the universality of the Anderson three dimensional metal-insulator transition, using a quasiperiodic atomic kicked rotor. Nine sets of parameters controlling the microscopic details have been tested. Our observation indicates that the transition is of second order, with a critical exponent independent of the microscopic details; the average value 1.63±0.05 agrees very well with the numerically predicted value ν=1.58.

Perceptions on barriers, facilitators, and recommendations related to mental health service delivery during the COVID-19 pandemic in Quebec, Canada: a qualitative descriptive study.

BACKGROUND: There was an increase in self-reported mental health needs during the COVID-19 pandemic in Canada, with research showing reduced access to mental health services in comparison to pre-pandemic levels. This paper explores 1) barriers and facilitating factors associated with mental health service delivery via primary care settings during the first two pandemic waves in Quebec, Canada, and 2) recommendations to addressing these barriers. METHODS: A qualitative descriptive study design was used. Semi-structured interviews with 20 participants (health managers, family physicians, mental health clinicians) were conducted and coded using a thematic analysis approach. RESULTS: Barriers and facilitating factors were organized according to Chaudoir et al. (2013)'s framework of structural, organizational, provider- and patient-related, as well as innovation (technological modalities for service delivery) categories. Barriers included relocation of mental health staff to non-mental health related COVID-19 tasks (structural); mental health service interruption (organizational); mental health staff on preventive/medical leave (provider); the pandemic's effect on consultations (i.e., perceptions of increased demand) (patients); and challenges with the use of technological modalities (innovation). Facilitating factors included reinforcements to mental health care teams (structural); perceptions of reductions in wait times for mental health evaluations during the second wave due to diminished FP referrals in the first wave, as well as supports (i.e., management, private sector, mental health trained staff) for mental health service delivery (organizational); staff's mental health consultation practices (provider); and advantages in increasing the use of technological modalities in practice (innovation). CONCLUSIONS: To our knowledge, this is the first study to explore barriers and facilitating factors to mental health service delivery during the pandemic in Quebec, Canada. Some barriers identified were caused by the pandemic, such as the relocation of staff to non-mental health services and mental health service interruption. Offering services virtually seemed to facilitate mental health service delivery only for certain population groups. Recommendations related to building and strengthening human and technological capacity during the pandemic can inform mental health practices and policies to improve mental health service delivery in primary care settings and access to mental health services via access points.

Multicore fiber for cold-atomic cloud monitoring.

Thanks to an all solid core photonic crystal fiber (PCF) used as a multicore fiber, we propose and experimentally demonstrate what is to our knowledge a new optical detection scheme for the spontaneous emission collection of cold atoms. A Magneto-Optical Trap (MOT) is placed in front of a polished PCF end-face. As they display a higher optical index than the surrounding cladding silica, the 108 rods (equivalent to a 108 pixels camera) of this PCF are light guiding and behave like an array of detectors. Both global and local properties of the trapped atoms are probed. A MOT lifetime is reported. We also take advantage of the multi-core geometry for a real time detection of the center-of-mass motion of the atomic cloud.

Technical note: Correlation of respiratory motion between external patient surface and internal anatomical landmarks.

PURPOSE: Current respiratory motion monitoring devices used for motion synchronization in medical imaging and radiotherapy provide either 1D respiratory signal over a specific region or 3D information based on few external or internal markers. On the other hand, newer technology may offer the potential to monitor the entire patient external surface in real time. The main objective of this study was to assess the motion correlation between such an external patient surface and internal anatomical landmarks motion. METHODS: Four dimensional computed tomography (4D CT) volumes for ten patients were used in this study. Anatomical landmarks were manually selected in the thoracic region across the 4D CT datasets by two experts. The landmarks included normal structures as well as the tumor location. In addition, a distance map representing the entire external patient surface, which corresponds to surfaces acquired by a time of flight (ToF) camera or similar devices, was created by segmenting the skin of all 4D CT volumes using a thresholding algorithm. Finally, the correlation between the internal landmarks and external surface motion was evaluated for different regions (placement and size) throughout a patient's surface. RESULTS: Significant variability was observed in the motion of the different parts of the external patient surface. The larger motion magnitude was consistently measured in the central regions of the abdominal and the thoracic areas for the different patient datasets considered. The highest correlation coefficients were observed between the motion of these external surface areas and internal landmarks such as the diaphragm and mediastinum structures as well as the tumor location landmarks (0.8 +/- 0.18 and 0.72 +/- 0.12 for the abdominal and the thoracic regions, respectively). Worse correlation was observed when one considered landmarks not significantly influenced by respiratory motion such as the apex and the sternum. CONCLUSIONS: There were large differences in the motion correlation observed considering different regions of interest placed over a patients' external surface and internal anatomical landmarks. The positioning of current devices used for respiratory motion synchronization may reduce such correlation by averaging the motion over correlated and poorly correlated external regions. The potential of capturing in real-time the motion of the complete external patient surface as well as choosing the area of the surface that correlates best with the internal motion should allow reducing such variability and associated errors in both respiratory motion synchronization and subsequent motion modeling processes.

Surface imaging for real-time patient respiratory function assessment in intensive care.

PURPOSE: Monitoring of physiological parameters is a major concern in Intensive Care Units (ICU) given their role in the assessment of vital organ function. Within this context, one issue is the lack of efficient noncontact techniques for respiratory monitoring. In this paper, we present a novel noncontact solution for real-time respiratory monitoring and function assessment of ICU patients. METHODS: The proposed system uses a Time-of-Flight depth sensor to analyze the patient's chest wall morphological changes in order to estimate multiple respiratory function parameters. The automatic detection of the patient's torso is also proposed using a deep neural network model trained on the COCO dataset. The evaluation of the proposed system was performed on a mannequin and on 16 mechanically ventilated patients (a total of 216 recordings) admitted in the ICU of the Brest University Hospital. RESULTS: The estimation of respiratory parameters (respiratory rate and tidal volume) showed high correlation with the reference method (r = 0.99; P < 0.001 and r = 0.99; P < 0.001) in the mannequin recordings and (r = 0.95, P < 0.001 and r = 0.90, P < 0.001) for patients. CONCLUSION: This study describes and evaluates a novel noncontact monitoring system suitable for continuous monitoring of key respiratory parameters for disease assessment of critically ill patients.

Phosphorylation of IRF-3 on Ser 339 generates a hyperactive form of IRF-3 through regulation of dimerization and CBP association.

The IkappaB kinase-related kinases, TBK1 and IKKi, were recently shown to be responsible for the C-terminal phosphorylation of IRF-3. However, the identity of the phosphoacceptor site(s) targeted by these two kinases remains unclear. Using a biological assay based on the IRF-3-mediated production of antiviral cytokines, we demonstrate here that all Ser/Thr clusters of IRF-3 are required for its optimal transactivation capacity. In vitro kinase assays using full-length His-IRF-3 as a substrate combined with mass spectrometry analysis revealed that serine 402 and serine 396 are directly targeted by TBK1. Analysis of Ser/Thr-to-Ala mutants revealed that the S396A mutation, located in cluster II, abolished IRF-3 homodimerization, CBP association, and nuclear accumulation. However, production of antiviral cytokines was still present in IRF-3 S396A-expressing cells. Interestingly, mutation of serine 339, which is involved in IRF-3 stability, also abrogated CBP association and dimerization without affecting gene transactivation as long as serine 396 remained available for phosphorylation. Complementation of IRF-3-knockout mouse embryonic fibroblasts also revealed a compensatory mechanism of serine 339 and serine 396 in the ability of IRF-3 to induce expression of the interferon-stimulated genes ISG56 and ISG54. These data lead us to reconsider the current model of IRF-3 activation. We propose that conventional biochemical assays used to measure IRF-3 activation are not sensitive enough to detect the small fraction of IRF-3 needed to elicit a biological response. Importantly, our study establishes a molecular link between the role of serine 339 in IRF-3 homodimerization, CBP association, and its destabilization.

The IKK-related kinases: from innate immunity to oncogenesis.

Over the past four years, the field of the innate immune response has been highly influenced by the discovery of the IkappaB kinase (IKK)-related kinases, TANK Binding Kinase 1 (TBK1) and IKKi, which regulate the activity of interferon regulatory factor (IRF)-3/IRF-7 and NF-kappaB transcription factors. More recently, additional essential components of the signaling pathways that activate these IKK homologues have been discovered. These include the RNA helicases RIGi and MDA5, and the downstream mitochondrial effector known as CARDIF/MAVS/VISA/IPS-1. In addition to their essential functions in controlling the innate immune response, recent studies have highlighted a role of these kinases in cell proliferation and oncogenesis. The canonical IKKs are well recognized to be a bridge linking chronic inflammation to cancer. New findings now suggest that the IKK-related kinases TBK1 and IKKi also participate in signaling pathways that impact on cell transformation and tumor progression. This review will therefore summarize and discuss the role of TBK1 and IKKi in cellular transformation and oncogenesis by focusing on their regulation and substrate specificity.

A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11.

Idiopathic generalized epilepsy (IGE) has evidence of a strong genetic etiology. We conducted genomewide linkage analysis for genes responsible for familial IGE in French-Canadian pedigrees. Twenty families segregating autosomal dominant epilepsy were collected. Four larger IGE families sufficiently powerful for independent linkage analysis were genome-scanned and follow-up fine mapping was performed over regions with LOD scores >3.0. The genotyping of 16 smaller families was carried out at significantly linked loci for supportive linkage analysis and haplotype comparisons. One of the four families provided a significant linkage result at marker D10S1426 on chromosome 10 (two-point LOD score = 3.05, theta = 0, multipoint LOD score = 3.18). Fine mapping revealed a segregating haplotype and key recombination breakpoints, suggesting a candidate gene interval of 6.5 Mb. Multipoint linkage analyses using the additional 16 families yielded a maximum LOD score under heterogeneity of 4.23 (alpha = 0.34) at this locus. Evaluation of recombination breakpoints in these families narrowed the candidate region to 1.7 Mb. Sequencing of the two known genes in this region, NRP1 and PARD3, was negative for mutation. Replication of linkage to this locus in other cohorts of IGE families is essential to characterize the underlying genetic mechanism for the disease.

Congenital axonal neuropathy and encephalopathy.

Congenital axonal neuropathy associated with encephalopathy appears to be very rare. Only a few cases have been reported in the literature. In the last 25 years, we have seen seven patients affected by congenital axonal neuropathy with encephalopathy. Biopsies of their sural nerves revealed axonal atrophy and loss of large-diameter nerve fibers. All of these patients presented at birth or soon thereafter with hypotonia associated with distal weakness and diffuse areflexia. Central nervous system manifestations included microcephaly, seizures, and developmental delay. Outcomes were poor. Four children died before age 3 years from respiratory insufficiency or aspiration pneumonia. The three surviving patients manifested severe developmental delay. In our most recent patient, Western-blot analysis of snap-frozen specimens of the temporal and cerebellar cortex demonstrated an absence or marked decrease of microtubule-associated protein types 1A and 2, compared with age-matched control subjects. Calloso-splenial hypogenesis and neurofilament swellings were also documented in the deep white matter and adjacent cortex. The absence or hypo-expression of central nervous system microtubule-associated proteins has never been reported in congenital neuropathies, and may represent a new clinicopathologic entity.

Controlling symmetry and localization with an artificial gauge field in a disordered quantum system.

Anderson localization, the absence of diffusion in disordered media, draws its origins from the destructive interference between multiple scattering paths. The localization properties of disordered systems are expected to be dramatically sensitive to their symmetries. So far, this question has been little explored experimentally. Here we investigate the realization of an artificial gauge field in a synthetic (temporal) dimension of a disordered, periodically driven quantum system. Tuning the strength of this gauge field allows us to control the parity-time symmetry properties of the system, which we probe through the experimental observation of three symmetry-sensitive signatures of localization. The first two are the coherent backscattering, marker of weak localization, and the recently predicted coherent forward scattering, genuine interferential signature of Anderson localization. The third is the direct measurement of the ß(g) scaling function in two different symmetry classes, allowing to demonstrate its universality and the one-parameter scaling hypothesis.