Endoscopic imaging of white matter fiber tracts using polarization-sensitive optical coherence tomography.

Polarization sensitive optical coherence tomography (PSOCT) has been shown to image and delineate white matter fibers in a label-free manner by revealing optical birefringence within the myelin sheath using a microscope setup. In this proof-of-concept study, we adapt recent advancements in endoscopic PSOCT to perform depth-resolved imaging of white matter structures deep inside intact porcine brain tissue ex-vivo, through a small, rotational fiber probe. The probe geometry is comparable to microelectrodes currently used in neurosurgical interventions. The presented imaging system is mobile, robust, and uses biologically safe levels of optical radiation making it well suited for clinical translation. In neurosurgery, where accuracy is imperative, endoscopic PSOCT through a narrow-gauge fiber probe could provide intra-operative feedback on the location of critical white matter structures.

Ethnocultural Minority Workers and Sustainable Return to Work Following Work Disability: A Qualitative Interpretive Description Study.

Purpose This article provides a state-of-the-art review of issues and factors associated with the sustainable return to work (S-RTW) of ethnocultural minority workers experiencing disability situations attributable to one of four major causes: musculoskeletal disorders, common mental disorders, other chronic diseases or cancer. Methods Using an interpretive description method, an integrative review was conducted of the literature on ethnocultural factors influencing S-RTW issues and factors associated with these four major work-disability causes. An initial review of the 2006-2016 literature was subsequently updated for November 2016-May 2021. To explore and contextualize the results, four focus groups were held with RTW stakeholders representing workplaces, insurers, the healthcare system and workers. Qualitative thematic analysis was performed. Results A total of 56 articles were analyzed and 35 stakeholders participated in four focus groups. Two main findings emerged. First, belonging to an ethnocultural minority group appears associated with cumulative risk factors that may contribute to vulnerability situations and compound the complexity of S-RTW. Second, cultural differences with respect to the prevailing host-country culture may generate communication and trust issues, and conflicts in values and representations, in turn possibly hindering the establishment of positive relationships among all stakeholders and the ability to meet workers' needs. Being a woman in these groups and/or having a lower level of integration into the host country's culture also appear associated with greater S-RTW challenges. Conclusions Based on our findings, we recommend several possible strategies, such as the cultural humility model, for preventing differences from exacerbating the already significant vulnerability situation of some ethnocultural minority workers.

Building a Common Language to Facilitate Discussion Among Stakeholders in Work Disability: A Consensus Group Approach.

PURPOSE: Work disability stakeholders may not share the same understanding and solutions among themselves or with researchers, causing misunderstandings and hindering collaboration regarding solutions for preventing work disability. To reduce such differences, this study sought to build a common vocabulary among stakeholders and researchers, using a transdisciplinary research framework. METHODS: A consensus method based on a constructivist approach was used. A theoretical sampling method was applied to identify researchers or stakeholders representing one of the four systems in the work disability paradigm. A preliminary set of definitions for key terms was assessed using a Web-based questionnaire. It documented participants' level of agreement with each term's inclusion and relevance in the field, and the clarity of the definition, while soliciting suggestions for other terms or clearer definitions. Disagreements were discussed at group meetings, yielding consensus on the final terms and definitions. RESULTS: Eleven stakeholders representing patients, employers, unions, healthcare professionals, and legislative and insurance systems, along with 10 multidisciplinary researchers, participated. The questionnaire yielded initial consensus on the inclusion and definitions of 49 terms, and 109 suggestions mostly for modified definitions (average = 6 suggestions/term). Two preliminary terms were excluded and three terms were added. Ultimately, 80 terms and their definitions yielded consensus. CONCLUSIONS: The process we used to build a common vocabulary was carried out within a transdisciplinary framework. It required a constructivist approach, promoting idea exchanges among participants and co-construction of generally agreed results. The results were rooted in local contexts, thus ensuring the same reference points, regardless of participants' different understandings.

Versatile Microfluidic Platform for Automated Live-Cell Hyperspectral Imaging Applied to Cold Climate Cyanobacterial Biofilms.

Microfluidic bioanalytical platforms are driving discoveries from synthetic biology to the health sciences. In this work, we present a platform for in vivo live-cell imaging and automated species detection in mixed cyanobacterial biofilms from cold climate environments. Using a multimodal microscope with custom optics applied to a chip with six parallel growth channels, we monitored biofilm dynamics via continuous imaging at natural irradiance levels. Machine learning algorithms were applied to the collected hyperspectral images for automatic segmentation of mixed-species biofilms into individual species of cyanobacteria with similar filamentous morphology. The coupling of microfluidic technology with modern multimodal imaging and computer vision systems provides a versatile platform for the study of cause-and-effect scenarios of cyanobacterial biofilms, which are important elements of many ecosystems, including lakes and rivers of the polar regions.

MCVD-based GRIN-axicon for the generation of scalable Bessel-Gauss beams.

In this Letter, we introduce a graded-index (GRIN)-lens combination named GRIN-axicon, which is a versatile component capable of generating high-quality scalable Bessel-Gauss beams. To the best of our knowledge, the GRIN-axicon is the only optical component that can be introduced in both larger-scale laboratory setups and miniaturized all-fiber optical setups, while having an easy control of the dimensioning of the generated focal line. We show that a GRIN lens with a hyperbolic secant refractive index profile with a sharp central dip and no ripples generates a Bessel-Gauss beam with a high-intensity central lobe when coupled to a simple lens. Such fabrication characteristics are very suitable for the modified chemical vapor deposition (MCVD) process and enable easy manufacturing of an adaptable component that can fit in any optical setup.

Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

A rapid scoping review of COVID-19 and vulnerable workers: Intersecting occupational and public health issues.

BACKGROUND: This article reports the results of a rapid scoping review of the literature on COVID-19 transmission risk to workers in essential sectors such as retail, health care, manufacturing, and agriculture, and more particularly the experiences of workers in precarious employment and social situations. METHODS: Following scoping review methods, we included 30 studies that varied in terms of methodology and theoretical approaches. The search included peer-reviewed articles and grey literature published between March and September 2020. RESULTS: Based on the studies reviewed, we found that COVID-19 infection and death rates increased not only with age and comorbidities, but also with discrimination and structural inequities based on racism and sexism. Racial and ethnic minority workers, including migrant workers, are concentrated in high-risk occupations and this concentration is correlated to lower socioeconomic conditions. The COVID-19 pandemic appears in the occupational health and safety spotlight as an exacerbator of already existing socioeconomic inequalities and social inequalities in health, especially in light of the intersection of issues related to racism, ethnic minority status, and sexism. CONCLUSIONS: This review provides early evidence about the limitations of institutions' responses to the pandemic, and their capacity to provide a safe and decent working environment for all workers, regardless of their employment status or the social protections they may enjoy under normal circumstances. It is also important to think about these issues in the postpandemic context, when conditions of precariousness and vulnerability persist and possibly worsen.

How does Gender Influence Sustainable Return to Work Following Prolonged Work Disability? An Interpretive Description Study.

PURPOSE: A sustainable return to work (S-RTW) following prolonged work disability poses different challenges, depending on gender. This article provides a synthesis of gender differences in the issues and factors influencing the S-RTW of workers following such a disability. METHODS: Using an interpretive description method, an integrative review was conducted of the literature on gender differences in S-RTW issues and factors associated with four major causes of work disability. The initial review concerned the 2000-2016 literature; it was subsequently updated for November 2016-March 2020. To explore and contextualise the results, four focus groups were held with stakeholders representing the workplace, insurance, and healthcare systems and workers. Qualitative thematic analysis was performed. RESULTS: A total of 47 articles were reviewed, and 35 stakeholders participated in the focus groups. The prevailing traditional gender roles were found to have a major gender-specific influence on the attitudes, behaviours, processes and outcomes associated with S-RTW. These differences related to the (1) cumulative workload, (2) work engagement, and (3) expressed and addressed needs. CONCLUSIONS: The results highlight the importance of taking into account both professional and personal aspects when integrating gender issues into the assessment of workers' needs and subsequently into interventions.

Insights into the Sustainable Return to Work of Aging Workers with a Work Disability: An Interpretative Description Study.

Purpose A sustainable return to work (S-RTW) following prolonged work disability poses particular challenges as workers age. This article provides a synthesis of the factors and issues involved in a S-RTW process for aging workers following such a disability. Methods Using interpretive description methods, a critical review was conducted of the literature specifying return-to-work factors and issues for aging workers with regard to four major causes of work disability (musculoskeletal disorders, common mental disorders, cancer or other chronic diseases). The initial review concerned the 2000-2016 literature, and was subsequently updated for November 2016-December 2018. To further explore and contextualise the results of this literature review, four focus groups were held with stakeholders, representing the workplace, insurance, and healthcare systems and workers. Qualitative thematic analysis was performed. Results Fifty-five articles were reviewed and 35 stakeholders participated in the focus groups. Returning to work and staying at work appear to be particularly challenging for aging workers, who face notable issues and stigma concerning their ability to meet work demands, as well as their mobilisation and engagement in these processes. Such findings echo in many ways the main assertions of the literature on aging at work, except those regarding the transformation of capacities with aging, which is not mentioned in relation to workers with a work disability. The influence of healthcare and compensation systems on the S-RTW of aging work-disabled workers has also received little attention to date. Conclusions The results underscore that aging workers with a disability are frequently vulnerable in terms of their health or their jobs. Intersectoral efforts are needed to remedy this situation to keep them at work.

Direct measurement of local oxygen concentration in the bone marrow of live animals.

Characterization of how the microenvironment, or niche, regulates stem cell activity is central to understanding stem cell biology and to developing strategies for the therapeutic manipulation of stem cells. Low oxygen tension (hypoxia) is commonly thought to be a shared niche characteristic in maintaining quiescence in multiple stem cell types. However, support for the existence of a hypoxic niche has largely come from indirect evidence such as proteomic analysis, expression of hypoxia inducible factor-1α (Hif-1α) and related genes, and staining with surrogate hypoxic markers (for example, pimonidazole). Here we perform direct in vivo measurements of local oxygen tension (pO2) in the bone marrow of live mice. Using two-photon phosphorescence lifetime microscopy, we determined the absolute pO2 of the bone marrow to be quite low (<32 mm Hg) despite very high vascular density. We further uncovered heterogeneities in local pO2, with the lowest pO2 (∼9.9 mm Hg, or 1.3%) found in deeper peri-sinusoidal regions. The endosteal region, by contrast, is less hypoxic as it is perfused with small arteries that are often positive for the marker nestin. These pO2 values change markedly after radiation and chemotherapy, pointing to the role of stress in altering the stem cell metabolic microenvironment.

Overlapping vulnerabilities in workers of the electronics recycling industry formal sector: A commentary.

Vulnerabilities in workers performing electronics recycling (e-recycling) in the informal sector worldwide have been well documented. However, the growing e-recycling industry in the formal sector still brings many challenges to protect the health of workers and their environment. This commentary aims to draw attention to the overlooked vulnerabilities faced by the workers of the e-recycling industry formal sector in high-income countries and discuss the potential impact on health inequalities experienced by these workers. Expanding the definition of vulnerability, not limited to the biological susceptibility to chemical and physical exposures, the demographic characteristics of workers in the e-recycling formal sector often reveal social groups known to be disadvantaged regarding occupational exposures and health effects, including young workers, immigrant or ethnic minorities, and workers with mental or physical health issues or disabilities. Overlapping structural vulnerabilities of the e-recycling industry stem from its newness, its working conditions, its conditions of employment, and the sociodemographic characteristics of its workforce. This phenomenon in high-income countries is not restricted to the e-recycling industry alone. It is rather a symptom of more generalized macro socioeconomical phenomena. The present challenges are in line with the new gig and green economies and changes in the global market, and their consequences on the solid waste sector. Continued efforts to strengthen the inclusion of social aspects of health into the complex interaction of the structural vulnerabilities met by e-recycling workers will be essential to anticipate and prevent health issues in this essential but still emerging workforce.

Betacellulin regulates schwann cell proliferation and myelin formation in the injured mouse peripheral nerve.

When a nerve fiber is cut or crushed, the axon segment that is separated from the soma degenerates distal from the injury in a process termed Wallerian degeneration (WD). C57BL/6OlaHsd-WldS (WldS ) mutant mice exhibit significant delays in WD. This results in considerably delayed Schwann cell and macrophage responses and thus in impaired nerve regenerations. In our previous work, thousands of genes were screened by DNA microarrays and over 700 transcripts were found to be differentially expressed in the injured sciatic nerve of WldS compared with wild-type (WT) mice. One of these transcripts, betacellulin (Btc), was selected for further analysis since it has yet to be characterized in the nervous system, despite being known as a ligand of the ErbB receptor family. We show that Btc mRNA is strongly upregulated in immature and dedifferentiated Sox2+ Schwann cells located in the sciatic nerve distal stump of WT mice, but not WldS mutants. Transgenic mice ubiquitously overexpressing Btc (Tg-Btc) have increased numbers of Schmidt-Lantermann incisures compared with WT mice, as revealed by Coherent anti-Stokes Raman scattering (CARS). Tg-Btc mice also have faster nerve conduction velocity. Finally, we found that deficiency in Btc reduces the proliferation of myelinating Schwann cells after sciatic nerve injury, while Btc overexpression induces Schwann cell proliferation and improves recovery of locomotor function. Taken together, these results suggest a novel regulatory role of Btc in axon-Schwann cell interactions involved in myelin formation and nerve repair. GLIA 2017 GLIA 2017;65:657-669.

In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche.

Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.

Epidural optogenetics for controlled analgesia.

BACKGROUND: Optogenetic tools enable cell selective and temporally precise control of neuronal activity; yet, difficulties in delivering sufficient light to the spinal cord of freely behaving animals have hampered the use of spinal optogenetic approaches to produce analgesia. We describe an epidural optic fiber designed for chronic spinal optogenetics that enables the precise delivery of light at multiple wavelengths to the spinal cord dorsal horn and sensory afferents. RESULTS: The epidural delivery of light enabled the optogenetic modulation of nociceptive processes at the spinal level. The acute and repeated activation of channelrhodopsin-2 expressing nociceptive afferents produced robust nocifensive behavior and mechanical sensitization in freely behaving mice, respectively. The optogenetic inhibition of GABAergic interneurons in the spinal cord dorsal horn through the activation of archaerhodopsin also produced a transient, but selective induction of mechanical hypersensitivity. Finally, we demonstrate the capacity of optogenetics to produce analgesia in freely behaving mice through the inhibition of nociceptive afferents via archaerhodopsin. CONCLUSION: Epidural optogenetics provides a robust and powerful solution for activation of both excitatory and inhibitory opsins in sensory processing pathways. Our results demonstrate the potential of spinal optogenetics to modulate sensory behavior and produce analgesia in freely behaving animals.

Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases.

Disruption of the blood-brain and blood-spinal cord barriers (BBB and BSCB, respectively) and immune cell infiltration are early pathophysiological hallmarks of multiple sclerosis (MS), its animal model experimental autoimmune encephalomyelitis (EAE), and neuromyelitis optica (NMO). However, their contribution to disease initiation and development remains unclear. In this study, we induced EAE in lys-eGFP-ki mice and performed single, nonterminal intravital imaging to investigate BSCB permeability simultaneously with the kinetics of GFP(+) myeloid cell infiltration. We observed a loss in BSCB integrity within a day of disease onset, which paralleled the infiltration of GFP(+) cells into the CNS and lasted for ∼4 d. Neutrophils accounted for a significant proportion of the circulating and CNS-infiltrating myeloid cells during the preclinical phase of EAE, and their depletion delayed the onset and reduced the severity of EAE while maintaining BSCB integrity. We also show that neutrophils collected from the blood or bone marrow of EAE mice transmigrate more efficiently than do neutrophils of naive animals in a BBB cell culture model. Moreover, using intravital videomicroscopy, we demonstrate that the IL-1R type 1 governs the firm adhesion of neutrophils to the inflamed spinal cord vasculature. Finally, immunostaining of postmortem CNS material obtained from an acutely ill multiple sclerosis patient and two neuromyelitis optica patients revealed instances of infiltrated neutrophils associated with regions of BBB or BSCB leakage. Taken together, our data provide evidence that neutrophils are involved in the initial events that take place during EAE and that they are intimately linked with the status of the BBB/BSCB.

Activity of the principal cells of the olfactory bulb promotes a structural dynamic on the distal dendrites of immature adult-born granule cells via activation of NMDA receptors.

The adult olfactory bulb is continuously supplied with neuronal precursors that differentiate into granule and periglomerular cells. Little is known about the structural dynamic of adult-born granule cells (GCs) at their different maturational stages, the mechanisms controlling the integration of new neurons into the pre-existing neuronal circuitry, or the role of principal cell activity in these processes. We used two-photon time-lapse imaging to reveal a high level of filopodia formation and retraction on the distal dendrites of adult-born GCs at their early maturational stages. This dynamic decreased as the adult-born interneurons matured. Filopodia formation/retraction on the dendrites of adult-born GCs at the early maturational stages depended on the activation of NMDA receptors (NMDARs). The stimulation of mitral cells using a pattern that mimics activity of these principal neurons to odor presentation promotes the NMDAR-dependent filopodia dynamic of adult-born GCs during their early but not late maturational stages. Moreover, NMDA iontophoresis was sufficient to induce the formation of new filopodia on the distal dendrites of immature adult-born GCs. The maturation of adult-born interneurons was accompanied by a progressive hyperpolarization of the membrane potential and an increased Mg(2+) block of NMDARs. Decreasing the extracellular Mg(2+) concentration led to filopodia formation on the dendrites of mature adult-born GCs following NMDA iontophoresis. Our findings reveal an increased structural dynamic of adult-born GCs during the early stages of their integration into the mouse bulbar circuitry and highlight a critical period during which the principal cells' activity influences filopodia formation/retraction on the dendrites of interneurons.

In vivo histology of the myelin g-ratio with magnetic resonance imaging.

The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment.

Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche.

Stem cells reside in a specialized, regulatory environment termed the niche that dictates how they generate, maintain and repair tissues. We have previously documented that transplanted haematopoietic stem and progenitor cell populations localize to subdomains of bone-marrow microvessels where the chemokine CXCL12 is particularly abundant. Using a combination of high-resolution confocal microscopy and two-photon video imaging of individual haematopoietic cells in the calvarium bone marrow of living mice over time, we examine the relationship of haematopoietic stem and progenitor cells to blood vessels, osteoblasts and endosteal surface as they home and engraft in irradiated and c-Kit-receptor-deficient recipient mice. Osteoblasts were enmeshed in microvessels and relative positioning of stem/progenitor cells within this complex tissue was nonrandom and dynamic. Both cell autonomous and non-autonomous factors influenced primitive cell localization. Different haematopoietic cell subsets localized to distinct locations according to the stage of differentiation. When physiological challenges drove either engraftment or expansion, bone-marrow stem/progenitor cells assumed positions in close proximity to bone and osteoblasts. Our analysis permits observing in real time, at a single cell level, processes that previously have been studied only by their long-term outcome at the organismal level.

Multiple tutorial-based assessments: a generalizability study.

BACKGROUND: Tutorial-based assessment commonly used in problem-based learning (PBL) is thought to provide information about students which is different from that gathered with traditional assessment strategies such as multiple-choice questions or short-answer questions. Although multiple-observations within units in an undergraduate medical education curriculum foster more reliable scores, that evaluation design is not always practically feasible. Thus, this study investigated the overall reliability of a tutorial-based program of assessment, namely the Tutotest-Lite. METHODS: More specifically, scores from multiple units were used to profile clinical domains for the first two years of a system-based PBL curriculum. RESULTS: G-Study analysis revealed an acceptable level of generalizability, with g-coefficients of 0.84 and 0.83 for Years 1 and 2, respectively. Interestingly, D-Studies suggested that as few as five observations over one year would yield sufficiently reliable scores. CONCLUSIONS: Overall, the results from this study support the use of the Tutotest-Lite to judge clinical domains over different PBL units.

NBS-SNI, an extension of the network-based statistic: Abnormal functional connections between important structural actors.

Elucidating the coupling between the structure and the function of the brain and its development across maturation has attracted a lot of interest in the field of network neuroscience in the last 15 years. Mounting evidence supports the hypothesis that the onset of certain brain disorders is linked with the interplay between the structural architecture of the brain and its functional processes, often accompanied with unusual connectivity features. This paper introduces a method called the network-based statistic-simultaneous node investigation (NBS-SNI) that integrates both representations into a single framework, and identifies connectivity abnormalities in case-control studies. With this method, significance is given to the properties of the nodes, as well as to their connections. This approach builds on the well-established network-based statistic (NBS) proposed in 2010. We uncover and identify the regimes in which NBS-SNI offers a gain in statistical resolution to identify a contrast of interest using synthetic data. We also apply our method on two real case-control studies, one consisting of individuals diagnosed with autism and the other consisting of individuals diagnosed with early psychosis. Using NBS-SNI and node properties such as the closeness centrality and local information dimension, we found hypo- and hyperconnected subnetworks and show that our method can offer a 9 percentage points gain in prediction power over the standard NBS.