Radiation hardness of open Fabry-Pérot microcavities.

High-finesse microcavities offer a platform for compact, high-precision sensing by employing high-reflectivity, low-loss mirrors to create effective optical path lengths that are orders of magnitude larger than the device geometry. Here, we investigate the radiation hardness of Fabry-Pérot microcavities formed from dielectric mirrors deposited on the tips of optical fibers. The microcavities are irradiated under both conventional (∼ 0.1 Gy/s) and ultrahigh (FLASH, ∼ 20 Gy/s) radiotherapy dose rates. Within our measurement sensitivity of ∼ 40 ppm loss, we observe no degradation in the mirror absorption after irradiation with over 300 Gy accumulated dose. This result highlights the excellent radiation hardness of the dielectric mirrors forming the cavities, enabling new optics-based, real-time, in-vivo, tissue-equivalent radiation dosimeters with ∼ 10 micron spatial resolution (our motivation), as well as other applications in high-radiation environments.

Quality Assurance and Prevention of COVID-19 Before Admission in Geriatric Rehabilitation Unit in Long-Term Care Facilities.

Background: This quality assurance study was conducted during the COVID-19 pandemic to describe the profile of patients aged 65 years and older admitted to a transition unit in a long-term care (LTC) facility and to evaluate the impact of admission modalities, compliance with screening and hand hygiene practices, risk of COVID-19, and time to access a geriatric rehabilitation unit (GRU). Methods: A prospective study was conducted using administrative and medical records from three Montreal public LTC facilities offering a rehabilitation program for 312 patients admitted between May 2020 and February 2021. The results are reported for the entire sample and compared according to the mode of admission. Results: The incidence of COVID-19 during the transition unit stay was estimated to be 11 cases or 3.5% in 14 days. Assessment of screening compliance showed deficiencies for 41.3% of patients, and the frequency of hand hygiene audits was not strictly adhered to. More COVID-19 cases were recorded in patients admitted to the transition unit by bed availability than in the cohort mode. The time to access a rehabilitation unit was 7.2 days or 23.5% shorter for patients admitted by bed availability. Conclusions: The study, conducted from a continuous practice improvement perspective, showed that the implementation of a transition unit in the LTC facilities helped control the transmission of COVID-19, but also revealed flaws in screening and hand hygiene practices.

Exogenous IL-2 delays memory precursors generation and is essential for enhancing memory cells effector functions.

To investigate the impact of paracrine IL-2 signals on memory precursor (MP) cell differentiation, we activated CD8 T cell in vitro in the presence or absence of exogenous IL-2 (ex-IL-2). We assessed memory differentiation by transferring these cells into virus-infected mice. Both conditions generated CD8 T cells that participate in the ongoing response and gave rise to similar memory cells. Nevertheless, when transferred into a naive host, T cells activated with ex-IL-2 generated a higher frequency of memory cells displaying increased functional memory traits. Single-cell RNA-seq analysis indicated that without ex-IL-2, cells rapidly acquire an MP signature, while in its presence they adopted an effector signature. This was confirmed at the protein level and in a functional assay. Overall, ex-IL-2 delays the transition into MP cells, allowing the acquisition of effector functions that become imprinted in their progeny. These findings may help to optimize the generation of therapeutic T cells.

The multi-level regulation of clownfish metamorphosis by thyroid hormones.

Most marine organisms have a biphasic life cycle during which pelagic larvae transform into radically different juveniles. In vertebrates, the role of thyroid hormones (THs) in triggering this transition is well known, but how the morphological and physiological changes are integrated in a coherent way with the ecological transition remains poorly explored. To gain insight into this question, we performed an integrated analysis of metamorphosis of a marine teleost, the false clownfish (Amphiprion ocellaris). We show how THs coordinate a change in color vision as well as a major metabolic shift in energy production, highlighting how it orchestrates this transformation. By manipulating the activity of liver X regulator (LXR), a major regulator of metabolism, we also identify a tight link between metabolic changes and metamorphosis progression. Strikingly, we observed that these regulations are at play in the wild, explaining how hormones coordinate energy needs with available resources during the life cycle.

RNA-Seq comparative study reveals molecular effectors linked to the resistance of Pinna nobilis to Haplosporidium pinnae parasite.

With the intensification of maritime traffic, recently emerged infectious diseases have become major drivers in the decline and extinction of species. Since 2016, mass mortality events have decimated the endemic Mediterranean Sea bivalve Pinna nobilis, affecting ca. 100% of individuals. These events have largely been driven by Haplosporidium pinnae's infection, an invasive species which was likely introduced by shipping. While monitoring wild populations of P. nobilis, we observed individuals that survived such a mass mortality event during the summer of 2018 (France). We considered these individuals resistant, as they did not show any symptoms of the disease, while the rest of the population in the area was devastated. Furthermore, the parasite was not detected when we conducted a PCR amplification of a species-specific fragment of the small subunit ribosomal DNA. In parallel, the transcriptomic analysis showed evidence of some parasite RNA indicating that the resistant individuals had been exposed to the parasite without proliferating. To understand the underlying mechanisms of resistance in these individuals, we compared their gene expression with that of susceptible individuals. We performed de novo transcriptome assembly and annotated the expressed genes. A comparison of the transcriptomes in resistant and susceptible individuals highlighted a gene expression signature of the resistant phenotype. We found significant differential expressions of genes involved in immunity and cell architecture. This data provides the first insights into how individuals escape the pathogenicity associated with infection.

CD8 memory precursor cell generation is a continuous process.

In this work, we studied the generation of memory precursor cells following an acute infection by analyzing single-cell RNA-seq data that contained CD8 T cells collected during the postinfection expansion phase. We used different tools to reconstruct the developmental trajectory that CD8 T cells followed after activation. Cells that exhibited a memory precursor signature were identified and positioned on this trajectory. We found that these memory precursors are generated continuously with increasing numbers arising over time. Similarly, expression of genes associated with effector functions was also found to be raised in memory precursors at later time points. The ability of cells to enter quiescence and differentiate into memory cells was confirmed by BrdU pulse-chase experiment in vivo. Analysis of cell counts indicates that the vast majority of memory cells are generated at later time points from cells that have extensively divided.

Ultrasound Computed Tomography.

This chapter presents theoretical, numerical, and experimental frameworks for the use of Ultrasound Computed Tomography (USCT) for cortical bone tissue imaging. Most of the research conducted on this topic concerns adult bone, although some work presented in this chapter is specific to the study of child bone. USCT is recognized as a powerful method for soft tissue imaging. In bone imaging, the difficulties arise from the very high impedance contrast between tissues which alters the propagation of the ultrasonic waves and limits the linear inversion algorithms used. Solutions consist in optimally assessing non-linear effects in an iterative approach aiming at local linearization. When the problem can be reduced to the study of a fluid-like cavity buried in an elastic cylinder surrounded by water, the signal processing and/or compound algorithms can be added as an extension to the linear algorithms. The main limitation of these methods is the heavy experimental costs involved. We have then suggested the introduction of purely numerical non-linear full-waveform inversion algorithms. The performances and the limitations of these linear and non-linear methods applied to cortical bone tissue imaging problems are overviewed and discussed.

Measurement of Cortical Bone Elasticity Tensor with Resonant Ultrasound Spectroscopy.

Resonant Ultrasound Spectroscopy estimates the stiffness coefficients of a material from the free resonant frequencies of a single specimen. It is particularly suitable for complete stiffness characterization of anisotropic materials available only as small samples (typically a few mm), and it does not suffer from some limitations associated to quasi-static mechanical test and ultrasound wave velocity measurements. RUS has been used for decades on geological samples and single crystals, but was until recently not applied to mineralized tissues such as bone. The reason is the significant mechanical damping presents in these materials, which causes the resonant peaks to overlap and prevent a direct measurement of the resonant frequencies. This chapter describes the use of RUS for the elastic characterization of mineralized tissues, cortical bone in particular. All steps are described, from sample preparation and measurement setup to signal processing and data analysis, including the developments and adaptions necessary to overcome the difficulties linked to damping. Viscoelastic characterization, from the width of the resonant peaks, is also presented. Mostly technical aspects are developed in this chapter, while the data obtained from RUS on several collections of mineralized tissues specimens are presented and discussed in Chap. 13.

Documenting the Anisotropic Stiffness of Hard Tissues with Resonant Ultrasound Spectroscopy.

Recent advances in resonant ultrasound spectroscopy (RUS) leverage accurate measurements of the anisotropic stiffness of hard tissues at millimeter scale. RUS is the only available technique to date to assess the entire stiffness tensor of bone from a unique rectangular parallelepiped specimen. Accurately measured stiffness constants are required for bone mechanics models and may provide information on some fundamental aspects of hard tissues biology such as regulation of bone mass, remodeling and healing. In this chapter, we review the anisotropic stiffness data of human hard tissues measured with RUS, mostly during the last decade. Hard tissues covered here include human enamel and dentin, cortical bone from the femur and tibia of human adults, and child cortical bone tissue, accounting for 288 specimens in total. Data was collected in the literature and from previous works of our group. We performed a comparative study to depict the differences in the elastic properties of these hard tissues. Our objectives were to: (1) document the range of anisotropic stiffness constants in human hard tissues (orthotropic or transverse isotropic symmetry); and (2) provide empirical laws between mass density and anisotropic stiffness of cortical bone at different skeletal sites. Finally, we discuss the challenges and perspectives to use RUS for large collections of specimens.

Dichotomy in Neutralizing Antibody Induction to Peptide-Conjugated Vaccine in Squalene Emulsion Contrast With Aluminum Hydroxide Formulation.

W614A-3S peptide is a modified 3S motif of the HIV-gp41 (mutation W614A). We previously detected the presence of natural neutralizing antibodies directed against W614A-3S peptide (NAbs) in long-term non-progressor HIV+ patients. Here, we compared the efficacy of W614A-3S peptide formulated in either squalene emulsion (SQE) or in aluminum hydroxide (Alum) in inducing broadly-NAbs (bNAbs). Rabbit and mouse models were used to screen the induction of bNAbs following 4 immunizations. SQE was more efficient than Alum formulation in inducing W614A-3S-specific bNAbs with up to 67%-93% of HIV strains neutralized. We then analyzed the quality of peptide-specific murine B cells by single-cell gene expression by quantitative reverse transcription-PCR and single-cell V(D)J sequencing. We found more frequent germinal center B cells in SQE than in Alum, albeit with a different gene expression profile. The V(D)J sequencing of W614A-3S-specific BCR showed significant differences in BCR sequences and validates the dichotomy between adjuvant formulations. All sixteen BCR sequences which were cloned were specific of peptide. Adjuvant formulations of W614A-3S-peptide-conjugated immunogen impact the quantity and quality of B cell immune responses at both the gene expression level and BCR sequence.

Gene profiling reveals a contact allergy signature in most positive Amerchol L-101 patch test reactions.

BACKGROUND: Diagnosis of contact allergy (CA) to Amerchol L-101 (AL-101), a marker for lanolin allergy, is problematic. Positive patch test reactions are frequently doubtful or weakly positive and difficult to associate with clinical relevance. OBJECTIVE: To gain further insight on the allergic or irritant nature of skin reactions induced by AL-101 patch test. METHODS: We re-tested in a dose-response fashion, 10 subjects with AL-101 CA and performed comprehensive transcriptomic analysis (gene arrays, quantitative real-time polymerase chain reaction [qRT-PCR]) of samples of their skin reactions. RESULTS: Eight of the 10 CA subjects reacted positively upon re-test, whereas two did not react. Most of AL-101 positive patch tests expressed an allergy signature with strong activation of gene modules associated with adaptive immunity and downregulation of cornification pathway genes. In addition, the breadth of gene modulation correlated with the magnitude of patch test reactions and the concentration of AL-101 applied. However, we observed that some of the positive patch test reactions to AL-101 expressed no/few allergy biomarkers, suggesting the induction of an irritant skin inflammation in these samples. CONCLUSIONS: This study confirms that AL-101 is an allergen that can cause both contact allergy and contact irritation. Our results also highlight that molecular profiling might help to strengthen clinical diagnosis.

Sideband cavity absorption readout (SideCAR) with a robust frequency lock.

We present a simple, continuous, cavity-enhanced optical absorption measurement technique based on high-bandwidth Pound-Drever-Hall (PDH) sideband locking. The technique provides a resonant amplitude quadrature readout that can be mapped onto the cavity's internal loss rate and is naturally compatible with weak probe beams. With a proof-of-concept 5-cm-long Fabry-Perot cavity, we measure an absorption sensitivity ∼10-10cm-1/Hz from 30 kHz to 1 MHz, and a minimum value of 6.6×10-11cm-1/Hz at 100 kHz, with 38 µW collected from the cavity's circulating power.

Comparison of Photo-optical Transcutaneous Oxygen Tension Measurement with Electro-chemical Transcutaneous Oxygen Tension Measurement in Patients with Arterial Claudication.

PURPOSE: Photo-optical TCpO2 (pTCpO2) has been proposed as a new method to determine the partial oxygen pressure of the lower extremity in patients with peripheral arterial disease. It is aimed to determine the level of agreement between pTCpO2 and the traditional electro-chemical transcutaneous oxygen tension measurement (eTCpO2). METHODS: Eighteen patients with intermittent claudication underwent simultaneous ankle-brachial index measurement, toe-pressure, pTCpO2 and eTCpO2 tests. Oxygen tension levels were measured on anterior chest and calf prior in rest (T0), during induced ischemia (T1) and after blood flow restoration (T2). TCpO2 agreement was assessed according to the principles of Bland and Altman. RESULTS: Absolute average TCpO2 values differed between eTCpO2 and pTCpO2 for calf in T2 (38,1 mmHg (σ 14,4) vs. 49,8 (σ 22.3) with P = 0.35). The Bland-Altman plots demonstrated eTCpO2 and pTCpO2 bias of 3,7 mmHg (σ 18,8), 11,6 mmHg (σ 17,6) and 6,7 mmHg (σ 23,5) for T0, T1 and T2 for the calf. CONCLUSION: pTCpO2 is in agreement with eTCpO2 in measuring pO2 levels of the lower extremity in rest and during induced ischemia in patients with vascular claudication. The large variability between eTCpO2 and pTCpO2 should be accounted for, while pTCpO2 values have a tendency to demonstrate higher values in comparison to eTCpO2.

Unique molecular signatures typify skin inflammation induced by chemical allergens and irritants.

BACKGROUND: Skin exposure to chemicals may induce an inflammatory disease known as contact dermatitis (CD). Distinguishing the allergic and irritant forms of CD often proves challenging in the clinic. METHODS: To characterize the molecular signatures of chemical-induced skin inflammation, we conducted a comprehensive transcriptomic analysis on the skin lesions of 47 patients with positive patch tests to reference contact allergens and nonallergenic irritants. RESULTS: A clear segregation was observed between allergen- and irritant-induced gene profiles. Distinct modules pertaining to the epidermal compartment, metabolism, and proliferation were induced by both contact allergens and irritants; whereas only contact allergens prompted strong activation of adaptive immunity, notably of cytotoxic T-cell responses. Our results also confirmed that: (a) unique pathways characterize allergen- and irritant-induced dermatitis; (b) the intensity of the clinical reaction correlates with the magnitude of immune activation. Finally, using a machine-learning approach, we identified and validated several minimal combinations of biomarkers to distinguish contact allergy from irritation. CONCLUSION: These results highlight the value of molecular profiling of chemical-induced skin inflammation for improving the diagnosis of allergic versus irritant contact dermatitis.

Low-Level Light Therapy Downregulates Scalp Inflammatory Biomarkers in Men With Androgenetic Alopecia and Boosts Minoxidil 2% to Bring a Sustainable Hair Regrowth Activity.

BACKGROUND AND OBJECTIVES: Low-level light therapies using visible to infrared light are known to activate several cellular functions, such as adenosine triphosphate and nitric oxide synthesis. However, few clinical observations report its biological consequences for skin and scalp homeostasis. Since scalp inflammation was recognized as a potential physiological obstacle to the efficacy of the reference hair regrowth drug Minoxidil in vivo and since perifollicular inflammation is the hallmark of about 50%-70% follicular units in androgenetic alopecia, we decided to investigate whether the anti-inflammatory activity of LLLT/GentleWaves® device were assigned to L'Oréal by Light BioScience L.L.C., Virginia Beach, VA (US) could enhance hair regrowth activity of Minoxidil. STUDY DESIGN/MATERIALS AND METHODS: We conducted a first experimental clinical study on 64 men with androgenetic alopecia using LLLT/GentleWaves®, 590-nm predominant wavelength 70 seconds, specifically pulsed once per day, for 3 days, and we performed a whole-genome analysis of treated scalp biopsies. In a second clinical study, including 135 alopecic volunteers, we evaluated the hair regrowth activity in response to the upgraded LLLT/GentleWaves® device and Minoxidil. RESULTS: In the first clinical study, whole-genome analysis of treated scalp biopsies showed downregulation of scalp inflammatory biomarkers, such as AP1/FOSB messenger RNA (mRNA) and mir21, together with the disappearance of CD69 mRNA, specific to scalp-infiltrating T cells of about 50% of the studied volunteers prior to the LLLT/GentleWaves® treatment. In the second clinical study, we observed that LLLT/GentleWaves® was able to boost the hair regrowth activity of a Minoxidil 2% lotion to the extent of the highest concentration (5%) in terms of efficacy, number of responders, and perceived performance. CONCLUSIONS: Altogether, these observations suggest the potential benefit of LLLT/GentleWaves® as a noninvasive adjunctive technology for skin and scalp conditions, where a mild perifollicular inflammation is involved. Lasers Surg. Med. 2021. Copyright © 2021 Wiley Periodicals LLC.

Ultrasonic Imaging of High-contrasted Objects Based on Full-waveform Inversion: Limits under Fluid Modeling.

Quantitative ultrasound techniques have been previously used to evaluate biological hard tissues, characterized by a large acoustic impedance contrast. Here, we are interested in the imaging of experimental data from different test-targets with high acoustic impedance contrast, using the Full Waveform Inversion (FWI) method to solve the inverse problem. This method is based on high-resolution numerical modeling of the forward problem of interaction between waves and medium, considering the full time series. To reduce the complexity of the numerical implementation, the model considers a fluid medium. Therefore, the aim is to evaluate the precision of the reconstruction under this assumption for materials with a different level of attenuation of shear waves, to study the limits of this hypothesis. Images of the sound speed obtained using the experimental data are presented, and the precision of the reconstruction is evaluated. Future work should include viscoelastic materials.

Identifying early pulmonary arterial hypertension biomarkers in systemic sclerosis: machine learning on proteomics from the DETECT cohort.

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.

Monitored wet-etch removal of individual dielectric layers from high-finesse Bragg mirrors.

It is prohibitively expensive to deposit customized dielectric coatings on individual optics. One solution is to batch-coat many optics with extra dielectric layers, then remove layers from individual optics as needed. Here we present a low-cost, single-step, monitored wet etch technique for reliably removing individual SiO2 and Ta2O5 dielectric layers, in this case from a high-reflectivity fiber mirror. By immersing in acid and monitoring off-band reflected light, we show it is straightforward to iteratively (or continuously) remove six bilayers. At each stage, we characterize the coating performance with a Fabry-Pérot cavity, observing the expected stepwise decrease in finesse from 92,000 ± 3,000 to 3, 950 ± 50, finding no evidence of added optical losses. The etch also removes the fiber's sidewall coating after a single bilayer, and, after six bilayers, confines the remaining coating to a 60-µm-diameter pedestal at the center of the fiber tip. Vapor etching above the solution produces a tapered "pool cue" cladding profile, reducing the fiber diameter (nominally 125 µm) to 95 µm at an angle of ∼0.3° near the tip. Finally, we note that the data generated by this technique provides a sensitive estimate of the layers' optical depths. This technique could be readily adapted to free-space optics and other coatings.

Immune Profiles Identification by Vaccinomics After MVA Immunization in Randomized Clinical Study.

Background: Our previous work has demonstrated the benefits of transcutaneous immunization in targeting Langerhans cells and preferentially inducing CD8 T-cell responses. Methods: In this randomized phase Ib clinical trial including 20 HIV uninfected volunteers, we compared the safety and immunogenicity of the MVA recombinant vaccine expressing HIV-B antigen (MVA-B) by transcutaneous and intramuscular routes. We hypothesized that the quality of innate and adaptive immunity differs according to the route of immunization and explored the quality of the vector vaccine-induced immune responses. We also investigated the early blood transcriptome and serum cytokine levels to identify innate events correlated with the strength and quality of adaptive immunity. Results: We demonstrate that MVA-B vaccine is safe by both routes, but that the quality and intensity of both innate and adaptive immunity differ significantly. Transcutaneous vaccination promoted CD8 responses in the absence of antibodies and slightly affected gene expression, involving mainly genes associated with metabolic pathways. Intramuscular vaccination, on the other hand, drove robust changes in the expression of genes involved in IL-6 and interferon signalling pathways, mainly those associated with humoral responses, and also some levels of CD8 response. Conclusion: Thus, vaccine delivery route perturbs early innate responses that shape the quality of adaptive immunity. Clinical Trial Registration: http://ClinicalTrials.gov, identifier PER-073-13.