Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell-Targeted Therapy in the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS).

OBJECTIVE: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints. METHODS: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing. RESULTS: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins  and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders  according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell-related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration. CONCLUSION: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification.

Severity of COVID-19 infection in primary Sjögren's syndrome and the emerging evidence of COVID-19-induced xerostomia.

Since the beginning of the COVID-19 disease pandemic caused by the new coronavirus SARS-CoV-2, the disease has claimed over 205M cases (205,338,159) and 4,333,094 deaths (WHO dashboard - accessed 15/08/2021). In addition to the overwhelming impact on healthcare systems treating acutely ill patients, the pandemic has had an impact on all other aspects of health care delivery, including the management of chronic diseases, the risk that is posed in patients with chronic conditions and the risk of the infection itself in those with chronic conditions. Autoimmune rheumatic diseases (ARDs), including primary Sjögren's syndrome (pSS), characterised by immune dysregulation affecting several organs in variable severity, have been of particular interest given the accelerated phase of the immune response in the course of SARS-CoV-2 infection leading to the acute inflammatory response and respiratory distress syndrome or multi-organ failure. On the other hand, the effect of immunosuppressive drug therapies can represent a double edge sword on the course of the disease, either by increased susceptibility to and severity of the infection, or by preventing the accelerated inflammatory response induced by the infection. Additionally, the long-term impact of SARS-CoV-2 infection on the host immune system has led to the onset of novel complex clinical manifestations, comprised under the large umbrella of "long-COVID", which we are only starting to understand. In this review we focus on two interrelated aspects: i) the impact of COVID-19 on patients with pSS and ii) the emerging evidence of long-term xerostomia after SARS-CoV-2 infection.

NKp30 Receptor Upregulation in Salivary Glands of Sjögren's Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands.

Biological Therapy in Primary Sjögren's Syndrome: Effect on Salivary Gland Function and Inflammation.

Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease. It is the second most common rheumatic autoimmune disorder, affecting 0.7% of European Americans and up to 1% of people globally. pSS is characterized by the impaired secretory function of exocrine glands, including salivary and lachrymal glands. A lymphocytic infiltration of these organs leads to the common and debilitating symptoms of oral and ocular dryness, majorly affecting the quality of life of these patients. Currently, no disease-modifying drug has been approved for the treatment of pSS, with therapies largely aimed at relieving symptoms of dry mouth and dry eyes. In particular, management of oral dryness still represents a major unmet clinical need in pSS and a significant burden for patients with this condition. Recently, several randomized clinical trials in pSS with biological therapies targeting specific mechanistic pathways implicated in the disease pathogenesis, including B-cell hyperactivity, T-cell co-stimulation and the aberrant role of cytokines, have been completed with mixed results. In this review, we summarize evidence from recent clinical trials investigating biological therapy in pSS, specifically highlighting efficacy, or lack thereof, in modulating local inflammation and improving salivary gland function.

Perovskite Quantum Dot-Reduced Graphene Oxide Superstructure for Efficient Photodetection.

High-performance photodetectors require efficient photogeneration and charge transport. Perovskite quantum dots (PQDs) have received enormous interest for applications in optoelectronics due to their high photogeneration efficiency. However, they offer meager carrier transport. Reduced graphene oxide (RGO) exhibits inferior photoresponse compared to materials such as quantum dots. An effective synthesis protocol to grow PQDs from the RGO lattice may facilitate direct charge transfers from PQDs to RGO, which could not be accomplished by mixing individual PQDs with RGO or making a bilayer. At ambient condition, the photodetector fabricated with the PQD-RGO superstructure showed high responsivity of 1.07 × 103 A/W, detectivity of 1 × 1013 Jones as well as sharp switching in the visible wavelength. After 3 months in an unencapsulated sample, the photocurrent was decreased ∼10% of its initial value while preserving speed and cycle stability at ambient condition.

Ultrasensitive and ultrathin phototransistors and photonic synapses using perovskite quantum dots grown from graphene lattice.

Organic-inorganic halide perovskite quantum dots (PQDs) constitute an attractive class of materials for many optoelectronic applications. However, their charge transport properties are inferior to materials like graphene. On the other hand, the charge generation efficiency of graphene is too low to be used in many optoelectronic applications. Here, we demonstrate the development of ultrathin phototransistors and photonic synapses using a graphene-PQD (G-PQD) superstructure prepared by growing PQDs directly from a graphene lattice. We show that the G-PQDs superstructure synchronizes efficient charge generation and transport on a single platform. G-PQD phototransistors exhibit excellent responsivity of 1.4 × 108 AW-1 and specific detectivity of 4.72 × 1015 Jones at 430 nm. Moreover, the light-assisted memory effect of these superstructures enables photonic synaptic behavior, where neuromorphic computing is demonstrated by facial recognition with the assistance of machine learning. We anticipate that the G-PQD superstructures will bolster new directions in the development of highly efficient optoelectronic devices.

B cell depletion with rituximab in the treatment of primary Sjögren's syndrome: what have we learnt?

Despite the well-established role of B cells in the pathogenesis of primary Sjögren's syndrome (pSS), the beneficial role of B-cell depletion therapy with rituximab remains elusive in this condition, contrary to other autoimmune diseases. Although early, small-scale studies showed promising results, two recent large randomised controlled trials did not meet their primary end-points. It is evident from most trials that rituximab has a positive impact on B-cell numbers and activity, both in the peripheral blood and in salivary glands, but clinical outcomes vary among studies. We review here the evidence to date of B-cell depletion in pSS, analysing the underlying causes for the discrepancies in different studies and their limitations. We also discuss the potential use of peripheral and salivary gland biomarkers for patient stratification and targeted patient selection. Overall, rituximab remains a plausible treatment for pSS provided future studies address the shortfalls that emerged from our current knowledge of the use of B-cell depletion in this condition.

Influence of composition on the external quantum efficiency of reduced graphene oxide/carbon nanoparticle based photodetector used for human body IR detection.

Here, we developed an efficient infrared (IR) detector comprising reduced graphene oxide (RGO) and carbon nanoparticles (CNPs) for detecting human body IR radiation under ambient conditions. The RGO/CNP nanocomposite thin-film based photodetectors were assembled via a simple solution-phase cost-effective route with different concentrations of RGO solution while keeping CNP concentration constant. Three RGO/CNP nanocomposite photodetector devices were fabricated with three different concentrations of RGO (keeping CNP concentration constant) and their photoresponse properties have been studied. The devices showed a sharp response to IR radiation emitted by the human body at room temperature having a wavelength of nearly 780 nm. I-V characteristics, radiation current responsivity, and time response curves as well as their external quantum efficiencies have been studied and explained. We measured two important parameters, namely, IR responsivity (R λ) and external quantum efficiency (EQE) of RGO/CNP based IR detector devices. Our annotations show that R λ and EQE increase with increasing concentration of GO in RGO/CNP nanocomposites as expected. This simple and inexpensive approach based on the integration of RGO and CNP could also be useful for the design of other potential optoelectronic devices such as photosensors for use in auto-doors to permit the entrance of human bodies only and in spaceships or robots to identify the existence of humans on Mars and the Moon.

Therapeutic Effects of Doxycycline on the Quality of Repaired and Unrepaired Achilles Tendons.

BACKGROUND: Achilles tendon tears are devastating injuries, especially to athletes. Elevated matrix metalloproteinase (MMP) activity after a tendon injury has been associated with deterioration of the collagen network and can be inhibited with doxycycline (Doxy). HYPOTHESIS: Daily oral administration of Doxy will enhance the histological, molecular, and biomechanical quality of transected Achilles tendons. Additionally, suture repair will further enhance the quality of repaired tendons. STUDY DESIGN: Controlled laboratory study. METHODS: Randomized unilateral Achilles tendon transection was performed in 288 adult male Sprague-Dawley rats. The injured tendons were either unrepaired (groups 1 and 2) or surgically repaired (groups 3 and 4). Animals from groups 2 and 4 received Doxy daily through oral gavage, and animals from groups 1 and 3 served as controls (no Doxy). Tendons were harvested at 1.5, 3, 6, and 9 weeks after the injury (n = 18 per group and time point). The quality of tendon repair was evaluated based on the histological grading score, collagen fiber orientation, gene expression, and biomechanical properties. RESULTS: In surgically repaired samples, Doxy enhanced the quality of tendon repair compared with no Doxy ( P = .0014). Doxy had a significant effect on collagen fiber dispersion, but not principal fiber angle. There was a significant effect of time on the gene expression of MMP-3, MMP-9 and TIMP1, and Doxy significantly decreased MMP-3 expression at 9 weeks. Doxy treatment with surgical repair increased the dynamic modulus at 6 weeks but not at 9 weeks after the injury ( P < .001). Doxy also increased the equilibrium modulus and decreased creep strain irrespective of the repair group. Doxy did not have a significant effect on the histology or biomechanics of unrepaired tendons. CONCLUSION: The findings indicate that daily oral administration of Doxy accelerated matrix remodeling and the dynamic and equilibrium biomechanics of surgically repaired Achilles tendons, although such enhancements were most evident at the 3- to 6-week time points. CLINICAL RELEVANCE: The inhibition of MMPs at the optimal stage of the repair process may accelerate Achilles tendon repair and improve biomechanical properties, especially when paired with surgical management.

Timing of mesenchymal stem cell delivery impacts the fate and therapeutic potential in intervertebral disc repair.

Cell-based therapies offer a promising approach to treat intervertebral disc (IVD) degeneration. The impact of the injury microenvironment on treatment efficacy has not been established. This study used a rat disc stab injury model with administration of mesenchymal stromal cells (MSCs) at 3, 14, or 30 days post injury (DPI) to evaluate the impact of interventional timing on IVD biochemistry and biomechanics. We also evaluated cellular localization within the disc with near infrared imaging to track the time and spatial profile of cellular migration after in vivo delivery. Results showed that upon injection into a healthy disc, MSCs began to gradually migrate outwards over the course of 14 days, as indicated by decreased signal intensity from the disc space and increased signal within the adjacent vertebrae. Cells administered 14 or 30 DPI also tended to migrate out 14 days after injection but cells injected 3 DPI were retained at a significantly higher amount versus the other groups (p < 0.05). Correspondingly the 3 DPI group, but not 14 or 30 DPI groups, had a higher GAG content in the MSC injected discs (p = 0.06). Enrichment of MSCs and increased GAG content in 3 DPI group did not lead to increased compressive biomechanical properties. Findings suggest that cell therapies administered at an early stage of injury/disease progression may have greater chances of mitigating matrix loss, possibly through promotion of MSC activity by the inflammatory microenvironment associated with injury. Future studies will evaluate the mode and driving factors that regulate cellular migration out of the disc. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:32-40, 2017.

An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh.

A total of 45 patients with acute hepatitis were detected in a medical facility of Bangladesh over a period of 6 months. All of them were physicians, nurses, students or employees of the hospital. About 50% of these patients suffered from acute hepatitis within a period of 2 months. All of them had clinical and biochemical evidences of acute hepatitis. All of them shared common working places as well as common dining and cooking facilities. Although the disease was supposed to be caused by hepatitis viruses, none of them were expressing IgM type antibody to hepatitis B core antigen (IgM anti-HBc) or hepatitis C virus (IgM anti-HCV). IgM type antibody to hepatitis A virus (IgM HAV) was detected in one patient and IgM type antibody to hepatitis E virus (anti-HEV IgM) were found in 14 patients. In conclusion, diagnosis of etiological agent of viral acute hepatitis constitutes a formidable challenge to the existing health care delivery system in developing countries as available serological and routine screening fails to find the proper etiological agent. How to cite this article: Mahtab MA, Akbar SMF, Podder DC, Saha PK, Jahan M, Begum L, Afrose T, Chowdhury F, Rahman S. An Outbreak of Acute Hepatitis in a Medical Facility of Bangladesh. Euroasian J Hepato-Gastroenterol 2014;4(1):66-67.