Bulletin of Computer Science and Electrical Engineering (BCSEE)
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Chapter 16 - Pathways and Mechanisms of Ocular Pain and Photophobia in Dry Eye Disease
No full textThe trigeminal nerve gives rise to the corneal nerve system, which plays a crucial role in sensory processing on the ocular surface (touch, pain, and temperature) as well as in healing and homeostasis through release of neuromodulators. Several forms of noxious stimuli can lead to dysfunctions along this pathway, manifesting as disease states such as dry eye disease (DED) characterized by chronic unpleasant ocular symptoms, including pain, discomfort, and photophobia. Ocular pain is part of a multidimensional sensory and emotional experience mediated by complex peripheral and central pathogenetic mechanisms. Different forms of ocular pain exist, including pain due to chronic noxious stimulation at the ocular surface (e.g., nociceptive pain), pain due to corneal nerve dysfunction causing hyperexcitability and sensitizing mechanisms (neuropathic pain), or both. Typically, noxious stimuli activate peripheral nerve terminals and generate signals that are relayed and processed in the spinal trigeminal nucleus of the medulla and then conveyed to the thalamus and other subcortical and cortical areas of the central nervous system. Normally, with removal of the stimulus, pain dissipates in an acute fashion. However, peripheral and central sensitization of neurons (due to spatially and temporally excessive noxious signal traffic, neuroinflammation, and glial activation) can result in hyperexcitability, allowing for chronicity with heightened spontaneous pain and abnormally painful evoked responses to stimuli (allodynia, hyperalgesia, photophobia). This chapter discusses concepts of corneal nerve anatomy and how they relate to ascending pathways of ocular pain and photophobia in DED
Pirtobrutinib in Covalent BTK-Inhibitor Pre-treated Mantle Cell Lymphoma
No full textPirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent (c) BTKi pre-treated mantle cell lymphoma (MCL), a population with poor prognosis.
Patients with cBTKi pre-treated relapsed/refractory MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 trial (BRUIN, NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DOR) and safety.
Median patient age was 70 years (range, 46-87), median prior lines of therapy 3 (range, 1-8), 82.2% had discontinued a prior cBTKi due to disease progression, and 77.8% had intermediate or high risk sMIPI score. The ORR was 57.8% (95% CI, 46.9-68.1), including 20.0% complete responses (n=18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5-not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n=164), the most common treatment-emergent adverse events (TEAE) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAE of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib due to a treatment-related AE.
Pirtobrutinib is a first-in-class novel non-covalent (reversible) BTKi, and the first BTKi of any kind to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated relapsed/refractory MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation due to toxicity
Corrigendum to “A systematic conservation plan identifying critical areas for improved chondrichthyan protection in South Africa” [Biol. Conserv. 284 (2023) 110163]
No full text712 CHILDREN WITH ABDOMINAL PAIN PREDOMINANT DISORDERS OF GUT-BRAIN INTERACTION HAVE MORE SLEEP DISTURBANCES. FIRST OF A KIND SCHOOL STUDY
No full textChapter 23 - Horizon scan of oceans and human health
No full textIn this chapter, we review the concept of “horizon scanning” for both emerging risks and opportunities, its uses, methods and approaches, and limitations. Horizon scanning can be a useful process if a diverse group of people are involved, and if there is the possibility of instituting preventive measures in the case of risks (i.e., the “Precautionary Principle”) or taking advantage of opportunities in sufficient time to make a difference to the outcomes. We discuss various examples of horizon scanning in the environmental and ocean sciences and then what has been done to date in the area of oceans and human health. Finally, we present a brief initial sampling of emerging issues in oceans and human health as identified by members of this research community. A much larger portion of the community should be engaged for a truly representative insight into potential emerging risks and opportunities in Oceans and Human Health
Acute Thrombotic Events in Association With Coronavirus Disease of 2019 Immunization as Initial Presentation of Congenital Factor VII Deficiency
No full textDiscordant Pathologic Diagnoses of Myelodysplastic Neoplasms and Their Implications for Registries and Therapies
No full textMyelodysplastic neoplasms (MDS) are a collection of hematopoietic disorders with widely variable prognoses and treatment options. Accurate pathologic diagnoses present challenges due to interobserver variability in interpreting morphology and quantifying dysplasia. We compared local clinical site diagnoses with central, adjudicated review from 918 participants enrolled in the ongoing National Heart, Lung, and Blood Institute National MDS Natural History Study (NCT02775383), a prospective observational cohort study of participants with suspected MDS or MDS/myeloproliferative neoplasms (MPNs). Locally, 264 (29%) were diagnosed as having MDS, 15 (2%) MDS/MPN overlap, 62 (7%) idiopathic cytopenia of undetermined significance (ICUS), 0 (0%) acute myeloid leukemia (AML) with <30% blasts, and 577 (63%) other. Approximately one-third of cases were reclassified following central review with 266 (29%) diagnosed as MDS, 45 (5%) MDS/MPN overlap, 49 (5%) ICUS, 15 (2%) AML <30%, and 543 (59%) other. Site miscoding errors accounted for over half (53%) of the local misdiagnoses, leaving a true misdiagnosis rate of 15% overall, 21% for MDS. Therapies were reported in 37% of patients, including 43% of patients with MDS, 49% of MDS/MPN, and 86% of AML <30% blasts. Treatment rates were lower (25%) in cases with true discordance in diagnosis compared to those where local and central diagnoses agreed (40%), and receipt of inappropriate therapy occurred in 7% of misdiagnosed cases. Discordant diagnoses were frequent, which has implications for the accuracy of study-related and national registries and can lead to inappropriate therapy
First study to assess the reliability of commonly used pain scales in children with disorders of gut‐brain interaction
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Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex.
No full textAutosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases.
We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities. SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities.SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites.SPEGα and SPEGβ have different interacting partners suggestive of differential function.Transcriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling.Mitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling.</AbstractText