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Stress is a process that activates neuronal, metabolic, and neuroendocrine mechanisms. The individual's response may be determined by variables such as genetic factors, environmental conditions, sex, and age, among others. These responses are critical for survival, and the involvement of the hypothalamic-pituitary-adrenal axis is necessary for adaptation, which through counter-regulatory mechanisms seeks to restore homeostasis. Dentists are aware that there are variations in people's response to treatment, and there are many patients in whom dental treatment generates an important source of stress, which in many cases leads to treatment avoidance behavior., Competing Interests: Disclosures V. Iturriaga and N. Velasquez contributed to the conception and design and wrote the initial draft and figure preparation. D.C. Thomas and E. Eliav contributed to the manuscript by critically revising important intellectual content. All authors gave final approval and agreed to be accountable for all aspects of this work. The study was financed by Project DI20-0018 and the Temporomandibular Disorder and Orofacial Pain Program, Universidad de La Frontera, Chile. The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In recent years, extensive research has focused on cannabidiol (CBD), a well-studied non-psychoactive component of the plant-derived cannabinoids. CBD has shown significant therapeutic potential for treating various diseases and disorders, including antioxidants and anti-inflammatory effects. Due to the promising therapeutic effect of CBD in a wide variety of diseases, synthetic derivatization of this compound has attracted the attention of drug discovery in both industry and academia. In the current research, we focused on the derivatization of CBD by introducing Schiff base moieties, particularly (thio)-semicarbazide and aminoguanidine motifs, at the 3-position of the olivetolic ring. We have designed, synthesized, and characterized new derivatives based on CBD's framework, specifically aminoguanylhydrazone- and (thio)-semicarbazones-CBD-aldehyde compounds. Their antioxidant potential was assessed using FRAP and DPPH assays, alongside an evaluation of their effect on LDL oxidation induced by Cu 2+ and AAPH. Our findings suggest that incorporating the thiosemicarbazide motif into the CBD framework produces a potent antioxidant, warranting further investigation.

Background: Implementing the Age-Friendly Health System (AFHS) framework into dental care provides a significant opportunity to link oral health to healthy aging. This project aimed to implement the AFHS 4Ms (what matters, medications, mentation, and mobility) in the provision of oral health care. This article describes the planning, integration, training development, and outcome measurements supporting a 4Ms approach at an academic dental clinic., Methods: The Eastman Institute for Oral Health (EIOH) implemented screening instruments based on the 4Ms framework recommended for ambulatory care clinics by the Institute for Health Care Improvement (IHI). These ambulatory instruments were integrated into the workflows of a Specialty Care Clinic through the development of a plan-do-study-act cycle, utilization of available clinic resources, and creation of interdisciplinary collaborations., Results: This project demonstrated the feasibility of implementing an AFHS checklist and tracking forms in dental practice by integrating available resources and prioritizing the 4Ms elements. This effort necessitated interdisciplinary collaborations between dental, medical, and social service professionals. It also created a new age-friendly focused education and training curriculum for dental residents and faculty., Conclusions: This pilot project is the first to establish dental standards for AFHS implementation, adapting the 4Ms assessment and metrics to oral health. This AFHS underscores key oral health processes, including assessment, planning, and personalized oral health care, adapted to the unique needs of the older adult population, especially those with cognitive impairment., (© 2024 The American Geriatrics Society.)

Molecules containing short-lived, radioactive nuclei are uniquely positioned to enable a wide range of scientific discoveries in the areas of fundamental symmetries, astrophysics, nuclear structure, and chemistry. Recent advances in the ability to create, cool, and control complex molecules down to the quantum level, along with recent and upcoming advances in radioactive species production at several facilities around the world, create a compelling opportunity to coordinate and combine these efforts to bring precision measurement and control to molecules containing extreme nuclei. In this manuscript, we review the scientific case for studying radioactive molecules, discuss recent atomic, molecular, nuclear, astrophysical, and chemical advances which provide the foundation for their study, describe the facilities where these species are and will be produced, and provide an outlook for the future of this nascent field., (© 2024 IOP Publishing Ltd.)

The nuclear charge radius of ^{32}Si was determined using collinear laser spectroscopy. The experimental result was confronted with ab initio nuclear lattice effective field theory, valence-space in-medium similarity renormalization group, and mean field calculations, highlighting important achievements and challenges of modern many-body methods. The charge radius of ^{32}Si completes the radii of the mirror pair ^{32}Ar-^{32}Si, whose difference was correlated to the slope L of the symmetry energy in the nuclear equation of state. Our result suggests L≤60  MeV, which agrees with complementary observables.

Contextual embeddings, derived from deep language models (DLMs), provide a continuous vectorial representation of language. This embedding space differs fundamentally from the symbolic representations posited by traditional psycholinguistics. We hypothesize that language areas in the human brain, similar to DLMs, rely on a continuous embedding space to represent language. To test this hypothesis, we densely record the neural activity patterns in the inferior frontal gyrus (IFG) of three participants using dense intracranial arrays while they listened to a 30-minute podcast. From these fine-grained spatiotemporal neural recordings, we derive a continuous vectorial representation for each word (i.e., a brain embedding) in each patient. Using stringent zero-shot mapping we demonstrate that brain embeddings in the IFG and the DLM contextual embedding space have common geometric patterns. The common geometric patterns allow us to predict the brain embedding in IFG of a given left-out word based solely on its geometrical relationship to other non-overlapping words in the podcast. Furthermore, we show that contextual embeddings capture the geometry of IFG embeddings better than static word embeddings. The continuous brain embedding space exposes a vector-based neural code for natural language processing in the human brain., (© 2024. The Author(s).)

Purpose: This study explored the relationship between central sensitization symptoms, assessed using the Central Sensitization Inventory (CSI), and psychophysical factors in patients with chronic masticatory myofascial pain (MMP) transitioning from the acute to chronic stages., Methods: In this study, 23 patients with MMP and 22 healthy volunteers were assessed using psychophysical tests, including measurements of pressure pain threshold (PPT) and temporal summation of pain (TSP). Additionally, CSI scores were recorded to evaluate central sensitization symptoms., Results: Patients with chronic MMP showed significantly lower PPT in all masticatory muscles and extratrigeminal areas compared with controls. However, there was no significant correlation between CSI scores and psychophysical test results in patients with MMP., Conclusion: The significant enhancement of TSP in patients with subchronic MMP suggests a potential role in the onset of myofascial pain. The main finding suggests that sub-chronic symptom patients show higher CSI scores despite no sensory testing changes, indicating that central sensitization possibly precedes observable symptoms.

Mechanisms underlying neuropathic pain (NP) are complex with multiple genes, their interactions, environmental and epigenetic factors being implicated. Transcriptional changes in the trigeminal (TG) and dorsal root (DRG) ganglia have been implicated in the development and maintenance of NP. Despite efforts to unravel molecular mechanisms of NP, many remain unknown. Also, most of the studies focused on the spinal system. Although the spinal and trigeminal systems share some of the molecular mechanisms, differences exist. We used RNA-sequencing technology to identify differentially expressed genes (DEGs) in the TG and DRG at baseline and 3 time points following the infraorbital or sciatic nerve injuries, respectively. Pathway analysis and comparison analysis were performed to identify differentially expressed pathways. Additionally, upstream regulator effects were investigated in the two systems. DEG (differentially expressed genes) analyses identified 3,225 genes to be differentially expressed between TG and DRG in naïve animals, 1,828 genes 4 days post injury, 5,644 at day 8 and 9,777 DEGs at 21 days postinjury. A comparison of top enriched canonical pathways revealed that a number of signaling pathway was significantly inhibited in the TG and activated in the DRG at 21 days postinjury. Finally, CORT upstream regulator was predicted to be inhibited in the TG while expression levels of the CSF1 upstream regulator were significantly elevated in the DRG at 21 days postinjury. This study provides a basis for further in-depth studies investigating transcriptional changes, pathways, and upstream regulation in TG and DRG in rats exposed to peripheral nerve injuries. PERSPECTIVE: Although trigeminal and dorsal root ganglia are homologs of each other, they respond differently to nerve injury and therefore treatment. Activation/inhibition of number of biological pathways appear to be ganglion/system specific suggesting that different approaches might be required to successfully treat neuropathies induced by injuries in spinal and trigeminal systems., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

CRISPR/Cas9 technology is revolutionizing the field of gene editing. While this technology enables the targeting of any gene, it may also target unplanned loci, termed off-target sites (OTS), which are a few mismatches, insertions, and deletions from the target. While existing methods for finding OTS up to a given mismatch threshold are efficient, other methods considering insertions and deletions are limited by long runtimes, incomplete OTS lists, and partial support of versatile thresholds. Here, we developed SWOffinder, an efficient method based on Smith-Waterman alignment to find all OTS up to some edit distance. We implemented an original trace-back approach to find OTS under versatile criteria, such as separate limits on the number of insertions, deletions, and mismatches. Compared to state-of-the-art methods, only SWOffinder finds all OTS in the genome in just a few minutes. SWOffinder enables accurate and efficient genomic search of OTS, which will lead to safer gene editing., Competing Interests: The authors declare that they have no competing interests., (© 2023 The Author(s).)

Objective: Postdoctoral dental education in caring for older adults lacks didactic and clinical training in mentation topics, one of the core elements of the Age-Friendly Health Systems (AFHS) framework. Our primary goal was to launch a pilot project in clinical geriatrics focusing on older adults' mentation concerns, with a secondary goal to improve dental residents' confidence and competence in dental care and oral health., Background: Age-friendly care elements are not routinely incorporated into the dental education of residents caring for older adults with cognitive impairment or dementia. Therefore, we implemented a pilot educational project, providing the missing educational opportunity for residents in geriatric training covering cognitive impairment and focusing on Alzheimer's disease and related dementias., Materials and Methods: We designed educational sessions through a needs assessment, focus group discussions, and expert validation. We developed three e-Learning modules covering mentation concerns and dementia screening. We tested the modules in a pilot study of 15 dental postdoctoral residents as an essential part of their clinical practice., Results: The dementia dental learning module increased the residents' satisfaction with didactic preparedness (4.45  ± $ \pm \ $ 0.97) and knowledge acquisition (4.36  ± $ \pm \ $ 0.84). Residents strongly believed that learning about the AFHS-mentation topic would improve patient care., Conclusion: Our pilot study is a pioneer project in support of a new AFHS-themed dental curriculum for clinical education. Further expansion of the age-friendly principles to include mobility, medications, and what matters to older adults will establish a model framework of redesigned geriatric dental education for academic centers., (© 2023 Special Care Dentistry Association and Wiley Periodicals LLC.)

Scarcity of freshwater for agriculture has led to increased utilization of treated wastewater (TWW), establishing it as a significant and reliable source of irrigation water. However, years of research indicate that if not managed adequately, TWW may deleteriously affect soil functioning and plant productivity, and pose a hazard to human and environmental health. This review leverages the experience of researchers, stakeholders, and policymakers from Israel, the United-States, and Europe to present a holistic, multidisciplinary perspective on maximizing the benefits from municipal TWW use for irrigation. We specifically draw on the extensive knowledge gained in Israel, a world leader in agricultural TWW implementation. The first two sections of the work set the foundation for understanding current challenges involved with the use of TWW, detailing known and emerging agronomic and environmental issues (such as salinity and phytotoxicity) and public health risks (such as contaminants of emerging concern and pathogens). The work then presents solutions to address these challenges, including technological and agronomic management-based solutions as well as source control policies. The concluding section presents suggestions for the path forward, emphasizing the importance of improving links between research and policy, and better outreach to the public and agricultural practitioners. We use this platform as a call for action, to form a global harmonized data system that will centralize scientific findings on agronomic, environmental and public health effects of TWW irrigation. Insights from such global collaboration will help to mitigate risks, and facilitate more sustainable use of TWW for food production in the future., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hila Korach-Rechtman reports a relationship with Kando Environmental Services LTD that includes: employment., (© 2023 The Author(s).)

Combined molecular, physicochemical and chemical properties of electrophilic warheads can be applied to create covalent drugs with diverse facets. Here we study these properties in fluorinated diketones (FDKs) and their multicomponent equilibrium systems in the presence of protic nucleophiles, revealing the potential of the CF 2 (CO) 2 group to act as a multifaceted warhead for reversible covalent drugs. The equilibria compositions of various FDKs in water/octanol contain up to nine species. A simultaneous direct species-specific 19 F-NMR-based log P determination of these complex equilibria systems was achieved and revealed in some cases lipophilic to hydrophilic shifts, indicating possible adaptation to different environments. This was also demonstrated in 19 F-MAS-NMR-based water-membrane partitioning measurements. An interpretation of the results is suggested by the aid of a DFT study and 19 F-DOSY-NMR spectroscopy. In dilute solutions, a model FDK reacted with protected cysteine to form two hemi-thioketal regioisomers, indicating possible flexible regio-reactivity of CF 2 (CO) 2 warheads toward cysteine residues., (© 2023. Springer Nature Limited.)

The carriage of Candida albicans in children's oral cavities is associated with a higher risk for early childhood caries, so controlling this fungus in early life is essential for preventing caries. In a prospective cohort of 41 mothers and their children from 0 to 2 years of age, this study addressed four main objectives: (1) Evaluate in vitro the antifungal agent susceptibility of oral Candida isolates from the mother-child cohort; (2) compare Candida susceptibility between isolates from the mothers and children; (3) assess longitudinal changes in the susceptibility of the isolates collected between 0 and 2 years; and (4) detect mutations in C. albicans antifungal resistance genes. Susceptibility to antifungal medications was tested by in vitro broth microdilution and expressed as the minimal inhibitory concentration (MIC). C. albicans clinical isolates were sequenced by whole genome sequencing, and the genes related to antifungal resistance, ERG3 , ERG11 , CDR1 , CDR2 , MDR1 , and FKS1 , were assessed. Four Candida spp. (n = 126) were isolated: C. albicans, C. parapsilosis, C. dubliniensis , and C. lusitaniae . Caspofungin was the most active drug for oral Candida , followed by fluconazole and nystatin. Two missense mutations in the CDR2 gene were shared among C. albicans isolates resistant to nystatin. Most of the children's C. albicans isolates had MIC values similar to those from their mothers, and 70% remained stable on antifungal medications from 0 to 2 years. For caspofungin, 29% of the children's isolates showed an increase in MIC values from 0 to 2 years. Results of the longitudinal cohort indicated that clinically used oral nystatin was ineffective in reducing the carriage of C. albicans in children; novel antifungal regimens in infants are needed for better oral yeast control.

The science of temporomandibular disorder (TMD) pain and its management has gone through significant changes during the last several decades. The authors strongly feel that the effect of systemic factors influencing TMD pain has been largely overlooked and poorly accounted for, even in established pain-management programs and protocols. The hope is that this article will act as a wake-up call for the pain management community to consider the importance of adequate knowledge of the systemic factors that affect the experience of TMD pain by the patient., Competing Interests: Disclosure D.C. Thomas, E. Eliav, A.R. Garcia, and M. Fatahzadeh have no commercial or financial conflicts of interest. No funding was received for this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In the fear memory network, the hippocampus modulates contextual aspects of fear learning while mutual connections between the amygdala and the medial prefrontal cortex are widely involved in fear extinction. G-protein-coupled receptors (GPCRs) are involved in the regulation of fear and anxiety, so the regulation of GPCRs in fear signaling pathways can modulate the mechanisms of fear memory acquisition, consolidation and extinction. Various studies suggested a role of M-type K+ channels in modulating fear expression and extinction, although conflicting data prevented drawing of clear conclusions. In the present work, we examined the impact of M-type K+ channel blockade or activation on contextual fear acquisition and extinction. In addition, regarding the pivotal role of the hippocampus in contextual fear conditioning (CFC) and the involvement of the axon initial segment (AIS) in neuronal plasticity, we investigated whether structural alterations of the AIS in hippocampal neurons occurred during contextual fear memory acquisition and short-time extinction in mice in a behaviorally relevant context., Results: When a single systemic injection of the M-channel blocker XE991 (2 mg/kg, IP) was carried out 15 minutes before the foot shock session, fear expression was significantly reduced. Expression of c-Fos was increased following CFC, mostly in GABAergic neurons at day 1 and day 2 post-fear training in CA1 and dentate gyrus hippocampal regions. A significantly longer AIS segment was observed in GABAergic neurons of the CA1 hippocampal region at day 2., Conclusions: Our results underscore the role of M-type K + channels in CFC and the importance of hippocampal GABAergic neurons in fear expression., Competing Interests: Conflict of interests: The authors declare that they have no competing interests., (© 2023 the Author(s), licensee AIMS Press.)

Treatment of chronic orofacial pain remains a major therapeutic challenge despite available medications. Melanocortins have been implicated in pathologic pain. Intrathecal administration of MC4R antagonists has been shown to alleviate neuropathic pain (NP) in male rats. However, intrathecal delivery is very invasive and requires surgeon's intervention. Intra-nasal rout offers a non-invasive drug delivery method that can be self-administered making it very attractive clinically. In this study, we investigated the effects of intra-nasally delivered MC4R antagonist (HS014) on trigeminal neuropathic pain (TNP) in male and female rats. We also measured the MC4R protein levels in the trigeminal ganglia (TG) and infraorbital nerve (ION) of rats. We used ION chronic constriction injury (ION-CCI) to induce TNP in rats. We used von Frey and pinprick assays to measure the development of hypersensitivity in the face following ION-CCI. At 22 days post-ION-CCI, we delivered HS014 intra-nasally to measure its effects on TNP in rats. We used enzyme linked immunosorbent assay to measure MC4R protein levels in the TG and ION. ION-CCI resulted in a significant increase of MC4R protein levels in the ipsilateral TG and ION of male and female rats. Intra-nasal delivered HS014 resulted in a significant reduction of ION-CCI induced hypersensitivity in male and female rats. These results demonstrate that intranasal delivery of MC4R antagonist alleviated TNP in male and female rats and suggest that such treatment could be beneficial therapeutically for individuals with chronic NP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise., Objectives: A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain., Methods: EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications., Results: Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH., Conclusions: The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment., Significance: Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile., (© 2022 European Pain Federation - EFIC ®.)

Mitochondrial Ca 2+ efflux by NCLX is a critical rate-limiting step in mitochondria signaling. We previously showed that NCLX is phosphorylated at a putative Casein Kinase 2 (CKII) site, the serine 271 (S271). Here, we asked if NCLX is regulated by CKII and interrogated the physiological implications of this control. We found that CKII inhibitors down-regulated NCLX-dependent Ca 2+ transport activity in SH-SY5Y neuronal cells and primary hippocampal neurons. Furthermore, we show that the CKII phosphomimetic mutants on NCLX inhibited (S271A) and constitutively activated (S271D) NCLX transport, respectively, rendering it insensitive to CKII inhibition. These phosphomimetic NCLX mutations also control the allosteric regulation of NCLX by mitochondrial membrane potential (ΔΨm). Since the omnipresent CKII is necessary for modulating the plasticity of the axon initial segment (AIS), we interrogated, in hippocampal neurons, if NCLX is required for this process. Similarly to WT neurons, NCLX-KO neurons can exhibit homeostatic plasticity following M-channel block. However, while WT neurons utilize a CKII-sensitive distal relocation of AIS Na + and Kv7 channels to decrease their intrinsic excitability, we did not observe such translocation in NCLX-KO neurons. Thus, our results indicate that NCLX is regulated by CKII and is a crucial link between CKII signaling and fast neuronal plasticity., Competing Interests: The authors declare no conflict of interest.

Trigeminal nerve injury is one of the causes of chronic orofacial pain. Patients suffering from this condition have a significantly reduced quality of life. The currently available management modalities are associated with limited success. This article reviews some of the common causes and clinical features associated with post-traumatic trigeminal neuropathic pain (PTNP). A cascade of events in the peripheral and central nervous system function is involved in the pathophysiology of pain following nerve injuries. Central and peripheral processes occur in tandem and may often be co-dependent. Due to the complexity of central mechanisms, only peripheral events contributing to the pathophysiology have been reviewed in this article. Future investigations will hopefully help gain insight into trigeminal-specific events in the pathophysiology of the development and maintenance of neuropathic pain secondary to nerve injury and enable the development of new therapeutic modalities.

Studies have underscored the complexity of psychotherapy for Ultra-Orthodox Jews, and cross-cultural therapy in particular, which evokes fear of disruption of basic values. Parents' sense of responsibility for their child's religious education exacerbates these problems in child therapy. However, there is scant research on child therapy for the Ultra-Orthodox, especially in the field of arts therapies. The present study examined the perceptions of 17 Ultra-Orthodox parents whose children were receiving arts therapies (including art therapy, dance/movement therapy, music therapy, psychodrama and bibliotherapy). Semi-structured interviews were conducted with the parents and analyzed based on the principles of Consensual Qualitative Research. The study covered five domains: (1) The parents' experiences in therapy; (2) The parents' perceptions of the child's experiences in therapy; (3) Implications of environmental-social factors on the parents' perceptions and experiences of therapy; (4) Effects of intercultural aspects on therapy; (5) Perceptions of the use of the arts in therapy. The findings show that the experiences of ultra-Orthodox parents in the arts therapies of their children is complex due to the influence of the socio-cultural context, which involves dealing with stigma and tensions in their relationship with the education system. This context also shapes their perceptions of therapy, which can be characterized as purpose-oriented. The findings also highlight the parents' challenges in coping with the intercultural therapeutic relationship, and emphasizes the parents' preference for a therapist from a similar religious/cultural background and for cultural supervision of therapy. However, the results also suggest that there are benefits inherent to intercultural therapy in general and arts therapies in particular, including a sense of security, openness and acceptance of the parents and children.

Background: Hepatitis C virus (HCV) reinfection after successful treatment may reduce the benefits of cure among people who inject drugs., Objective: To evaluate the rate of HCV reinfection for 3 years after successful treatment among people receiving opioid agonist therapy (OAT)., Design: A 3-year, long-term, extension study of persons enrolled in the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) study (ClinicalTrials.gov: NCT02105688)., Setting: 55 clinical trial sites in 13 countries., Patients: Aged 18 years and older with chronic HCV infection with genotypes 1, 4, or 6 receiving stable OAT., Intervention: No treatments were administered., Measurements: Serum samples were assessed for HCV reinfection. Urine drug screening was performed., Results: Among 296 participants who received treatment, 286 were evaluable for reinfection and 199 were enrolled in the long-term extension study. The rate of HCV reinfection was 1.7 [95% CI, 0.8 to 3.0] per 100 person-years; 604 person-years of follow-up). A higher rate of reinfection was seen among people with recent injecting drug use (1.9 [95% CI, 0.5 to 4.8] per 100 person-years; 212 person-years). Ongoing drug use and injecting drug use were reported by 59% and 21% of participants, respectively, at the 6-month follow-up visit and remained stable during 3 years of follow-up., Limitations: Participants were required to be 80% adherent to OAT at baseline and may represent a population with higher stability and lower risk for HCV reinfection. Rate of reinfection may be underestimated because all participants did not continue in the long-term extension study; whether participants who discontinued were at higher risk for reinfection is unknown., Conclusion: Reinfection with HCV was low but was highest in the first 24 weeks after treatment completion and among people with ongoing injecting drug use and needle-syringe sharing., Primary Funding Source: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Departing from traditional linguistic models, advances in deep learning have resulted in a new type of predictive (autoregressive) deep language models (DLMs). Using a self-supervised next-word prediction task, these models generate appropriate linguistic responses in a given context. In the current study, nine participants listened to a 30-min podcast while their brain responses were recorded using electrocorticography (ECoG). We provide empirical evidence that the human brain and autoregressive DLMs share three fundamental computational principles as they process the same natural narrative: (1) both are engaged in continuous next-word prediction before word onset; (2) both match their pre-onset predictions to the incoming word to calculate post-onset surprise; (3) both rely on contextual embeddings to represent words in natural contexts. Together, our findings suggest that autoregressive DLMs provide a new and biologically feasible computational framework for studying the neural basis of language., (© 2022. The Author(s).)

Aims: To investigate the predictive power of depression and anxiety for conditioned pain modulation (CPM) and to examine the relationships of CPM at 40°C and CPM at 47°C with age, disease-related pain, pain duration, and psychosocial factors in burning mouth syndrome (BMS)., Methods: A total of 22 patients with BMS and 22 healthy female controls participated in this study. Temporal summation was used as the test stimulus for CPM, and subsequent exposure either to a nonpainful (40°C) or a painful (47°C) Peltier thermode was used as the conditioning stimulus. CPM was calculated as the difference in pain perception following the conditioning stimulus. Psychosocial factors were examined using the Profile of Mood States (POMS) and the State-Trait Anxiety Inventory (STAI)., Results: State anxiety and tension-anxiety scores were significantly higher for patients with BMS than for control participants. Multiple regression analyses showed that CPM47°C was affected by vigor, fatigue, confusion, and trait anxiety (adjusted R 2 = 0.685, F = 5.147, P = .098). The corresponding analysis for CPM40°C showed that the model was not predictive for the following variables: disease-related pain, pain duration, or components of the POMS or STAI. A significant positive correlation was found between CPM47°C and trait anxiety, suggesting that trait anxiety negatively affected the endogenous pain modulation system., Conclusion: Increases in trait anxiety reduced the CPM effect. These findings suggest that CPM impairments and increases in trait anxiety are involved in the development of BMS.

Background/purpose: Burning mouth syndrome (BMS) is a chronic condition presenting as intraoral burning or dysesthesia, with a high preponderance in menopausal women. This study aimed to examine the association between somatosensory dysfunction and BMS in premenopausal, early postmenopausal, and late postmenopausal patients, using a standardized Quantitative Sensory Testing (QST) protocol, and to determine the predictive value of thermal or mechanical perception by QST for detecting BMS., Materials and Methods: An observational case-control study was performed with 36 female participants with BMS (12 premenopausal, 10 early postmenopausal, and 14 late postmenopausal) and 42 age- and sex-matched healthy volunteers (21 premenopausal, 10 early postmenopausal, and 11 late postmenopausal). Neurophysiological tests were used to evaluate somatosensory dysfunction at the tongue., Results: Z-score in the late postmenopausal BMS group revealed a gain of function for the cold pain threshold and heat pain threshold (Z = 2.08 and 3.38, respectively). In the multiple regression analysis with the Visual Analog Scale as the dependent variable, the vibration detection threshold predicted the severity of burning mouth sensation in the premenopausal group., Conclusion: Late postmenopausal patients with BMS showed an increased response of the tongue to noxious thermal stimuli. This supports the theory that changes in sex hormones may affect trigeminal somatosensory function, particularly during the late postmenopausal stage in patients with BMS., Competing Interests: The authors declare that they have no competing interests., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

The changes in the mean-square charge radius (relative to ^{209}Bi), magnetic dipole, and electric quadrupole moments of ^{187,188,189,191}Bi were measured using the in-source resonance-ionization spectroscopy technique at ISOLDE (CERN). A large staggering in radii was found in ^{187,188,189}Bi^{g}, manifested by a sharp radius increase for the ground state of ^{188}Bi relative to the neighboring ^{187,189}Bi^{g}. A large isomer shift was also observed for ^{188}Bi^{m}. Both effects happen at the same neutron number, N=105, where the shape staggering and a similar isomer shift were observed in the mercury isotopes. Experimental results are reproduced by mean-field calculations where the ground or isomeric states were identified by the blocked quasiparticle configuration compatible with the observed spin, parity, and magnetic moment.

Background: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis., Methods: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva., Results: SNP rs4680 (val 158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender., Conclusions: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations., (© 2021 John Wiley & Sons, Ltd.)

We recently developed a molecule (GT-73) that blocked leukocyte transendothelial migration from blood to the peripheral tissues, supposedly by affecting the platelet endothelial cell adhesion molecule (PECAM-1) function. GT-73 was tested in an LPS-induced acute respiratory distress syndrome (ARDS) mouse model. The rationale for this is based on the finding that the mortality of COVID-19 patients is partly caused by ARDS induced by a massive migration of leukocytes to the lungs. In addition, the role of tert -butyl and methyl ester moieties in the biological effect of GT-73 was investigated. A human leukocyte, transendothelial migration assay was applied to validate the blocking effect of GT-73 derivatives. Finally, a mouse model of LPS-induced ARDS was used to evaluate the histological and biochemical effects of GT-73. The obtained results showed that GT-73 has a unique structure that is responsible for its biological activity; two of its chemical moieties ( tert -butyl and a methyl ester) are critical for this effect. GT-73 is a prodrug, and its lipophilic tail covalently binds to PECAM-1 via Lys536. GT-73 significantly decreased the number of infiltrating leukocytes in the lungs and reduced the inflammation level. Finally, GT-73 reduced the levels of IL-1β, IL-6, and MCP-1 in bronchoalveolar lavage fluid (BALF). In summary, we concluded that GT-73, a blocker of white blood cell transendothelial migration, has a favorable profile as a drug candidate for the treatment of ARDS in COVID-19 patients.

A measurement of the magnitude of the electric dipole moment of the electron (eEDM) larger than that predicted by the Standard Model (SM) of particle physics is expected to have a huge impact on the search for physics beyond the SM. Polar diatomic molecules containing heavy elements experience enhanced sensitivity to parity (P) and time-reversal (T)-violating phenomena, such as the eEDM and the scalar-pseudoscalar (S-PS) interaction between the nucleons and the electrons, and are thus promising candidates for measurements. The NL-eEDM collaboration is preparing an experiment to measure the eEDM and S-PS interaction in a slow beam of cold BaF molecules [P. Aggarwal et al., Eur. Phys. J. D 72, 197 (2018)]. Accurate knowledge of the electronic structure parameters, W d and W s , connecting the eEDM and the S-PS interaction to the measurable energy shifts is crucial for the interpretation of these measurements. In this work, we use the finite field relativistic coupled cluster approach to calculate the W d and W s parameters in the ground state of the BaF molecule. Special attention was paid to providing a reliable theoretical uncertainty estimate based on investigations of the basis set, electron correlation, relativistic effects, and geometry. Our recommended values of the two parameters, including conservative uncertainty estimates, are 3.13 ±0.12×10 24 Hzecm for W d and 8.29 ± 0.12 kHz for W s .

It is important for dental care professionals to reliably assess carbon dioxide (CO 2 ) levels and ventilation rates in their offices in the era of frequent infectious disease pandemics. This study was to evaluate CO 2 levels in dental operatories and determine the accuracy of using CO 2 levels to assess ventilation rate in dental clinics. Mechanical ventilation rate in air change per hour (ACH VENT ) was measured with an air velocity sensor and airflow balancing hood. CO 2 levels were measured in these rooms to analyze factors that contributed to CO 2 accumulation. Ventilation rates were estimated using natural steady-state CO 2 levels during dental treatments and experimental CO 2 concentration decays by dry ice or mixing baking soda and vinegar. We compared the differences and assessed the correlations between ACH VENT and ventilation rates estimated by the steady-state CO 2 model with low (0.3 L/min, ACH SS30 ) or high (0.46 L/min, ACH SS46 ) CO 2 generation rates, by CO 2 decay constants using dry ice (ACH DI ) or baking soda (ACH BV ), and by time needed to remove 63% of excess CO 2 generated by dry ice (ACH DI63% ) or baking soda (ACH BV63% ). We found that ACH VENT varied from 3.9 to 35.0 in dental operatories. CO 2 accumulation occurred in rooms with low ventilation (ACH VENT ≤6) and overcrowding but not in those with higher ventilation. ACH SS30 and ACH SS46 correlated well with ACH VENT ( r = 0.83, P = 0.003), but ACH SS30 was more accurate for rooms with low ACH VENT . Ventilation rates could be reliably estimated using CO 2 released from dry ice or baking soda. ACH VENT was highly correlated with ACH DI ( r = 0.99), ACH BV ( r = 0.98), ACH DI63% ( r = 0.98), and ACH BV63% ( r = 0.98). There were no statistically significant differences between ACH VENT and ACH DI63% or ACH BV63% . We conclude that ventilation rates could be conveniently and accurately assessed by observing the changes in CO 2 levels after a simple mixing of household baking soda and vinegar in dental settings.

Background: Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain., Methods: Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made., Results: The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury., Conclusion: EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recycling of all- trans -retinal to 11- cis -retinal through the visual cycle is a fundamental metabolic pathway in the eye. A potent retinoid isomerase (RPE65) inhibitor, ( R )-emixustat, has been developed and tested in several clinical trials; however, it has not received regulatory approval for use in any specific retinopathy. Rapid clearance of this drug presents challenges to maintaining concentrations in eyes within a therapeutic window. To address this pharmacokinetic inadequacy, we rationally designed and synthesized a series of emixustat derivatives with strategically placed fluorine and deuterium atoms to slow down the key metabolic transformations known for emixustat. Crystal structures and quantum chemical analysis of RPE65 in complex with the most potent emixustat derivatives revealed the structural and electronic bases for how fluoro substituents can be favorably accommodated within the active site pocket of RPE65. We found a close (∼3.0 Å) F-π interaction that is predicted to contribute ∼2.4 kcal/mol to the overall binding energy.

Aims: To investigate the role of exercise-induced hypoalgesia (EIH) in the development of neuropathic pain (NP) following infraorbital nerve (ION) injury and to explore possible underlying mechanisms defining the differences between rats with high and low EIH., Methods: EIH was evaluated by measuring the percentage of withdrawal responses to a series of 30 mechanical stimuli applied to the hind paw before and after 180 seconds of exercise on a rotating rod. The rats were assigned to low- and high-EIH groups based on reduction in the percent of withdrawal responses following exercise. NP was induced in high- and low-EIH rats via ION constriction injury. Rats were tested with graded nylon monofilaments to establish the withdrawal threshold. Increasingly stiff monofilaments were applied to the ION territory until there was a clear withdrawal by the rat. This was repeated a total of three times. A decreased withdrawal threshold indicates allodynia. Testing was performed at baseline and at 3, 10, and 17 days following the injury. On day 17 postinjury, IONs were harvested for the assessment of interleukin (IL)-6, IL-1β, and IL-10 levels. Samples from high-EIH and low-EIH surgically naïve rats served as control for the cytokines study. In this second part of the study, the effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) antagonists and naltrexone on EIH profiles and on the withdrawal thresholds to mechanical stimulation were measured. EIH and withdrawal thresholds in high- and low-EIH rats were measured before and after administration of antagonists., Results: Low-EIH rats developed significantly more pronounced allodynia in the ION territory following injury compared to high-EIH rats. At 17 days postinjury, ION IL-1β levels were higher in low-EIH rats, and IL-10 levels were higher in high-EIH rats. CB1 antagonist blocked the analgesic effect induced by exercise in high- but not in low-EIH rats. The CB2 antagonist had no significant effect on high- or low-EIH rats. Naltrexone blocked the effects of EIH in both high- and low-EIH rats. Exercise induced a significant analgesic effect in high-EIH but not in low-EIH rats. CB1 or CB2 antagonist administration had no effect on pre-exercise responses to mechanical stimulation, while naltrexone administration resulted in significant allodynia in both low- and high-EIH rats., Conclusion: This study demonstrated substantial differences between rats with high and low EIH. The results suggest that following ION injury, high-EIH rats may have a more prominent or activated endocannabinoids system and that their inflammatory response is moderated, with higher levels of IL-10 and lower levels of IL-1β.

Objectives: To evaluate the mechanical ventilation rates of dental treatment rooms and assess the effectiveness of aerosol removal by mechanical ventilation and a portable air cleaner (PAC) with a high-efficiency particulate air (HEPA) filter., Methods: Volumetric airflow were measured to assess air change rate per hour by ventilation (ACH vent ). Equivalent ventilation provided by the PAC (ACH pac ) was calculated based on its clean air delivery rate. Concentrations of 0.3, 0.5 and 1.0 μm aerosol particles were measured in 10 dental treatment rooms with various ventilation rates at baseline, after 5-min of incense burn, and after 30-min of observation with and without the PAC or ventilation system in operation. Velocities of aerosol removal were assessed by concentration decay constants for the 0.3 μm particles with ventilation alone (K n ) and with ventilation and PAC (K n+pac ), and by times needed to reach 95 % and 100 % removal of accumulated aerosol particles., Results: ACH vent varied from 3 to 45. K n and K n+pac were correlated with ACH vent (r = 0.90) and combined ACH total (r = 0.81), respectively. Accumulated aerosol particles could not be removed by ventilation alone within 30-min in rooms with ACH vent <15. PAC reduced aerosol accumulation and accelerated aerosol removal, and accumulated aerosols could be completely removed in 4 to 12-min by ventilation combined with PAC. Effectiveness of the PAC was especially prominent in rooms with poor ventilation. Added benefit of PAC in aerosol removal was inversely correlated with ACH vent ., Conclusions: Aerosol accumulation may occur in dental treatment rooms with poor ventilation. Addition of PAC with a HEPA filter significantly reduced aerosol accumulation and accelerated aerosol removal., Clinical Significance: Addition of PAC with a HEPA filter improves aerosol removal in rooms with low ventilation rates., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Data on barriers and facilitators to prenatal oral health care among low-income US women are lacking. The objective of this study was to understand barriers/facilitators and patient-centered mitigation strategies related to the use of prenatal oral health care among underserved US women., Methods: We used community-based participatory research to conduct two focus groups with eight pregnant/parenting women; ten individual in-depth interviews with medical providers, dental providers and community/social workers; and one community engagement studio with five representative community stakeholders in 2018-2019. Using an interpretive description research design, we conducted semi-structured interviews and focus groups which were audio-recorded, transcribed, and analyzed for thematic content., Results: We identified individual and systemic barriers/facilitators to the utilization of prenatal oral health care by underserved US women. Strategies reported to improve utilization included healthcare system-wide changes to promote inter-professional collaborations, innovative educational programs to improve dissemination and implementation of prenatal oral health care guidelines, and specialized dental facilities providing prenatal oral health care to underserved women. Moreover, smartphones have the potential to be an innovative entry point to promote utilization of prenatal oral care at the individual level., Conclusions: Low-income women face multiple, addressable barriers to obtaining oral health care during pregnancy. Inter-professional collaboration holds strong promise for improving prenatal oral health care utilization.

Subcutaneous emphysema is a rare but well-defined surgical complication. However, emphysema of the supraglottic mucosa has not been described in the literature. We present a case of a 2-year-old male who suffered supraglottic emphysema secondary to fiber optic CO 2 -laser use during laryngeal cleft repair. The patient required preemptive postoperative intubation; however, there were no long-lasting adverse effects at 6 and 12 weeks follow up. This report illustrates a rare CO 2 -laser complication and describes its sequela., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to examine temporal summation (TS) and conditioned pain modulation (CPM) in patients with burning mouth syndrome (BMS) and healthy controls using intra-epidermal electrical stimulation (IES)., Materials and Methods: Twenty-six female patients with BMS and 27 healthy female controls participated in this study. A single stimulus with electrical stimulation followed by a train of 10 successive stimuli was administered to the right chin of participants in both the BMS and control groups. CPM was evaluated with the changes of TS calculated from the difference in numerical pain scale data between these two test stimuli and the following warm (40°C) and hot (47°C) conditioning stimuli applied at the non-dominant hand in both the BMS and control groups., Results: TS was present in both the BMS and control groups. CPM in the BMS group was significantly less efficient at the 47°C condition than that in the control group, while no significant difference was observed in the CPM between the BMS and the control groups at the 40°C condition., Conclusion: These findings indicate that BMS is associated with a deficit inhibitory CPM and implicate the involvement of the central nervous system in the pathophysiology of BMS., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objectives: Heightened anxiety among dental healthcare professionals (DHPs) during the COVID-19 pandemic stems from uncertainties about the effectiveness of personal protective equipment (PPE) against dental aerosols and risk levels of asymptomatic patients. Our objective was to assess the risks for DHPs providing dental care during the pandemic based on available scientific evidence., Methods: We reviewed the best available evidence and estimated the annualized risk (p=d a s(1-1-p 0 p 1 (1-e) y n ) for a DHP during the COVID-19 pandemic based on the following basic parameters: p 0 , the probability that a DHP gets infected by an asymptomatic patient; e, the effectiveness of the PPE; s, the probability of becoming symptomatic after getting infected from asymptomatic patient; d 1 , the probability that a DHP gets infected by an asymptomatic patient; e, the effectiveness of the PPE; s, the probability of becoming symptomatic after getting infected from asymptomatic patient; d a , the probability of dying from the disease in age group a; n, number of patients seen per day; and y, number of days worked per year., Results: With the assumption that DHPs work fulltime and wear a N95 mask, the annualized probability for a DHP to acquire COVID-19 infection in a dental office, become symptomatic, and die from the infection is estimated at 1:13,000 (0.008 %) in a medium sized city in the US at the peak of the pandemic. The risk estimate is highly age-dependent. Risk to DHPs under the age of 70 is negligible when prevalence of asymptomatic cases is low in the local community., Conclusions: Risk of COVID-19 transmission in dental office is very low based on available evidence on effectiveness of PPE and prevalence of asymptomatic patients. Face shields and pre-procedure oral rinses may further reduce the risks., Clinical Significance: DHPs should follow guidelines on pre-appointment protocols and on PPE use during dental treatments to keep the risk low., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The discovery of how a photon is converted into a chemical signal is one of the most important achievements in the field of vision. A key molecule in this process is the visual chromophore retinal. Several eye diseases are attributed to the abnormal metabolism of retinal in the retina and the retinal pigment epithelium. Also, the accumulation of two toxic retinal derivatives, N-retinylidene-N-retinylethanolamine and the retinal dimer, can damage the retina leading to blindness. RPE65 (Retinal pigment epithelium-specific 65 kDa protein) is one of the central enzymes that regulates the metabolism of retinal and the formation of its toxic metabolites. Its inhibition might decrease the rate of the retina's degeneration by limiting the amount of retinal and its toxic byproducts. Two RPE65 inhibitors, (R)-emixustat and (R)-MB001, were recently developed for this purpose., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)