Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative movement disorder worldwide, which is primarily characterized by motor impairments. Even though multiple hypotheses have been proposed over the decades that explain the pathogenesis of PD, presently, there are no cures or promising preventive therapies for PD. This could be attributed to the intricate pathophysiology of PD and the poorly understood molecular mechanism. To address these challenges comprehensively, a thorough disease model is imperative for a nuanced understanding of PD's underlying pathogenic mechanisms. This review offers a detailed analysis of the current state of knowledge regarding the molecular mechanisms underlying the pathogenesis of PD, with a particular emphasis on the roles played by gene-based factors in the disease's development and progression. This study includes an extensive discussion of the proteins and mutations of primary genes that are linked to PD, including α-synuclein, GBA1, LRRK2, VPS35, PINK1, DJ-1, and Parkin. Further, this review explores plausible mechanisms for DAergic neural loss, non-motor and non-dopaminergic pathologies, and the risk factors associated with PD. The present study will encourage the related research fields to understand better and analyze the current status of the biochemical mechanisms of PD, which might contribute to the design and development of efficacious and safe treatment strategies for PD in future endeavors.

Loss of PKCδ/Prkcd prevents cartilage degeneration in joints but exacerbates hyperalgesia in an experimental osteoarthritis mouse model.

Pain is the prime symptom of osteoarthritis (OA) that directly affects the quality of life. Protein kinase Cδ (PKCδ/Prkcd) plays a critical role in OA pathogenesis; however, its significance in OA-related pain is not entirely understood. The present study investigated the functional role of PKCδ in OA pain sensation. OA was surgically induced in control (Prkcdfl/fl), global- (Prkcdfl/fl; ROSACreERT2), and sensory neuron-specific conditional knockout (cKO) mice (Prkcdfl/fl; NaV1.8/Scn10aCreERT2) followed by comprehensive analysis of longitudinal behavioral pain, histopathology and immunofluorescence studies. GlobalPrkcd cKO mice prevented cartilage deterioration by inhibiting matrix metalloproteinase-13 (MMP13) in joint tissues but significantly increased OA pain. Sensory neuron-specificdeletion of Prkcd in mice did not protect cartilage from degeneration but worsened OA-associated pain. Exacerbated pain sensitivity observed in global- and sensory neuron-specific cKO of Prkcd was corroborated with markedly increased specific pain mediators in knee synovium and dorsal root ganglia (DRG). These specific pain markers include nerve growth factor (NGF) and vascular endothelial growth factor (VEGF), and their cognate receptors, including tropomyosin receptor kinase A (TrkA) and vascular endothelial growth factor receptor-1 (VEGFR1). The increased levels of NGF/TrkA and VEGF/VEGFR1 were comparable in both global- and sensory neuron-specific cKO groups. These data suggest that the absence of Prkcd gene expression in the sensory neurons is strongly associated with OA hyperalgesia independent of cartilage protection. Thus, inhibition of PKCδ may be beneficial for cartilage homeostasis but could aggravate OA-related pain symptoms.

An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-ß (Aß)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. The early stages of neurodegeneration in AD include the loss of neurons, followed by synaptic impairment. Since the discovery of AD, substantial factual research has surfaced that outlines the disease's causes, molecular mechanisms, and prospective therapeutics, but a successful cure for the disease has not yet been discovered. This may be attributed to the complicated pathogenesis of AD, the absence of a well-defined molecular mechanism, and the constrained diagnostic resources and treatment options. To address the aforementioned challenges, extensive disease modeling is essential to fully comprehend the underlying mechanisms of AD, making it easier to design and develop effective treatment strategies. Emerging evidence over the past few decades supports the critical role of Aß and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aß- and tau-associated molecular mechanisms and glial dysfunction in AD. Moreover, the critical risk factors associated with AD including genetics, aging, environmental variables, lifestyle habits, medical conditions, viral/bacterial infections, and psychiatric factors have been summarized. The present study will entice researchers to more thoroughly comprehend and explore the current status of the molecular mechanism of AD, which may assist in AD drug development in the forthcoming era.

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain.

Pain is the major reason that patients suffering from osteoarthritis (OA) seek medical care. We found that vascular endothelial growth factors (VEGFs) mediate signaling in OA pain pathways. To determine the specific contributions of VEGFs and their receptors (VEGFRs) to joint pathology and pain transmission during OA progression, we studied intra-articular (IA) injections of VEGF ligands into murine knee joints. Only VEGF ligands specific for the activation of VEGFR1, but not VEGFR2, induced allodynia within 30 min. Interventions in OA by inhibitors of VEGFRs were done in vivo using a preclinical murine OA model by IA injections of selective inhibitors of VEGFR1/VEGFR2 kinase (pazopanib) or VEGFR2 kinase (vandetanib). OA phenotypes were evaluated using pain-associated murine behavioral tests and histopathologic analyses. Alterations in VEGF/VEGFR signaling by drugs were determined in knee joints, dorsal root ganglia, and spinal cord by immunofluorescence microscopy. Pazopanib immediately relieved OA pain by interfering with pain transmission pathways. Pain reduction by vandetanib was mainly due to the inhibition of cartilage degeneration by suppressing VEGFR2 expression. In conclusion, IA administration of pazopanib, which simultaneously inhibits VEGFR1 and VEGFR2, can be developed as an ideal OA disease-modifying drug that rapidly reduces joint pain and simultaneously inhibits cartilage degeneration.

TXNIP shuttling - a key molecular link in regulating inflammation and mitochondrial dysfunction in freeze tolerant wood frogs.

Amphibians such as the wood frogs,Rana sylvatica, are a primary example of a freeze-tolerant vertebrate that undergoes whole body freezing. Multiple adaptations including sequestering 65-70% of total body water as extracellular/extra organ ice and producing massive amounts of glucose as a cryoprotectant support this. Interestingly, the high glucose levels induced in response to freezing can amplify oxidative stress's effects (reactive oxygen species, ROS) and induce inflammation and mitochondrial dysfunction. Since both freezing and dehydration stress (independent of freezing) can render wood frogs hyperglycemic, this study focussed on these two stresses to elucidate the role of a scaffold protein thioredoxin interacting protein (TXNIP), which localizes in multiple compartments inside the cell under hyperglycemic conditions and mediate diverse stress responses. The results from this study suggest a stress-specific response of TXNIP in inducing the cell-damaging pathway of inflammasome activation via its cytoplasmic localization during freezing. Interestingly, mitochondrial localization of TXNIP did not leads to increase in its binding to thioredoxin 2 (TRX-2) and activating the dysfunction of this organelle by releasing a mitochondrial protein cytochrome c (Cyt c) in cytoplasm under both freezing and dehydration stresses. Post-translational modifications of TXNIP hinted on changes in the regulating proteins involved in the inflammasome and mitochondrial dysfunction pathways, whereas sequential differences (cytosine residues) of amphibian TXNIP (compared to mammalian) assessed via 3D-modeling attributed to its weak binding to TRX-2. Overall, this study summarizes differential role of proteins activated under freeze and dehydration induced hyperglycemic response in freeze tolerant wood frogs.

Role of unfolded protein response and ER-associated degradation under freezing, anoxia, and dehydration stresses in the freeze-tolerant wood frogs.

The North American amphibian, wood frogs, Rana sylvatica are the most studied anuran to comprehend vertebrate freeze tolerance. Multiple adaptations support their survival in frigid temperatures during winters, particularly their ability to produce glucose as natural cryoprotectant. Freezing and its component consequences (anoxia and dehydration) induce multiple stresses on cells. Among these is endoplasmic reticulum (ER) stress, a condition spawned by buildup of unfolded or misfolded proteins in the ER. The ER stress causes the unfolded protein response (UPR) and the ER-associated degradation (ERAD) pathway that potentially could lead to apoptosis. Immunoblotting was used to assess the responses of major proteins of the UPR and ERAD under freezing, anoxia, and dehydration stresses in the liver and skeletal muscle of the wood frogs. Targets analyzed included activating transcription factors (ATF3, ATF4, ATF6), the growth arrest and DNA damage proteins (GADD34, GADD153), and EDEM (ERAD enhancing α-mannosidase-like proteins) and XBP1 (X-box binding protein 1) proteins. UPR signaling was triggered under all three stresses (freezing, anoxia, dehydration) in liver and skeletal muscle of wood frogs with most tissue/stress responses consistent with an upregulation of the primary targets of all three UPR pathways (ATF4, ATF6, and XBP-1) to enhance the protein folding/refolding capacity under these stress conditions. Only frozen muscle showed preference for proteasomal degradation of misfolded proteins via upregulation of EDEM (ERAD). The ERAD response of liver was downregulated across three stresses suggesting preference for more refolding of misfolded/unfolded proteins. Overall, we conclude that wood frog organs activate the UPR as a means of stabilizing and repairing cellular proteins to best survive freezing exposures.

A Scoping Review and Field Guide of Theoretical Approaches and Recommendations to Studying the Decision to Adopt Hearing Aids.

OBJECTIVES: Given the low rates of hearing aid adoption among individuals with hearing loss, it is imperative to better understand the decision-making processes leading to greater hearing aid uptake. A careful analysis of the existing literature on theoretical approaches to studying these processes is needed to help researchers frame hypotheses and methodology in studies on audiology. Therefore, we conducted a scoping review with two aims. First, we examine theories that have been used to study research on hearing aid adoption. Second, we propose additional theories from the behavioral sciences that have not yet been used to examine hearing aid uptake but that can inform future research. DESIGN: We identified peer-reviewed publications whose research was driven by one or more theoretical approaches by searching through PubMed, ProQuest PsycINFO, CINHAL Plus, Web of Science, Scopus, and OVID Medline/Embase/PsycINFO. The publications were examined by two researchers for eligibility. RESULTS: Twenty-three papers were included in the analysis. The most common theoretical approaches studied include the Health Belief Model, the Transtheoretical Model of Behavior Change, Self-Determination Theory, and the COM-B Model. Seven other theoretical frameworks based on cognitive psychology and behavioral economics have also appeared in the literature. In addition, we propose considering nudge theory, framing effect, prospect theory, social learning theory, social identity theory, dual process theories, and affective-based theories of decision making when studying hearing aid adoption. CONCLUSIONS: We conclude that, although a number of theories have been considered in research on hearing aid uptake, there are considerable methodological limitations to their use. Furthermore, the field can benefit greatly from the inclusion of novel theoretical approaches drawn from outside of audiology.

Sex-Linked Biology and Gender-Related Research Is Essential to Advancing Hearing Health.

There is robust evidence that sex (biological) and gender (behavioral/social) differences influence hearing loss risk and outcomes. These differences are noted for animals and humans-in the occurrence of hearing loss, hearing loss progression, and response to interventions. Nevertheless, many studies have not reported or disaggregated data by sex or gender. This article describes the influence of sex-linked biology (specifically sex-linked hormones) and gender on hearing and hearing interventions, including the role of sex-linked biology and gender in modifying the association between risk factors and hearing loss, and the effects of hearing loss on quality of life and functioning. Most prevalence studies indicate that hearing loss begins earlier and is more common and severe among men than women. Intrinsic sex-linked biological differences in the auditory system may account, in part, for the predominance of hearing loss in males. Sex- and gender-related differences in the effects of noise exposure or cardiovascular disease on the auditory system may help explain some of these differences in the prevalence of hearing loss. Further still, differences in hearing aid use and uptake, and the effects of hearing loss on health may also vary by sex and gender. Recognizing that sex-linked biology and gender are key determinants of hearing health, the present review concludes by emphasizing the importance of a well-developed research platform that proactively measures and assesses sex- and gender-related differences in hearing, including in understudied populations. Such research focus is necessary to advance the field of hearing science and benefit all members of society.

Subjective Impact of Age-Related Hearing Loss Is Worse for Those Who Routinely Experience Boredom and Failures of Attention.

OBJECTIVES: Despite extensive evidence supporting the benefits of hearing treatments for individuals affected by hearing loss, many leave their hearing issues unaddressed. This underscores the need to better understand the individual factors influencing decision-making regarding hearing loss treatments. One consideration regarding the low uptake of treatment is the finding that the subjective impact of hearing loss is greater for some individuals than for others, yielding a significant discrepancy between subjective measures of hearing loss (e.g., self-report hearing-handicap scales) and objective audiometric assessments (e.g., audiograms). The current study seeks to elucidate some of the cognitive-affective factors that give rise to these individual differences in the subjective impact of hearing loss. Specifically, we hypothesized that a stronger trait tendency to experience boredom would be correlated with more intensely negative experiences of hearing-related issues, and that this relationship would be mediated by underlying attentional difficulties. METHODS: Through a partnership with hearing care clinics (Connect Hearing Canada), we recruited a large sample of older adults (n = 1840) through their network of hearing-care clinics. Audiometric thresholds provided an objective measure of hearing ability for each participant, while self-report questionnaires assessed individual differences in the subjective impact of hearing-related issues (hearing handicap), subjective strain experienced when listening (listening effort), tendency to experience boredom, tendency to experience difficulty maintaining task-focused attention (mind-wandering), and self-perceived level of cognitive functioning. RESULTS: The subjective impact of hearing loss-both in terms of hearing handicap and strain when listening-was found to be more intensely negative for those who are characteristically more susceptible to experiencing boredom, and this relationship was shown to be mediated by self-reported differences in the ability to maintain task-focused attention. This relationship between trait boredom proneness and the subjective impact of hearing-related issues was evident across all levels of objective hearing abilities. Moreover, there was no evidence that the subjective impact of hearing loss is worse for those who routinely experience boredom because of objectively-poorer hearing abilities in those individuals. CONCLUSIONS: A greater trait susceptibility to experiencing boredom was associated with a more aversive subjective experience of hearing loss, and this relationship is mediated by attentional difficulties. This is a novel discovery regarding the cognitive-affective factors that are linked to individual differences in the effect that hearing loss has on individuals' daily functioning. These results may be helpful for better understanding the determinants of hearing-rehabilitation decisions and how to improve the uptake of treatments for hearing loss. The observational nature of the current study restricts us from drawing any definitive conclusions about the casual directions among the factors being investigated. Further research is therefore needed to establish how individual differences in the characteristic tendency to experience boredom are related to attentional-control difficulties and the experience of hearing-related issues. More research is also required to determine how all of these factors may influence decisions regarding hearing-loss treatments.

Hearing Aid Adoption is Associated with the Type of Significant Other in Attendance at Hearing Care Appointments.

There is increasing evidence to suggest that the implementation of family-centered care practices in clinical audiology yields positive patient outcomes. Previous work showed that significant-other attendance at audiology appointments, a recommended practice consistent with family-centered care, was associated with greater odds of hearing aid adoption and increased satisfaction with hearing aids. The primary goal of this retrospective explorative study was to investigate the unexplored question of whether an association exists between the type of significant other (SO) in attendance at appointments and hearing aid adoption. The study sample consisted of adult patients from a chain of private clinics in the United Kingdom who either attended their audiology appointment with a SO (n = 10,015) or alone (n = 37,152). Six SO types were identified and classified: partner (n = 6,608), parent (n = 76), child (n = 2,577), sibling (n = 208), friend (n = 518), and carer (n = 28). In addition to replicating previous findings which showed that significant-other attendance at audiology appointments was positively associated with hearing aid adoption, results from the current paper also revealed that the odds of hearing aid adoption were greater if the SO was of a stronger relationship tie (i.e., partners, parents, children, and siblings) and not a weaker relationship tie (i.e., friends, carers). These findings suggest that an extension of the non-audiological factor of significant-other attendance during the hearing rehabilitation process should be considered: the relationship type patients have with their significant others.

Sensory Neuron-Specific Deletion of Tropomyosin Receptor Kinase A (TrkA) in Mice Abolishes Osteoarthritis (OA) Pain via NGF/TrkA Intervention of Peripheral Sensitization.

Tropomyosin receptor kinase A (TrkA/NTRK1) is a high-affinity receptor for nerve growth factor (NGF), a potent pain mediator. NGF/TrkA signaling elevates synovial sensory neuronal distributions in the joints and causes osteoarthritis (OA) pain. We investigated the mechanisms of pain transmission as to whether peripheral sensory neurons are linked to the cellular plasticity in the dorsal root ganglia (DRG) and are critical for OA hyperalgesia. Sensory neuron-specific deletion of TrkA was achieved by tamoxifen injection in 4-week-old TrkAfl/fl;NaV1.8CreERT2 (Ntrk1 fl/fl;Scn10aCreERT2) mice. OA was induced by partial medial meniscectomy (PMM) in 12-week-old mice, and OA-pain-related behavior was analyzed for 12 weeks followed by comprehensive histopathological examinations. OA-associated joint pain was markedly improved without cartilage protection in sensory-neuron-specific conditional TrkA knock-out (cKO) mice. Alleviated hyperalgesia was associated with suppression of the NGF/TrkA pathway and reduced angiogenesis in fibroblast-like synovial cells. Elevated pain transmitters in the DRG of OA-induced mice were significantly diminished in sensory-neuron-specific TrkA cKO and global TrkA cKO mice. Spinal glial activity and brain-derived neurotropic factor (BDNF) were significantly increased in OA-induced mice but were substantially eliminated by sensory-neuron-specific deletion. Our results suggest that augmentation of NGF/TrkA signaling in the joint synovium and the peripheral sensory neurons facilitate pro-nociception and centralized pain sensitization.

Influence of Turfgrass Parameters on the Abundance of Arthropods in Sod Farms.

Sod farms, where turfgrass is commercially produced, have a unique system, in which sod is harvested within 2 yr after planting. Understanding the turfgrass factors that influence the abundance of predators, herbivores, detritivores, and parasitoids that inhabit turfgrass paves the foundation for developing effective pest management programs. However, little is known about those factors in sod farms. The objective of the study was to determine the influence of turfgrass height, density, and thatch thickness on abundance of arthropod taxa in sod farms. The study was conducted at 18 and 10 sod field sites in 2019 and 2020, respectively. Four pitfall traps were deployed at each site. In 2019, each site was sampled in May, June, and July, whereas in 2020, each site was sampled in June and August. In 2019, the numbers of predatory heteropterans were two times greater in bermudagrass (Cynodon dactylon L.) than in zoysiagrass (Zoysia spp.). The numbers of predatory mirids, Spanogonicus albofasciatus (Reuter), and carabids significantly decreased with increases in turfgrass height. In 2020, the abundance of staphylinids increased as the thatch thickness increased. The abundance of Sphenophorus spp. adults were significantly greater in bermudagrass than in zoysiagrass in 2020 and were more abundant in the denser turfgrasses in both years. The predatory arthropods were positively correlated with increased densities of cicadellids, whereas predatory mirids were positively associated with cicadellids, delphacids, and chrysomelids. These results have implications on management of arthropod pests in sod farms as abundance of beneficial arthropods are influenced by turfgrass factors.

Tissue-specific response of the RB-E2F1 complex during mammalian hibernation.

Metabolic rate depression during prolonged bouts of torpor is characteristic of mammalian hibernation, reducing energy expenditures over the winter. Cell cycle arrest is observed in quiescent cells during dormancy, partly due to the retinoblastoma (Rb) protein at G1 /S, given cell division and proliferation are metabolic-costly processes. Rb binds to E2F transcription factors and recruits corepressors (e.g., SUV39H1) to E2F target genes, blocking their transcription and cell cycle passage. Phosphorylation by cyclin-CDK complexes at S780 or S795 abolishes Rb-mediated repression, allowing transition into S phase. The present study compares Rb-E2F1 responses between euthermic and torpid states in five organs (brain, heart, kidney, liver, skeletal muscle) of 13-lined ground squirrels (Ictidomys tridecemlineatus). Immunoblotting assessed the expression of Rb, pRb (S780, S795), E2F1, and SUV39H1. Our findings demonstrate multi-tissue upregulation of Rb and SUV39H1 during torpor, with tissue-specific changes to E2F1 and pRb (S780), suggesting Rb-E2F1 contributes to cell cycle control in hibernation.

Lactobacillus acidophilus Mitigates Osteoarthritis-Associated Pain, Cartilage Disintegration and Gut Microbiota Dysbiosis in an Experimental Murine OA Model.

To test probiotic therapy for osteoarthritis (OA), we administered Lactobacillus acidophilus (LA) by oral gavage (2×/week) after induction of OA by partial medial meniscectomy (PMM). Pain was assessed by von Frey filament and hot plate testing. Joint pathology and pain markers were comprehensively analyzed in knee joints, spinal cords, dorsal root ganglia and distal colon by Safranin O/fast green staining, immunofluorescence microscopy and RT-qPCR. LA acutely reduced inflammatory knee joint pain and prevented further OA progression. The therapeutic efficacy of LA was supported by a significant reduction of cartilage-degrading enzymes, pain markers and inflammatory factors in the tissues we examined. This finding suggests a likely clinical effect of LA on OA. The effect of LA treatment on the fecal microbiome was assessed by 16S rRNA gene amplicon sequencing analysis. LA significantly altered the fecal microbiota compared to vehicle-treated mice (PERMANOVA p < 0.009). Our pre-clinical OA animal model revealed significant OA disease modifying effects of LA as reflected by rapid joint pain reduction, cartilage protection, and reversal of dysbiosis. Our findings suggest that LA treatment has beneficial systemic effects that can potentially be developed as a safe OA disease-modifying drug (OADMD).

Regulation of the cell cycle under anoxia stress in tail muscle and hepatopancreas of the freshwater crayfish, Orconectes virilis.

Regulation of the cell cycle is an understudied response to oxygen deprivation among crustaceans. The virile crayfish, Orconectes virilis, is a freshwater crustacean that when challenged by environmental oxygen limitation undergoes metabolic rate depression (to ~30% of normal levels) and switches to anaerobic metabolism to generate energy. To understand how crayfish regulate the cell cycle in response to anoxia, key proteins involved in cell cycle control were analyzed in muscle and hepatopancreas. At the G1/S barrier, an overall upregulation of positive regulators of cell cycle progression was indicated by the responses of G1 cyclins (cyclin D and cyclin E) and Cyclin dependent kinases (CDK4, CDK6 and CDK2) under anoxia. Although the levels of Cyclin kinase inhibitors (CKIs) at this juncture were also upregulated (P15/16 and P21 (T145) in muscle and P16 (S152) in hepatopancreas), levels of a major regulator of this phase and driver to S-phase, E2F1, were significantly higher in both tissues in conjunction with deactivation of its inhibitor, Retinoblastoma (Rb) protein. At the G2/M barrier, expression profiles of the G2 cyclin B suggested cell cycle progression despite overall trend of higher activities of checkpoint kinases, (Chk1 (S317) and Chk2 (S19)), that also negatively regulate the cyclin B-CDK1 complex via CdC25C (cell division cycle 25) whose levels remained unchanged. Overall, the present study suggests continued cell cycle progression, albeit with potential deceleration, as indicated by checkpoint kinases and kinase inhibitor profiles that might play a role in protecting tissues from apoptotic damage under chronic anoxic stress.

Mitochondrial DNA methyltransferases and their regulation under freezing and dehydration stresses in the freeze-tolerant wood frog, Rana sylvatica.

Wood frogs are a few vertebrate species that can survive whole-body freezing. Multiple adaptations support this, including cryoprotectant production (glucose), metabolic rate depression, and selective changes in gene and protein expression to activate pro-survival pathways. The role of DNA methylation machinery (DNA methyltransferases, DNMTs) in regulating nuclear gene expression to support freezing survival has already been established. However, a comparable role for DNMTs in the mitochondria has not been explored in wood frogs. We examined the mitochondrial protein levels of DNMT-1, DNMT-3A, DNMT-3B, and DNMT-3L as well as mitochondrial DNMT activity in the liver and heart to assess the involvement of DNMT in the survival of freezing and dehydration stresses (cellular dehydration being a component of freezing). Our results showed stress- and tissue-specific responses to mitochondrial DNMT-1 in the liver and heart, respectively. During 24 h of freezing and whole-body dehydration, we observed an overall downregulation of mitochondrial DNMT-1, a major protein involved in maintaining methylation levels related to its role in the selective transcription of mitochondrial genes as well as antioxidant response. Tissue-specific responses of protein levels of DNMT-3A, DNMT-3B, DNMT-3L, and DNMT activity in the liver suggested a preference for a higher methylation state in the liver under both freezing and dehydration stress, but not in the heart.

COVID-19 risk index (CRI): a simple and validated emergency department risk score that predicts mortality and the need for mechanical ventilation.

Although certain risk factors have been associated with morbidity and mortality, validated emergency department (ED) derived risk prediction models specific to coronavirus disease 2019 (COVID-19) are lacking. The objective of this study is to describe and externally validate the COVID-19 risk index (CRI). A large retrospective longitudinal cohort study was performed to analyze consecutively hospitalized patients with COVID-19. Multivariate regression using clinical data elements from the ED was used to create the CRI. The results were validated with an external cohort of 1799 patients from the MI-COVID19 database. The primary outcome was the composite of the need for mechanical ventilation or inpatient mortality, and the secondary outcome was inpatient mortality. A total of 1020 patients were included in the derivation cohort. A total of 236 (23%) patients in the derivation cohort required mechanical ventilation or died. Variables independently associated with the primary outcome were age ≥ 65 years, chronic obstructive pulmonary disease, chronic kidney disease, cerebrovascular disease, initial D-dimer > 1.1 µg/mL, platelet count < 150 K/µL, and severity of SpO2:FiO2 ratio. The derivation cohort had an area under the receiver operator characteristic curve (AUC) of 0.83, and 0.74 in the external validation cohort Calibration shows close adherence between the observed and expected primary outcomes within the validation cohort. The CRI is a novel disease-specific tool that assesses the risk for mechanical ventilation or death in hospitalized patients with COVID-19. Discrimination of the score may change given continuous updates in contemporary COVID-19 management and outcomes.

Pacemaker following transcatheter aortic valve replacement and tricuspid regurgitation: A single-center experience.

BACKGROUND: As transcatheter aortic valve replacement (TAVR) procedures increase, more data is available on the development of conduction abnormalities requiring permanent pacemaker (PPM) implantation post-TAVR. Mechanistically, new pacemaker implantation and incidence of associated tricuspid regurgitation (TR) post-TAVR is not well understood. Studies have evaluated the predictability of patient anatomy towards risk for needing permanent pacemaker (PPM) post-TAVR; however, little has been reported on new PPM and TR in patients post-TAVR. METHODS: This retrospective study identified patients at our health system who underwent PPM following TAVR from January 2014 to June 2018. Data from both TAVR and PPM procedures as well as patient demographics were collected. Echocardiographic data before TAVR, between TAVR and PPM placement, and the most recent echocardiogram at the time of chart review were analyzed. RESULTS: Of 796 patients who underwent TAVR between January 2014 and June 2018, 89 patients (11%) subsequently required PPM. Out of the 89 patients who required PPM implantation, 82 patients had pre-TAVR and 2-year post-TAVR echocardiographic imaging data. At baseline, 22% (18/82) of patients had at least moderate TR. At 2-year post-TAVR echocardiographic imaging follow-up; 27% (22/82) of patients had at least moderate TR. Subgroup analysis was performed according to the TAVR valve size implanted. In patients who received a TAVR device < 29 mm in diameter in size, 25% (11/44) had worsening TR. In patients who received a TAVR device ≥ 29 mm in diameter, 37% (14/38) had worsening TR. CONCLUSION: We have demonstrated a patient population that may be predisposed to developing worsening TR and right heart function after TAVR and Pacemaker implantation.

A Comparison between a remote testing and a laboratory test setting for evaluating emotional responses to non-speech sounds.

OBJECTIVE: To evaluate remote testing as a tool for measuring emotional responses to non-speech sounds. DESIGN: Participants self-reported their hearing status and rated valence and arousal in response to non-speech sounds on an Internet crowdsourcing platform. These ratings were compared to data obtained in a laboratory setting with participants who had confirmed normal or impaired hearing. STUDY SAMPLE: Adults with normal and impaired hearing. RESULTS: In both settings, participants with hearing loss rated pleasant sounds as less pleasant than did their peers with normal hearing. The difference in valence ratings between groups was generally smaller when measured in the remote setting than in the laboratory setting. This difference was the result of participants with normal hearing rating sounds as less extreme (less pleasant, less unpleasant) in the remote setting than did their peers in the laboratory setting, whereas no such difference was noted for participants with hearing loss. Ratings of arousal were similar from participants with normal and impaired hearing; the similarity persisted in both settings. CONCLUSIONS: In both test settings, participants with hearing loss rated pleasant sounds as less pleasant than did their normal hearing counterparts. Future work is warranted to explain the ratings of participants with normal hearing.

Descriptions of Hearing Aids Influence the Experience of Listening to Hearing Aids.

OBJECTIVES: Experiences can be strongly influenced by expectations. In hearing healthcare, previous studies have shown that descriptions of hearing aids or contextual factors during the hearing aid fitting process can change subjective and even objective outcomes with hearing aids via the placebo effect. Personality factors have also been shown to affect susceptibility to placebo effects. The purposes of the present study were to (a) investigate the effects of communicating narratives designed to foster positive, negative, or neutral expectations about hearing aids on short-term patient outcomes, and (b) to determine if the degree to which the narratives affected end-user outcomes could be predicted by personality factors. DESIGN: Nineteen adults between the ages of 54 and 81 (mean age = 68.5, SD = 8.9) had 3 separate research appointments, each exposing them to a different narrative condition: positive, negative, or neutral. the appointment was designed to look and feel like a "traditional" hearing aid fitting appointment, during which the experimenter introduced (i.e., the narrative condition) and fit a pair of hearing aids, the participant was asked to provide their initial feedback about the hearing aids, and the participant performed speech-in-noise testing. Unbeknownst to the research participant, the hearing aids fitted at all three appointments were the same, and the only difference between the three appointments was the way the hearing aids were described to the participants. RESULTS: The results of this study showed that communication of a positive narrative about hearing aids before a hearing aid fitting led to better speech-in-noise performance on the QuickSIN as compared with performance following the negative or neutral narrative conditions. Also, the positive narrative led to the perception that acclimatization to the hearing aids would occur faster than the negative or neutral narrative conditions. Notably, the effect of communication of a positive narrative was stronger for individuals who scored higher on agreeableness, and susceptibility to positive and negative messaging was stronger for individuals low in neuroticism. CONCLUSIONS: The study suggests that short-term evaluations of hearing aids can be strongly influenced by narratives as provided by the hearing healthcare provider at the time of a hearing aid fitting.