A Potential Association between Ribonuclease 1 Dynamics in the Blood and the Outcome in COVID-19 Patients.

The COVID-19 pandemic caused by the new SARS-CoV-2 coronavirus is the most recent and well-known outbreak of a coronavirus. RNase 1 is a small endogenous antimicrobial polypeptide that possesses antiviral activity against viral diseases. In this study, we investigated a potential association between ribonuclease 1 and the outcome in COVID-19 patients and the impact of increased and decreased RNase 1 levels serum during the course of the disease. Therefore, two patient populations, Cohort A (n = 35) and B (n = 80), were subclassified into two groups, in which the RNase 1 concentration increased or decreased from time point one to time point two. We show that the RNase 1 serum levels significantly increased in the increasing group of both cohorts (p = 0.0171; p < 0.0001). We detect that patients in the increasing group who died had significantly higher RNase 1 serum levels at both time points in Cohort A (p = 0.0170; p = 0.0393) and Cohort B (p = 0.0253; p = 0.0034) than patients who survived. Additionally, we measured a significant correlation of RNase 1 serum levels with serum creatinine as well as creatinine clearance in the increasing and decreasing group at both time points of Cohort A. Based on these results, there is now good evidence that RNase 1 may play a role in renal dysfunction associated with ICU COVID-19 patients and that increasing RNase 1 serum level may be a potential biomarker to predict outcome in COVID-19 patients.

The association of psychological protective factors with caregiver mental health outcomes.

The primary objectives were to investigate the association of resilience, purpose-in-life, and social connections in additive combinations with mental health outcomes of caregivers: 1) reduced levels of loneliness and/or depression; and 2) higher levels of positive perception of aging and quality of life. The study sample was identified from adults age ≥65, who had completed a survey during May-June 2018 or May-June 2019, and self-identified as caregivers (N=1,015; 15.4%). Resilience, purpose-in-life, and social connections were dichotomized as high/low; then counted with equal weighting 0 to 3. Among caregiver respondents, 24%, 29%, 32%, and 15% had 0, 1, 2, or 3 of these protective factors, respectively. As the number of protective factors increased, loneliness and depression decreased and positive perception of aging and quality of life increased. Caregiver interventions that include a focus on psychological protective factors may help to buffer caregiving-related stress thereby improving mental health and quality of life.

DAMPs Released from Proinflammatory Macrophages Induce Inflammation in Cardiomyocytes via Activation of TLR4 and TNFR.

Cardiac dysfunction is a life-threatening complication in sepsis. Upon infection and cardiac stress, the cardiac macrophage population expands. Recruited macrophages exhibit a predominantly proinflammatory phenotype and release danger-associated molecular patterns (DAMPs) that contribute to cardiac dysfunction. However, the underlying pathomechanisms are highly complex and not fully understood. Here, we utilized an indirect macrophage-cardiomyocyte co-culture model to study the effects of proinflammatory macrophages on the activation of different cardiac receptors (TLR3, TLR4, and TNFR) and their role in cardiac inflammation and caspase-3/7 activation. The stimulation of cardiomyocytes with conditioned medium of LPS-stimulated macrophages resulted in elevated IL-6 protein concentrations and relative IL-6 and TNFα mRNA levels. Conditioned medium from LPS-stimulated macrophages also induced NFκB translocation and increased caspase-3/7 activation in cardiomyocytes. Analyzing the role of different cardiac receptors, we found that TLR4 and TNFR inhibition reduces cardiac inflammation and that the inhibition of TNFR prevents NFκB translocation into the nuclei of cardiomyocytes, induced by exposure to conditioned medium of proinflammatory macrophages. Moreover, we demonstrated that TLR3 inhibition reduces macrophage-mediated caspase-3/7 activation. Our results suggest that the immune response of macrophages under inflammatory conditions leads to the release of DAMPs, such as eRNA and cytokines, which in turn induce cardiomyocyte dysfunction. Thus, the data obtained in this study contribute to a better understanding of the pathophysiological mechanisms of cardiac dysfunction.

The Potential Impact of Heparanase Activity and Endothelial Damage in COVID-19 Disease.

SARS-CoV-2 was first detected in 2019 in Wuhan, China. It has been found to be the most pathogenic virus among coronaviruses and is associated with endothelial damage resulting in respiratory failure. Determine whether heparanase and heparan sulfate fragments, biomarkers of endothelial function, can assist in the risk stratification and clinical management of critically ill COVID-19 patients admitted to the intensive care unit. We investigated 53 critically ill patients with severe COVID-19 admitted between March and April 2020 to the University Hospital RWTH Aachen. Heparanase activity and serum levels of both heparanase and heparan sulfate were measured on day one (day of diagnosis) and day three in patients with COVID-19. The patients were classified into four groups according to the severity of ARDS. When compared to baseline data (day one), heparanase activity increased and the heparan sulfate serum levels decreased with increasing severity of ARDS. The heparanase activity significantly correlated with the lactate concentration on day one (r = 0.34, p = 0.024) and on day three (r = 0.43, p = 0.006). Heparanase activity and heparan sulfate levels correlate with COVID-19 disease severity and outcome. Both biomarkers might be helpful in predicting clinical course and outcomes in COVID-19 patients.

The association of resilience, social connections, and internal locus of control with pain outcomes among older adults.

Our objective was to investigate the hypothesis that psychological resources, including resilience, social connections, and internal locus of control, separately and in additive combinations, would be associated with selected pain outcomes: 1) days of opioid use and 2) medical/drug expenditures over 2 years. A mailed survey was sent to a stratified sample of older adults age≥65 with diagnosed back pain, osteoarthritis, and/or rheumatoid arthritis. Each of the resources was dichotomized as high/low and/or counted with equal weighting. Among respondents (N=3,131), the prevalence of mild/no and moderate/severe pain severity was 59% and 41%, respectively. As hypothesized, each resource was associated with lower levels of pain; additively, reported pain severity decreased as the number of resources increased. For moderate/severe pain, there was reduced opioid use among those with more resources; and, for mild/no pain, decreased medical/drug expenditures among those with ≥2 resources. Interventions that integrate psychological resources may enhance their effectiveness.

The association of physical activity with loneliness, social isolation, and selected psychological protective factors among older adults.

The primary objectives were to investigate the association of physical activity levels with 1) loneliness and social isolation; 2) protective factors: resilience, purpose-in-life, and perception of aging; and 3) the impact of these factors on healthcare expenditure patterns across physical activity levels. The study sample was identified from adults age ≥65 who completed a health survey in 2018 or 2019 (N=6,652). Among survey respondents, the prevalence of low, moderate, and high physical activity levels was 29%, 31%, and 41%, respectively. Moderate and high physical activity were associated with 15%-30% lower likelihoods of loneliness and social isolation; and with 27% to 150% higher protective factors. In addition, physical activity was associated with the mitigation of increased healthcare expenditures associated with loneliness, social isolation, and low levels of protective factors. Thus, physical activity could serve as an intervention to reduce loneliness and social isolation, augment protective factors, and mitigate excess healthcare expenditures.

Comparison of the Hemocompatibility of an Axial and a Centrifugal Left Ventricular Assist Device in an In Vitro Test Circuit.

BACKGROUND: Hemocompatibility of left ventricular assist devices is essential for preventing adverse events. In this study, we compared the hemocompatibility of an axial-flow (Sputnik) to a centrifugal-flow (HeartMate 3) pump. METHODS: Both pumps were integrated into identical in vitro test circuits, each filled with 75 mL heparinized human blood of the same donor. During each experiment (n = 7), the pumps were operated with equal flow for six hours. Blood sampling and analysis were performed on a regular schedule. The analytes were indicators of hemolysis, coagulation activation, platelet count and activation, as well as extracellular vesicles. RESULTS: Sputnik induced higher hemolysis compared to the HeartMate 3 after 360 min. Furthermore, platelet activation was higher for Sputnik after 120 min onward. In the HeartMate 3 circuit, the platelet count was reduced within the first hour. Furthermore, Sputnik triggered a more pronounced increase in extracellular vesicles, a potential trigger for adverse events in left ventricular assist device application. Activation of coagulation showed a time-dependent increase, with no differences between both groups. CONCLUSIONS: This experimental study confirms the hypothesis that axial-flow pumps may induce stronger hemolysis compared to centrifugal pumps, coming along with larger amounts of circulating extracellular vesicles and a stronger PLT activation.

Inhibition of Macrophage Migration Inhibitory Factor Activity Attenuates Haemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats.

Objective: The aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS. Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown. Methods: The MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver. Results: We demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver. Conclusion: Our results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage.

The association of increasing resilience with positive health outcomes among older adults.

Our objective was to investigate three levels of resilience (low, medium, and high), identify associated characteristics, and measure the impact of increasing resilience on quality of life (QOL), healthcare utilization and expenditures, and preventive services compliance. The study sample was identified from adults age ≥65 who completed surveys during May-June 2019 (N=3,573). Other protective factors, including purpose-in-life, optimism, locus of control, and social connections, were dichotomized as high/low and counted with equal weighting (0 to 4). Among survey respondents, the prevalence of low, medium, and high resilience levels was 27%, 29%, and 44%, respectively. The strongest predictors of medium and high resilience included increasing number of other protective factors, lower stress, and no depression. Individuals with medium and high resilience had significantly higher QOL and lower healthcare utilization and expenditures. Resilience strategies integrated into healthy aging programming could be associated with improvements in QOL and/or healthcare utilization and expenditure outcomes.

The impact of COVID-19 on older adults: Results from an annual survey.

OBJECTIVES: Assess well-being among older adults through secondary analysis measured during an annual survey in 2018, 2019, and 2020, to determine trends from before and during the COVID-19 pandemic. METHODS: Mailed surveys sent annually included measures related to various psychosocial factors. MAIN FINDINGS: Response rates were 29% in 2018, 25% in 2019, and 24% in 2020. Most respondents reported average or high resilience (89% 2018-2020), high purpose (64% in 2018 and 2019, 63% in 2020), moderate optimism (46% in 2019, 44% in 2020) and low stress (88% in 2019 and 2020). Reported loneliness increased 13% from 2018 to 2020. In 2020, only 45% reported high comfort with technology, decreasing with age (>75). PRINCIPAL CONCLUSION: Psychosocial well-being of respondents were doing well despite changes related to COVID-19. However, increased loneliness may negatively impact long-term health outcomes; thus, a focus on technology options to stay socially connected and access healthcare are needed.

Repetitive Treatment with Volatile Anesthetics Does Not Affect the In Vivo Plasma Concentration and Composition of Extracellular Vesicles in Rats.

BACKGROUND: Anesthetic-induced preconditioning (AIP) with volatile anesthetics is a well-known experimental technique to protect tissues from ischemic injury or oxidative stress. Additionally, plasmatic extracellular vesicle (EV) populations and their cargo are known to be affected by AIP in vitro, and to provide organ protective properties via their cargo. We investigated whether AIP would affect the generation of EVs in an in vivo rat model. METHODS: Twenty male Sprague Dawley rats received a repetitive treatment with either isoflurane or with sevoflurane for a duration of 4 or 8 weeks. EVs from blood plasma were characterized by nanoparticle tracking analysis, transmission electron microscopy (TEM) and Western blot. A scratch assay (H9C2 cardiomyoblast cell line) was performed to investigate the protective capabilities of the isolated EVs. RESULTS: TEM images as well as Western blot analysis indicated that EVs were successfully isolated. The AIP changed the flotillin and CD63 expression on the EV surface, but not the EV concentration. The scratch assay did not show increased cell migration and/or proliferation after EV treatment. CONCLUSION: AIP in rats changed the cargo of EVs but had no effect on EV concentration or cell migration/proliferation. Future studies are needed to investigate the cargo on a miRNA level and to investigate the properties of these EVs in additional functional experiments.

COVID-19 Era Social Isolation among Older Adults.

Risk of COVID-19 exposure and more severe illness are serious concerns for older adults. Social distancing has worsened existing social isolation, with severe impacts on connectedness among seniors. The pandemic is threatening to cause an extended health crisis, with impacts including serious health consequences. Our primary purpose is to summarize emerging research describing the impacts of the pandemic on social isolation among older adults. A streamlined search was conducted to fit the scope of this literature review. Common research databases and mainstream resources and websites were utilized to identify research published or released in 2020 to align with the pandemic. Early research indicates that the pandemic has worsened social isolation among older adults. Social isolation has become urgent, as seniors have lost their usual connections due to social distancing. While safety measures are critical to prevent virus exposure, this approach must be balanced with maintaining social connectedness. The pandemic highlights the importance of social connections, with significant impacts on both community-living older adults and those in nursing facilities. Safety protocols have created a paradox of reduced risk along with greater harm. Consequently, adapted approaches are urgently needed to address the consequences of a long-term social recession.

Safety Events Associated with Tramadol Use Among Older Adults with Osteoarthritis.

Tramadol is a low-level opioid increasingly recommended to treat moderate-to-severe acute and chronic pain. Although characterized as having fewer opioid-related adverse events, the longer term safety of tramadol use among older adults has not been thoroughly documented. Thus, the primary objective was to examine the risk of safety events associated with chronic tramadol use compared to other chronic opioid use or no opioids among older adults with osteoarthritis. Safety events considered included: ≥3 emergency room (ER) visits, falls/hip fractures, cardiovascular (CVD) hospitalization, composite safety event hospitalization, and all-cause mortality. The study population included older adults ages ≥65 years diagnosed with osteoarthritis and classified into new or continuing tramadol use, new or continuing other opioid use, or nonuse. Inclusion criteria included: 6-month pre period and up to 33 months post period. Tramadol, other opioid, and no opioid users were 1:1 propensity-matched providing study populations of 25,899 within each category; 72% were new chronic opioid users. Multiple logistic regression or Cox proportional hazard ratios were used to document risk. Generally, tramadol users had fewer adverse event risks compared to other opioid users but higher risks than nonusers. New users of tramadol or other opioids had higher risks than continuing users. Tramadol use was associated with increased risk of multiple ER utilizations, falls/fractures, CVD hospitalizations, safety event hospitalizations, and mortality (new users only) compared to nonuse. Thus, although tramadol use may be appropriately recommended within a pain management strategy for older adults with osteoarthritis, careful monitoring for adverse safety events is warranted.

Psychosocial Factors Associated with Sleep Quality and Duration Among Older Adults with Chronic Pain.

Sleep complaints are common among older adults with chronic pain. Because of the risk of significant side effects, sleep medications are not recommended as first-line treatments. Little is known about the association between positive psychosocial factors and sleep, but further awareness could support non-drug strategies to minimize poor sleep. The purpose of this study was to (1) determine the prevalence of self-reported poor sleep quality and short/long sleep duration in a population of older adults with chronic pain, and (2) examine the associations of negative risk factors, sleep-inducing medications, and positive psychosocial characteristics on sleep outcomes in this population. This study analyzed survey responses from 4201 adults ages ≥65 years with diagnosed back pain, osteoarthritis, and/or rheumatoid arthritis, and at least 1 year of continuous medical and drug plan enrollment. The most commonly reported sleep outcome was short sleep duration (39%), followed by poor sleep quality (22%), and long sleep duration (9%). Based on pharmaceutical claims, prescriptions for opioids (59%) or benzodiazepines (22%) were common. Perceived stress, depression, and pain or sleep prescription medications were independently associated with poor sleep quality and short or long sleep durations. The positive psychosocial factors of higher resilience and more diverse social networks were independently associated with good sleep quality and optimal sleep duration. These results underscore the importance of social and coping factors to sleep, which may provide new opportunities to improve sleep and well-being in older adults with chronic pain.

The additive impact of multiple psychosocial protective factors on selected health outcomes among older adults.

Our objective was to investigate the additive properties of five psychosocial protective factors: purpose-in-life, resilience, optimism, internal locus of control and social connections. Self-reported psychological (depression, stress) and physical (health status, functionality) health outcomes and measured healthcare utilization and expenditures were included. The study sample was identified from adults age ≥65 who completed a health survey during May-June 2019 (N = 3,577). Each of the five protective factors was dichotomized as high/low (1/0) and counted with equal weighting. The protective factors were additive such that significant improvements in psychological and physical health outcomes were evident across factor subgroups: as the number of factors increased, health outcomes improved. The magnitude of the improvements was greatest between 0 and 1 factor. In addition, a significant linear trend for reduced healthcare expenditures ($1,356 reduction per factor added) was evident. Interventions promoting at least one protective factor would be beneficial for older adult populations.

The association of pain locus of control with pain outcomes among older adults.

Our primary objective was to 1) determine the prevalence of pain locus of control (LOC) subscales in a population of older adults with pain conditions, and 2) estimate their associated protective effects on pain outcomes. A mailed survey was sent to a stratified sample of older adults age≥65 with diagnosed back pain, osteoarthritis and/or rheumatoid arthritis. Multivariate logistic regression modeling was used to determine the relative protective associations of positive resources, including LOC, resilience and social networks, on pain outcomes. Among respondents (N = 3,824), 31% were identified as internal; 34% as powerful others; and 35% as chance. In adjusted models, internal was associated with outcomes of lower pain severity, reduced chronic opioid use and increased physical functionality. Powerful others was partially protective; chance was associated with the poorest outcomes. Multidimensional pain programs should incorporate the enhancement of positive resources, including LOC, to maximize the effectiveness of pain management strategies.

The impact of internal locus of control on healthcare utilization, expenditures, and health status across older adult income levels.

Our objectives were to 1) determine the prevalence of locus of control (LOC) dimensions stratified by older adult income levels; 2) characterize internal LOC attributes within income subgroups; and 3) investigate LOC associations with healthcare utilization and expenditures; self-rated health and functionality. The survey sample was identified from adults age ≥65 years with diagnosed pain conditions. Internal LOC characteristics were determined from logistic regressions; outcomes regression-adjusted. Among respondents, internal prevalence for low (N = 554), medium (N = 1,394) and high income (N = 2040) was 27%, 30% and 30%, respectively. Internal was associated with high resilience, less stress, exercise and less opioid use across income levels. Lower-income internal was additionally associated with diverse social networks, physical therapy and less drug use. Those with high internal generally had lower healthcare utilization and expenditures; better self-rated health and functionality. Internal LOC is a powerful positive resource associated with better health outcomes, especially influential for lower income.

Association of Resilience and Social Networks with Pain Outcomes Among Older Adults.

Depression, stress, and poor sleep have been associated with increased pain among older adults; positive resources, such as resilience and social networks, may help to buffer the impacts of these negative attributes on pain outcomes. The primary objective was to determine the relative effects of positive resources and negative attributes on pain outcomes among older adults with diagnosed back pain, osteoarthritis, and rheumatoid arthritis. The stratified study sample was identified from older adults ages ≥65 years. Members received a survey assessing positive resources (resilience, social networks), negative attributes (depression, stress, poor sleep), and pain outcomes (severity, interference). Opioid and other medication use was determined from pharmaceutical claims. After weighting to representative distributions of pain conditions and adjusting for survey response bias, multinomial logistic regressions were used to determine the relative associations of positive and negative attributes on pain outcomes. Among survey respondents (N = 4161), prevalence of self-reported pain severity and interference for no/mild, moderate, and severe categories was 61%, 21%, and 18%, and 67%, 16%, and 17%, respectively. In bivariate models, negative attributes of depression, stress, and poor sleep had stronger associations with pain severity and interference than the moderating effects of positive resources of high resilience and diverse social networks. In fully adjusted multivariate models, the strongest associations with moderate and severe pain severity and interference remained depression, stress, and poor sleep. Based on these results, multidimensional pain management strategies should include management of negative attributes along with enhancement of positive resources for effective management of chronic pain.

Prevalence and characteristics associated with high dose opioid users among older adults.

Our primary objective was to determine the prevalence and characteristics of high dose opioid users among older adults. Study populations included adults ≥65 years with: 1) 12-month continuous medical plan enrollment; and 2) at least 2 opioid prescriptions with a cumulative day supply ≥15 days. Opioid users were categorized as high dose >120 milligram morphine equivalents (MME) per day or lower dose ≤120 MMEs per day. Among eligible insureds, 3% (N = 7616) were identified as high dose opioid users. Compared to lower dose users, high dose opioid users were male, younger, depressed, in poorer health, had back pain, used benzodiazepines and/or sleep medications, and used 4 or more pharmacies. The prevalence of high dose opioid users was relatively small but users were characterized by a complex mix of physical and mental health issues. Interventions to reduce reliance on opioids may need mental health management to promote more effective pain management.

Characteristics associated with transition from opioid initiation to chronic opioid use among opioid-naïve older adults.

Our primary objective was to determine the prevalence and characteristics of opioid-naïve older adults who initiated opioids and transitioned to chronic use. Study populations included older adults ≥ 65years with continuous medical and drug plan enrollment one-year prior to opioid initiation (pre-period) through one-year after initiation (post-period). Characteristics were determined using multivariate logistic regression. Among eligible insureds (N = 180,498), 70% used only the initial opioid prescription; 30% continued to use opioids requiring ≥ 2 prescriptions with ≥ 15 days' supply. Overall, 6% transitioned to chronic use > 90days. Characteristics associated with chronic use included: (1) Low income, older, females, in poor health, with new/chronic back pain; (2) opioid initiation with long-acting opioids or tramadol; (3) prescriptions for other pain, sleep or antipsychotic medications; and (4) indications of pre and/or post mental health issues. Careful screening, monitoring and/or alternative non-opioid pain management strategies may be warranted for those at risk for chronic opioid use.