Serum level of total histone 3, H3K4me3, and H3K27ac after non-emergent cardiac surgery suggests the persistence of smoldering inflammation at 3 months in an adult population.

BACKGROUND: Despite clinical relevance of immunological activation due to histone leakage into the serum following cardiac surgery, long-term data describing their longitudinal dynamic are lacking. Therefore, this study examines the serum levels of histone 3 (tH3) and its modifications (H3K4me3 and H3K27ac) alongside immune system activation during the acute and convalescence phases of cardiac surgery. METHODS: Blood samples from fifty-nine individuals were collected before non-emergent cardiac surgery (tpre-op) and 24 h (t24hr), seven days (t7d), and three months (t3m) post-procedure to examine serum levels of tH3, H3K4me3, and H3K27ac. Serum heat shock protein-60 (HSP-60) was a surrogate of the cellular damage marker. Serum C-reactive protein (CRP) and interleukin 6 (IL-6) assessed smoldering inflammation. TNFα and IL-6 production by whole blood in response to lipopolysaccharide (LPS) evaluated immunological activation. Electronic medical records provided demographic, peri-operative, and clinical information. Paired longitudinal analyses were employed with data expressed as mean and standard deviation (X ± SD) or median and interquartile range (Me[IQ25; 75%]. RESULTS: Compared to pre-operative levels (tH3Pre-op = 1.6[0.33;2.4]), post-operative serum tH3 significantly (p > 0.0001) increased after heart surgery (tH324hr = 2.2[0.3;28]), remained elevated at 7 days (tH37d = 2.4[0.37;5.3]), and at 3 months (tH33m = 2.0[0.31;2.9]). Serum H3K27ac was elevated at 24 h (H3K27ac24hr = 0.66 ± 0.51; p = 0.025) and seven days (H3K27ac7d = 0.94 ± 0.95; p = 0.032) as compared to baseline hours (H3K27acPre-op = 0.55 ± 0.54). Serum H3K4me3 was significantly diminished at three months (H3K4me3Pre-op = 0.94 ± 0.54 vs. H3K27ac3m = 0.59 ± 0.89; p = 0.008). tH3 correlated significantly with the duration of anesthesia (r2 = 0.38). In contrast, HSP-60 normalized seven days after surgery. Peri-operative intake of acetaminophen, but no acetylsalicylic acid (ASA), acid, ketorolac or steroids, resulted in the significant depression of serum H3K4me3 at 24 h (H3K4me3acetom- = 1.26[0.71; 3.21] vs H3K4me3acetom+ = 0.54[0.07;1.01]; W[50] = 2.26; p = 0.021). CRP, but not IL-6, remained elevated at 3 months compared to pre-surgical levels and correlated with tH324hrs (r2 = 0.43), tH37d (r2 = 0.71; p < 0.05), H3K4me37d (r2 = 0.53), and H3K27ac7d (r2 = 0.49). Production of TNFα by whole blood in response to LPS was associated with serum tH324hrs (r2 = 0.67). Diminished H3K4me324hrs, H3K27ac24hrs, and H3K27ac3m, accompanied the emergence of liver failure. CONCLUSIONS: We demonstrated a prolonged elevation in serum histone 3 three months after cardiac surgery. Furthermore, histone 3 modifications had a discrete time evolution indicating differential immune activation.

A disturbed balance between blood complement protective factors (FH, ApoE) and common pathway effectors (C5a, TCC) in acute COVID-19 and during convalesce.

A complement effect on homeostasis during infection is determined by both cytotoxic (activate complement component 5 (C5a) terminal cytotoxic complex (TCC)), and cytoprotective elements (complement factor H (FH), as well as apolipoprotein E (ApoE)). Here, we investigated the gap in knowledge in their blood milieu during SARS-CoV-2 infection with respect to the viral burden, level of tissue necrosis, and immunological response. 101 patients hospitalized with a PCR-confirmed diagnosis of COVID-19 had blood collected at H1 (48 h), H2 (3-4 Days), H3 (5-7 days), H4 (more than 7 days up to 93 days). Pre-existing conditions, treatment, the incidence of cerebrovascular events (CVA), a history of deep venous thrombosis (DVT) and pulmonary embolism (PE), and mortality was collected using electronic medical records. Plasma C5a, TCC, FH, and ApoE were considered as a complement milieu. Tissue necrosis (HMGB1, RAGE), non-specific inflammatory responses (IL-6, C-reactive protein), overall viral burden (SARS-CoV-2 spike protein), and specific immune responses (IgG, IgA, IgM directed αS- & N-proteins) were assessed simultaneously. C5a remained elevated across all time points, with the peak at 5-7 days. Studied elements of complement coalesced around three clusters: #0 (↑↑↑C5a, ↑↑TCC, ↓↓ApoE), #1 ↑C5a, ↑TCC, ↑↑↑FH); #2 (↑C5a, ↑TCC, ↑FH, ↑↑↑ApoE). The decline in FH and ApoE was a predictor of death, while TCC and C5a correlated with patient length of stay, APACHE, and CRP. Increased levels of C5a (Δ = 122.64; p = 0.0294; data not shown) and diminished levels of FH (Δ = 836,969; p = 0.0285; data not shown) co-existed with CVA incidence. C5a correlated storngly with blood RAGE and HMGB1, but not with viral load and immunological responsiveness. Remdesivir positively affected FH preservation, while convalescent plasma treatment elevated C5a levels. Three clusters of complement activation demonstrated a various milieu of ApoE & FH vs C5a & TCC in COVID-19 patients. Complement activation is linked to increased necrosis markers but not to viral burden or immune system response.

Long-Term Abnormalities of Lipid Profile After a Single Episode of Sepsis.

Background: Acute disturbances of the lipid profile are commonplace during acute sepsis episode. However, their long-term persistence has not to be investigated despite pivotal role of dyslipidemia in several comorbidities excessively noted in sepsis survivors (stroke, cardiomyopathy). Methods: A total of 9,861 individuals hospitalized for a singular episode of sepsis between 2009 and 2019 were identified from electronic medical records. Lab measurements of total cholesterol (Tchol), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), very low-density lipoprotein (VLDL), triglycerides (TG), lipoprotein(a) [Lp (a)], apolipoprotein B (ApoB), and C-reactive protein (CRP). The data were examined as baseline values before sepsis, during hospitalization, and <3 months, 3-6 months, 6-12 months, 1-2 years, and more than 2 years from initial sepsis. Results: Significant reductions in HDL-c (HDLbaseline = 44.06 vs. HDLsepsis = 28.2; U = -37.79, p < 0.0001, Cohen's d = 0.22) and LDL-c serum levels were observed during and up to three months post sepsis, with females much less affected. In contrast, male subjects had derangement in HDL present for up to two years after a singular septic episode. Total cholesterol levels were slightly yet significantly elevated for up to two years after sepsis. TG were elevated up to one year [TGbaseline = 128.26 vs. TGsepsis = 170.27, t(8255) = -21.33, p < 0.0001, Cohen's d = 0.49] and normalized. Lp(a) was elevated up to two years after initial episode [Lp(a)baseline = 24.6 ± 16.06; Lp(a)sepsis-2year = 8.25 ± 5.17; Lp(a)morethan2years = 61.4 ± 40.1; ANOVA F (2, 24) = 7.39; p = 0.0032]. Response to statin therapy was blunted in sepsis survivors for several years after sepsis resolution. Significant drop-out in prescription of statins and niacin after sepsis was observed. Serum high sensitivity C-reactive protein was elevated for up to five years after sepsis resolution (H [6;1685] = 502.2; p < 0.0001). Discussion: Lipid abnormalities persisted long after the initial septic insult suggesting potential role in accelerating atherosclerosis and other abnormalities. In addition, sepsis seems to blunt statin effectiveness. Additionally, a significant and unexplained drop in statin use was seen in post-septic period. Conclusions: Our study suggests that persistent derangements of lipid profile components for up to two years after sepsis may be associated with altered risk of atherosclerosis-related events among sepsis survivors.

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes.

The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2's neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid ß42, TDP43, NF-L, and KLK6 serum levels declined 2-3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3-7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-ß40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.

Longitudinal urinary biomarkers of immunological activation in covid-19 patients without clinically apparent kidney disease versus acute and chronic failure.

Kidney function is affected in COVID-19, while kidney itself modulates the immune response. Here, hypothesize if COVID-19 urine biomarkers level can assess immune activation vs. clinical trajectory. Considering the kidney's critical role in modulating the immune response, we sought to analyze activation markers in patients with pre-existing dysfunction. This was a cross-sectional study of 68 patients. Blood and urine were collected within 48 h of hospital admission (H1), followed by 96 h (H2), seven days (H3), and up to 25 days (H4) from admission. Serum level ferritin, procalcitonin, IL-6 assessed immune activation overall, while the response to viral burden was gauged with serum level of spike protein and αspike IgM and IgG. 39 markers correlated highly between urine and blood. Age and race, and to a lesser extend gender, differentiated several urine markers. The burden of pre-existing conditions correlated with urine DCN, CAIX and PTN, but inversely with IL-5 or MCP-4. Higher urinary IL-12 and lower CAIX, CCL23, IL-15, IL-18, MCP-1, MCP-3, MUC-16, PD-L1, TNFRS12A, and TNFRS21 signified non-survivors. APACHE correlated with urine TNFRS12, PGF, CAIX, DCN, CXCL6, and EGF. Admission urine LAG-3 and IL-2 predicted death. Pre-existing kidney disease had a unique pattern of urinary inflammatory markers. Acute kidney injury was associated, and to a certain degree, predicted by IFNg, TWEAK, MMP7, and MUC-16. Remdesavir had a more profound effect on the urine biomarkers than steroids. Urinary biomarkers correlated with clinical status, kidney function, markers of the immune system activation, and probability of demise in COVID-19.

Implications of Chronic Opioid Therapy on Perioperative Complications and Long-Term Surgical Recovery.

With chronic opioid use becoming an increasingly common occurrenceamong the general population, perioperative specialties must adapt to the physiologic changes caused by long-term opioids. However, data on the clinicalanesthetics implications of long-term opioid use is scarce. This review intends to survey the literature addressing the molecular mechanisms of long-term opioid use as well as their interaction with various organ systems.

Observational study of long-term persistent elevation of neurodegeneration markers after cardiac surgery.

Surgery and anesthesia induce inflammatory changes in the central nervous system, which ultimately lead to neuronal damage concomitant with an increase in the level of neurodegeneration markers. Despite some experimental data showing prolonged activation of the immune system post-surgery, no study has determined the extent of long-term elevation of neurodegeneration markers. The purpose of this study was to investigate the serum levels of tau protein, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and glial fibrillary acidic protein (GFAP) after elective cardiac surgery with the implementation of cardiopulmonary bypass (CPB). The serum levels of these markers from 30 patients were compared longitudinally to the baseline (pre-surgery or t0), at 24 hours (t+24), at 7 days (t+7d), and at 3 months (t+3m). The secondary outcome was the production of macrophage-colony stimulating factor (M-CSF) and tumor necrosis factor-α (TNF-α) in vitro by isolated monocytes in response to lipopolysaccharide (LPS) as the measure of immune system activation. The tertiary outcome was the serum level of C-reactive protein (CRP), serum amyloid P (SAP), and α-2-macroglobulin (A2M). Serum levels of tau protein increased 24 hours after surgery (p = 0.0015) and remained elevated at 7 days (p = 0.0017) and three months (p = 0.036). Serum levels of UCH-L1 peaked at 24 hours (p = 0.00055) and normalized at 3 months. In vitro secretion of M-CSF by LPS-stimulated peripheral monocytes, but not TNFα, correlated highly (r = 0.58; p = 0.04) with persistent elevation of serum tau levels at 3 months. The serum CRP and SAP increases correlated with tau post-CPB levels significantly at 3 months. We demonstrated that elevation of serum tau levels at 24 hours, 7 days, and 3 months after heart surgery is concomitant with some traits of inflammation after CPB. The elevation of tau several weeks into recovery is significantly longer than expected.

Global Brain Drain: How Can the Maslow Theory of Motivation Improve Our Understanding of Physician Migration?

The migration of physicians from low-resource to high-resource settings is a prevalent global phenomenon that is insufficiently understood. Most low-income countries are severely understaffed with physicians, and the emigration of the already limited number of physicians to other countries can significantly reduce access to healthcare in the source country. Despite a growing interest in global capacity building in these countries by academic and non-governmental organizations in high-income countries, efforts to stem physician migration have been mostly unsuccessful. The authors reviewed the current literature for the motivational factors leading to physician migration in the context of Maslow's hierarchy of human needs. Our study found that financial safety needs were major drivers of physician emigration. However, factors related to self-actualization such as the desire for professional development through training opportunities and research, were also major contributors. These findings highlight the multifactorial nature of physician motivations to emigrate from low-resource countries. Maslow's Theory of Motivation may provide a useful framework for future studies evaluating the concerns of physicians in low-income countries and as a guide to incentivize retention.

The "Centrality of Sepsis": A Review on Incidence, Mortality, and Cost of Care.

Sepsis is a serious and fatal medical condition that has overburdened the US healthcare system. The purpose of this paper is to provide a review of published literature on severe sepsis with a distinct focus on incidence, mortality, cost of hospital care, and postdischarge care. A review of the nature of postsepsis syndrome and its impact on septic patients is also included. The literature review was conducted utilizing the PubMed database, identifying 34 studies for inclusion. From the evaluation of these studies, it was determined that the incidence of sepsis continues to be on the rise according to three decades of epidemiological data. Readmissions, mortality, and length of stay were all higher among septic patients when compared to patients treated for other conditions. The cost of treating sepsis is remarkably high and exceeds the cost of treating patients with congestive heart failure and acute myocardial infarction. The overall cost of sepsis is reflective of not only the cost of initial hospitalization but also the postdischarge care costs, including postsepsis syndrome and cognitive and functional disabilities that require a significant amount of healthcare resources long term. Sepsis and its impact on patients and the US healthcare system is a current quality-of-life and cost-burden issue that needs to be addressed with a greater focus on preventative strategies.

Home Hemodialysis (HHD) Treatment as Effective yet Underutilized Treatment Modality in the United States.

End-stage renal disease (ESRD) is a major health burden and its incidence has been increasing yearly reaching 120,000 cases in 2014. Home hemodialysis (HHD) is a treatment modality option that has been shown to contribute to numerous clinical benefits but is largely underutilized due to many contributing factors. The purpose of this review paper is to analyze the advantages and disadvantages of HHD and the reasons for its low utilization with a special focus on its socioeconomic impact as compared to facility hemodialysis. Key factors contributing to HHD underutilization are related to the reimbursement system of the facility and nephrologists as well as the underutilization of the pre-dialysis educational benefit. Based on this comprehensive review of the literature, we propose several suggestions which may contribute to the expansion of HHD treatment modality.

Carotid intima-media thickness measurement promises to improve cardiovascular risk evaluation in head and neck cancer patients.

BACKGROUND: Radiation-treated head and neck cancer (HNC) patients are at high risk for developing radiation vasculopathy, as evidenced by an increased stroke risk. The benefits of screening and assessing the cardiovascular (CV) risk of HNC patients using carotid intima-media thickness (CIMT) ultrasound are not known. Our objective was to determine the prevalence of high CV risk in patients without known CV diseases who received radiation for HNC, determine the percentage of screened patients who had a change in clinical management as a result of an increased CIMT, and to compare this risk-assessment tool to patients' risk classification using the Framingham Risk Score (FRS) and Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation (recommended by American College of Cardiology/American Heart Association Guidelines on the Assessment of Cardiovascular Risk). HYPOTHESIS: Risk calculators may not accurately predict risk in this population with a unique risk factor. Carotid IMT may be used to detect radiation vasculopathy in HNC patients. METHODS: Retrospective medical chart review was conducted on 134 radiation-treated HNC patients. The main outcome measures were CV risk (as determined by CIMT) and clinical management. Also, the FRS and the Pooled Cohort ASCVD Risk Equation were used to compare classification with CIMT. RESULTS: Approximately 74% of the cases were at high CV risk using CIMT technique. Approximately half of the HNC patients screened had a change in clinical management characterized by recorded initiation of aspirin and recorded initiation or increase of statin therapies. The FRS and the Pooled Cohort ASCVD Risk Equation failed to detect 40% to 50% of cases found to be at high risk using the CIMT technique. CONCLUSIONS: Carotid IMT identified a much greater percentage of radiation-treated HNC patients at high CV risk compared with standard CV-risk calculators. By more accurately identifying the patients at high risk, this may lead to more effective prevention, and therefore a reduction in CV events.