Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults.

BACKGROUND: Hypoxemia is the most common complication during tracheal intubation of critically ill adults and may increase the risk of cardiac arrest and death. Whether positive-pressure ventilation with a bag-mask device (bag-mask ventilation) during tracheal intubation of critically ill adults prevents hypoxemia without increasing the risk of aspiration remains controversial. METHODS: In a multicenter, randomized trial conducted in seven intensive care units in the United States, we randomly assigned adults undergoing tracheal intubation to receive either ventilation with a bag-mask device or no ventilation between induction and laryngoscopy. The primary outcome was the lowest oxygen saturation observed during the interval between induction and 2 minutes after tracheal intubation. The secondary outcome was the incidence of severe hypoxemia, defined as an oxygen saturation of less than 80%. RESULTS: Among the 401 patients enrolled, the median lowest oxygen saturation was 96% (interquartile range, 87 to 99) in the bag-mask ventilation group and 93% (interquartile range, 81 to 99) in the no-ventilation group (P = 0.01). A total of 21 patients (10.9%) in the bag-mask ventilation group had severe hypoxemia, as compared with 45 patients (22.8%) in the no-ventilation group (relative risk, 0.48; 95% confidence interval [CI], 0.30 to 0.77). Operator-reported aspiration occurred during 2.5% of intubations in the bag-mask ventilation group and during 4.0% in the no-ventilation group (P = 0.41). The incidence of new opacity on chest radiography in the 48 hours after tracheal intubation was 16.4% and 14.8%, respectively (P = 0.73). CONCLUSIONS: Among critically ill adults undergoing tracheal intubation, patients receiving bag-mask ventilation had higher oxygen saturations and a lower incidence of severe hypoxemia than those receiving no ventilation. (Funded by Vanderbilt Institute for Clinical and Translational Research and others; PreVent ClinicalTrials.gov number, NCT03026322.).

Viable human brain microvessels for the study of aging and neurodegenerative diseases.

The brain microvasculature is altered in normal aging and in the presence of disease processes, such as neurodegeneration or ischemia, but there are few methods for studying living tissues. We now report that viable microvessels (MV) are readily isolated from brain tissue of subjects enrolled in studies of neurodegenerative diseases who undergo rapid autopsy (performed with <12 h postmortem interval - PMI). We find that these MV retain their morphology and cellular components and are fairly uniform in size. Sufficient MV (~3-5000) are obtained from 3 to 4 g of tissue to allow for studies of cellular composition as well as extracellular matrix (ECM). Using live/dead assays, these MV are viable for up to 5 days in tissue culture media (2D) designed to support endothelial cells and up to 11 days post-isolation in a 3-dimensional (3D) matrix (Low Growth Factor Matrigel™). Assays that measure the reducing potential of live cells \demonstrated that the majority of the MV maintain high levels of metabolic activity for a similar number of days as the live/dead assays. Functional cellular components (such as tight junctions and transporter proteins) and ECM of MV in tissue culture media, and to a lesser extent in 3D matrices, were readily visualized using immunofluorescence techniques. MV in tissue culture media are lysed and protein content analyzed, but MV in 3D matrix first require removal of the supporting matrix, which can confound the analysis of MV ECM. Finally, MV can be preserved in cryoprotective media, whereby over 50% retain their baseline viability upon thawing. In summary, we find that MV isolated from human brains undergoing rapid autopsy are viable in standard tissue culture for up to 5 days and the timeframe for experiments can be extended up to 11 days by use of a supportive 3D matrix. Viable human MV allow for temporal and spatial analysis of relevant cellular and ECM components that have implications for microvascular function in neurodegenerative diseases, vascular brain injury, and neurotrauma.

Liver Fibrosis Marker and Postoperative Mortality in Patients Without Overt Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can progress to advanced fibrosis, which, in the nonsurgical population, is associated with poor hepatic and extrahepatic outcomes. Despite its high prevalence, NAFLD and related liver fibrosis may be overlooked during the preoperative evaluation, and the role of liver fibrosis as an independent risk factor for surgical-related mortality has yet to be tested. The aim of this study was to assess whether fibrosis-4 (FIB-4), which consists of age, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and platelets, a validated marker of liver fibrosis, is associated with postoperative mortality in the general surgical population. METHODS: A historical cohort of patients undergoing general anesthesia at an academic medical center between 2014 and 2018 was analyzed. Exclusion criteria included known liver disease, acute liver disease or hepatic failure, and alcohol use disorder. FIB-4 score was categorized into 3 validated predefined categories: FIB-4 ≤1.3, ruling out advanced fibrosis; >1.3 and <2.67, inconclusive; and ≥2.67, suggesting advanced fibrosis. The primary analytic method was propensity score matching (FIB-4 was dichotomized to indicate advanced fibrosis), and a secondary analysis included a multivariable logistic regression. RESULTS: Of 19,861 included subjects, 1995 (10%) had advanced fibrosis per FIB-4 criteria. Mortality occurred intraoperatively in 15 patients (0.1%), during hospitalization in 272 patients (1.4%), and within 30 days of surgery in 417 patients (2.1%). FIB-4 ≥2.67 was associated with increased intraoperative mortality (odds ratio [OR], 3.63; 95% confidence interval [CI], 1.25-10.58), mortality during hospitalization (OR, 3.14; 95% CI, 2.37-4.16), and within 30 days from surgery (OR, 2.46; 95% CI, 1.95-3.10), after adjusting for other risk factors. FIB-4 was related to increased mortality in a dose-dependent manner for the 3 FIB-4 categories ≤1.3 (reference), >1.3 and <2.67, and ≥2.67, respectively; during hospitalization (OR, 1.89; 95% CI, 1.34-2.65 and OR, 4.70; 95% CI, 3.27-6.76) and within 30 days from surgery (OR, 1.77; 95% CI, 1.36-2.31 and OR, 3.55; 95% CI, 2.65-4.77). In a 1:1 propensity-matched sample (N = 1994 per group), the differences in mortality remained. Comparing the FIB-4 ≥2.67 versus the FIB-4 <2.67 groups, respectively, mortality during hospitalization was 5.1% vs 2.2% (OR, 2.70; 95% CI, 1.81-4.02), and 30-day mortality was 6.6% vs 3.4% (OR, 2.26; 95% CI, 1.62-3.14). CONCLUSIONS: A simple liver fibrosis marker is strongly associated with perioperative mortality in a population without apparent liver disease, and may aid in future surgical risk stratification and preoperative optimization.

Effect of Fluid Bolus Administration on Cardiovascular Collapse Among Critically Ill Patients Undergoing Tracheal Intubation: A Randomized Clinical Trial.

Importance: Hypotension is common during tracheal intubation of critically ill adults and increases the risk of cardiac arrest and death. Whether administering an intravenous fluid bolus to critically ill adults undergoing tracheal intubation prevents severe hypotension, cardiac arrest, or death remains uncertain. Objective: To determine the effect of fluid bolus administration on the incidence of severe hypotension, cardiac arrest, and death. Design, Setting, and Participants: This randomized clinical trial enrolled 1067 critically ill adults undergoing tracheal intubation with sedation and positive pressure ventilation at 11 intensive care units in the US between February 1, 2019, and May 24, 2021. The date of final follow-up was June 21, 2021. Interventions: Patients were randomly assigned to receive either a 500-mL intravenous fluid bolus (n = 538) or no fluid bolus (n = 527). Main Outcomes and Measures: The primary outcome was cardiovascular collapse (defined as new or increased receipt of vasopressors or a systolic blood pressure <65 mm Hg between induction of anesthesia and 2 minutes after tracheal intubation, or cardiac arrest or death between induction of anesthesia and 1 hour after tracheal intubation). The secondary outcome was the incidence of death prior to day 28, which was censored at hospital discharge. Results: Among 1067 patients randomized, 1065 (99.8%) completed the trial and were included in the primary analysis (median age, 62 years [IQR, 51-70 years]; 42.1% were women). Cardiovascular collapse occurred in 113 patients (21.0%) in the fluid bolus group and in 96 patients (18.2%) in the no fluid bolus group (absolute difference, 2.8% [95% CI, -2.2% to 7.7%]; P = .25). New or increased receipt of vasopressors occurred in 20.6% of patients in the fluid bolus group compared with 17.6% of patients in the no fluid bolus group, a systolic blood pressure of less than 65 mm Hg occurred in 3.9% vs 4.2%, respectively, cardiac arrest occurred in 1.7% vs 1.5%, and death occurred in 0.7% vs 0.6%. Death prior to day 28 (censored at hospital discharge) occurred in 218 patients (40.5%) in the fluid bolus group compared with 223 patients (42.3%) in the no fluid bolus group (absolute difference, -1.8% [95% CI, -7.9% to 4.3%]; P = .55). Conclusions and Relevance: Among critically ill adults undergoing tracheal intubation, administration of an intravenous fluid bolus compared with no fluid bolus did not significantly decrease the incidence of cardiovascular collapse. Trial Registration: ClinicalTrials.gov Identifier: NCT03787732.

Ultra-processed food is associated with features of metabolic syndrome and non-alcoholic fatty liver disease.

BACKGROUND & AIMS: High consumption of ultra-processed food (UPF) is associated with mortality and chronic morbidity but has not been studied concerning to non-alcoholic fatty liver disease (NAFLD). We aimed to test the association of UPF consumption with metabolic syndrome, NAFLD and related-liver damage. METHODS: A cross-sectional study among volunteers who underwent abdominal ultrasound (AUS), anthropometrics, blood pressure measurements, and fasting blood tests including FibroMax for non-invasive assessment of NASH and significant fibrosis. A food-frequency questionnaire was used to evaluate UPF consumption using the NOVA classification. RESULTS: A total of 789 subjects were included in the total sample (mean age 58.83 ± 6.58 years, 52.60% men), a reliable FibroMax test was obtained from 714 subjects, 305 subjects were diagnosed with NAFLD. High consumption of UPF was associated with higher odds for metabolic syndrome (OR = 1.88, 95% CI 1.31-2.71, P = .001) and its components; hypertension, hypertriglyceridemia, and low HDL, among the entire sample (OR = 1.53, 1.07-2.19, P = .026; OR = 1.51, 1.08-2.11, P = .017; OR = 1.55, 1.05-2.29, P = .028). In addition, it was associated with higher odds for NASH and hypertension (OR = 1.89, 1.07-3.38, P = .030; OR = 2.26, 1.20-4.26, P = .012 respectively) among subjects with NAFLD. Stratification by smoking status revealed an association between high UPF consumption and significant fibrosis among ever smokers in the entire sample and among subjects with NAFLD (OR = 1.89, 95% CI 1.03-3.45, P = .039; OR = 2.85, 1.14-7.14, P = .026 respectively). CONCLUSIONS: High UPF consumption is associated with metabolic syndrome in the general population, and among those with NAFLD it is associated with NASH marker. Ever-smoking may act synergistically with UPF to amplify the risk for fibrosis.

Frailty status as a potential factor in increased postoperative opioid use in older adults.

BACKGROUND: Prescription opioids are commonly used for postoperative pain relief in older adults, but have the potential for misuse. Both opioid side effects and uncontrolled pain have detrimental impacts. Frailty syndrome (reduced reserve in response to stressors), pain, and chronic opioid consumption are all complex phenomena that impair function, nutrition, psychologic well-being, and increase mortality, but links among these conditions in the acute postoperative setting have not been described. This study seeks to understand the relationship between frailty and patterns of postoperative opioid consumption in older adults. METHODS: Patients ≥ 65 years undergoing elective surgery with a planned hospital stay of at least one postoperative day were recruited for this cohort study at pre-anesthesia clinic visits. Preoperatively, frailty was assessed by Edmonton Frailty and Clinical Frailty Scales, pain was assessed by Visual Analog and Pain Catastrophizing Scales, and opioid consumption was recorded. On the day of surgery and subsequent hospitalization days, average pain ratings and total opioid consumption were recorded daily. Seven days after hospital discharge, patients were interviewed using uniform questionnaires to measure opioid prescription use and pain rating. RESULTS: One hundred seventeen patients (age 73.0 (IQR 67.0, 77.0), 64 % male), were evaluated preoperatively and 90 completed one-week post discharge follow-up. Preoperatively, patients with frailty were more likely than patients without frailty to use opioids (46.2 % vs. 20.9 %, p = 0.01). Doses of opioids prescribed at hospital discharge and the prescribed morphine milligram equivalents (MME) at discharge did not differ between groups. Seven days after discharge, the cumulative MME used were similar between cohorts. However, patients with frailty used a larger fraction of opioids prescribed to them (96.7 % (31.3, 100.0) vs. 25.0 % (0.0, 83.3), p = 0.007) and were more likely (OR 3.7, 95 % CI 1.13-12.13) to use 50 % and greater of opioids prescribed to them. Patients with frailty had higher pain scores before surgery and seven days after discharge compared to patients without frailty. CONCLUSIONS: Patterns of postoperative opioid use after discharge were different between patients with and without frailty. Patients with frailty tended to use almost all the opioids prescribed while patients without frailty tended to use almost none of the opioids prescribed.

Accuracy and Feasibility of Clinically Applied Frailty Instruments before Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: A barrier to routine preoperative frailty assessment is the large number of frailty instruments described. Previous systematic reviews estimate the association of frailty with outcomes, but none have evaluated outcomes at the individual instrument level or specific to clinical assessment of frailty, which must combine accuracy with feasibility to support clinical practice. METHODS: The authors conducted a preregistered systematic review (CRD42019107551) of studies prospectively applying a frailty instrument in a clinical setting before surgery. Medline, Excerpta Medica Database, Cochrane Library and the Comprehensive Index to Nursing and Allied Health Literature, and Cochrane databases were searched using a peer-reviewed strategy. All stages of the review were completed in duplicate. The primary outcome was mortality and secondary outcomes reflected routinely collected and patient-centered measures; feasibility measures were also collected. Effect estimates were pooled using random-effects models or narratively synthesized. Risk of bias was assessed. RESULTS: Seventy studies were included; 45 contributed to meta-analyses. Frailty was defined using 35 different instruments; five were meta-analyzed, with the Fried Phenotype having the largest number of studies. Most strongly associated with: mortality and nonfavorable discharge was the Clinical Frailty Scale (odds ratio, 4.89; 95% CI, 1.83 to 13.05 and odds ratio, 6.31; 95% CI, 4.00 to 9.94, respectively); complications was associated with the Edmonton Frail Scale (odds ratio, 2.93; 95% CI, 1.52 to 5.65); and delirium was associated with the Frailty Phenotype (odds ratio, 3.79; 95% CI, 1.75 to 8.22). The Clinical Frailty Scale had the highest reported measures of feasibility. CONCLUSIONS: Clinicians should consider accuracy and feasibility when choosing a frailty instrument. Strong evidence in both domains support the Clinical Frailty Scale, while the Fried Phenotype may require a trade-off of accuracy with lower feasibility.

Frailty assessment: from clinical to radiological tools.

Frailty is a syndrome of cumulative decline across multiple physiological systems, which predisposes vulnerable adults to adverse events. Assessing vulnerable patients can potentially lead to interventions that improve surgical outcomes. Anaesthesiologists who care for older patients can identify frailty to improve preoperative risk stratification and subsequent perioperative planning. Numerous clinical tools to diagnose frailty exist, but none has emerged as the standard tool to be used in clinical practice. Radiological modalities, such as computed tomography and ultrasonography, are widely performed before surgery, and are therefore available to be used opportunistically to objectively evaluate surrogate markers of frailty. This review presents the importance of frailty assessment by anaesthesiologists; lists common clinical tools that have been applied; and proposes that utilising radiological imaging as an objective surrogate measure of frailty is a novel, expanding approach for which anaesthesiologists can significantly contribute to broad implementation.

Trauma Providers' Perceptions of Frailty Assessment: A Mixed-Methods Analysis of Knowledge, Attitudes, and Beliefs.

OBJECTIVES: Quality improvement in geriatric trauma depends on timely identification of frailty, yet little is known about providers' knowledge and beliefs about frailty assessment. This study sought to understand trauma providers' understanding, beliefs, and practices for frailty assessment. METHODS: We developed a 20-question survey using the Health Belief Model of health behavior and surveyed physicians, advanced practice providers, and trainees on the trauma services at a single institution that does not use formal frailty screening of all injured seniors. Results were analyzed via mixed methods. RESULTS: One hundred fifty-one providers completed the survey (response rate 92%). Respondents commonly included calendar age as an integral factor in their determinations of frailty but also included a variety of other factors, highlighting limited definitional consensus. Respondents perceived frailty as important to older adult patient outcomes, but assessment techniques were varied because only 24/151 respondents (16%) were familiar with current formal frailty assessment tools. Perceived barriers to performing a formal frailty screening on all injured older adults included the burdensome nature of assessment tools, insufficient training, and lack of time. When prompted for solutions, 20% of respondents recommended automation of the screening process by trained, dedicated team members. CONCLUSIONS: Providers seem to recognize the impact that a diagnosis of frailty has on outcomes, but most lack a working knowledge of how to assess for frailty syndrome. Some providers recommended screening by designated, formally trained personnel who could notify decision makers of a positive screen result.

Anesthesiologists and Disaster Medicine: A Needs Assessment for Education and Training and Reported Willingness to Respond.

BACKGROUND: Anesthesiologists provide comprehensive health care across the emergency department, operating room, and intensive care unit. To date, anesthesiologists' perspectives regarding disaster medicine and public health preparedness have not been described. METHODS: Anesthesiologists' thoughts and attitudes were assessed via a Web-based survey at 3 major academic institutions. Frequencies, percentages, and odds ratios (ORs) were used to assess self-reported perceptions of knowledge and skills, as well as attitudes and beliefs regarding education and training, employee development, professional obligation, safety, psychological readiness, efficacy, personal preparedness, and willingness to respond (WTR). Three representative disaster scenarios (natural disaster [ND], radiological event [RE], and pandemic influenza [PI]) were investigated. Results are reported as percent or OR (95% confidence interval). RESULTS: Participants included 175 anesthesiology attendings (attendings) and 95 anesthesiology residents (residents) representing a 47% and 51% response rate, respectively. A minority of attendings indicated that their hospital provides adequate pre-event preparation and training (31% [23-38] ND, 14% [9-21] RE, and 40% [31-49] PI). Few residents felt that their residency program provided them with adequate preparation and training (22% [14-33] ND, 16% [8-27] RE, and 17% [9-29] PI). Greater than 85% of attendings (89% [84-94] ND, 88% [81-92] RE, and 87% [80-92] PI) and 70% of residents (81% [71-89] ND, 71% [58-81] RE, and 82% [70-90] PI) believe that their hospital or residency program, respectively, should provide them with preparation and training. Approximately one-half of attendings and residents are confident that they would be safe at work during response to a ND or PI (55% [47-64] and 58% [49-67] of attendings; 59% [48-70] and 48% [35-61] of residents, respectively), whereas approximately one-third responded the same regarding a RE (31% [24-40] of attendings and 28% [18-41] of residents). Fewer than 40% of attendings (34% [26-43]) and residents (38% [27-51]) designated who would take care of their family obligations in the event they were called into work during a disaster. Regardless of severity, 79% (71-85) of attendings and 73% (62-82) of residents indicated WTR to a ND, whereas 81% (73-87) of attendings and 70% (58-81) of residents indicated WTR to PI. Fewer were willing to respond to a RE (63% [55-71] of attendings and 52% [39-64] of residents). In adjusted logistic regression analyses, those anesthesiologists who reported knowing one's role in response to a ND (OR, 15.8 [4.5-55.3]) or feeling psychologically prepared to respond to a ND (OR, 6.9 [2.5-19.0]) were found to be more willing to respond. Similar results were found for RE and PI constructs. Both attendings and residents were willing to respond in whatever capacity needed, not specifically to provide anesthesia. CONCLUSIONS: Few anesthesiologists reported receiving sufficient education and training in disaster medicine and public health preparedness. Providing education and training and enhancing related employee services may further bolster WTR and help to build a more capable and effective medical workforce for disaster response.

Lidocaine Impairs Proliferative and Biosynthetic Functions of Aged Human Dermal Fibroblasts.

BACKGROUND: The aged are at increased risk of postoperative wound healing complications. Because local anesthetics are infiltrated commonly into the dermis of surgical wounds, we sought to determine whether local anesthetics adversely affect proliferative and biosynthetic functions of dermal fibroblasts. We also evaluated the effect of local anesthetics on insulin-like growth factor-1 (IGF-1) and transforming growth factor-ß1 (TGF-ß1), growth factors that are important regulators of wound healing. METHODS: Human dermal fibroblasts (HFB) from aged and young donors were exposed to local anesthetic agents at clinically relevant concentrations. We screened the effects of lidocaine, bupivacaine, mepivacaine, and ropivacaine on proliferation of HFB. Lidocaine was most detrimental to proliferation in HFB. We then evaluated the effect of lidocaine on expression and function of the growth factors, IGF-1 and TGF-ß1. Lastly, concurrent exposure to lidocaine and IGF-1 or TGF-ß1 was evaluated for their effects on proliferation and expression of dermal collagens, respectively. RESULTS: Lidocaine and mepivacaine inhibited proliferation in aged HFB (for lidocaine 88% of control, 95% confidence interval [CI], 80%-98%, P = .009 and for mepivacaine 90% of control, 95% CI, 81%-99%, P = .032) but not in young HFB. Ropivacaine and bupivacaine did not inhibit proliferation. Because of the clinical utility of lidocaine relative to mepivacaine, we focused on lidocaine. Lidocaine decreased proliferation in aged HFB, which was abrogated by IGF-1. Lidocaine inhibited transcripts for IGF-1 and insulin-like growth factor-1 receptor (IGF1R) in fibroblasts from aged donors (IGF-1, log2 fold-change -1.25 [42% of control, 95% CI, 19%-92%, P = .035] and IGF1R, log2 fold-change -1.00 [50% of control, 95% CI, 31%-81%, P = .014]). In contrast, lidocaine did not affect the expression of IGF-1 or IGF1R transcripts in the young HFB. Transcripts for collagen III were decreased after lidocaine exposure in aged and young HFB (log2 fold-change -1.28 [41% of control, 95% CI, 20%-83%, P = .022] in aged HFB and log2 fold-change -1.60 [33% of control, 95% CI, 15%-73%, P = .019] in young HFB). Transcripts for collagen I were decreased in aged HFB (log2 fold-change -1.82 [28% of control, 95% CI, 14%-58%, P = .006]) but not in the young HFB. Similar to the transcripts, lidocaine also inhibited the protein expression of collagen III in young and aged HFB (log2 fold-change -1.79 [29% of control, 95% CI, 18%-47%, P = .003] in young HFB and log2 fold-change -1.76 [30% of control, 95% CI, 9%-93%, P = .043] in aged HFB). The effect of lidocaine on the expression of collagen III protein was obviated by TGF-ß1 in both young and aged HFB. CONCLUSIONS: Our results show that lidocaine inhibits processes relevant to dermal repair in aged HFB. The detrimental responses to lidocaine are due, in part, to interactions with IGF-1 and TGF-ß1.

The effect of aging on the cutaneous microvasculature.

Aging is associated with a progressive loss of function in all organs. Under normal conditions the physiologic compensation for age-related deficits is sufficient, but during times of stress the limitations of this reserve become evident. Explanations for this reduction in reserve include the changes in the microcirculation that occur during the normal aging process. The microcirculation is defined as the blood flow through arterioles, capillaries and venules, which are the smallest vessels in the vasculature and are embedded within organs and tissues. Optimal strategies to maintain the microvasculature following surgery and other stressors must use multifactorial approaches. Using skin as the model organ, we will review the anatomical and functional changes in the microcirculation with aging, and some of the available clinical strategies to potentially mitigate the effect of these changes on important clinical outcomes.

Anesthesia, microcirculation, and wound repair in aging.

Age-related changes in skin contribute to impaired wound healing after surgical procedures. Changes in skin with age include decline in thickness and composition, a decrease in the number of most cell types, and diminished microcirculation. The microcirculation provides tissue perfusion, fluid homeostasis, and delivery of oxygen and other nutrients. It also controls temperature and the inflammatory response. Surgical incisions cause further disruption of the microvasculature of aged skin. Perioperative management can be modified to minimize insults to aged tissues. Judicious use of fluids, maintenance of normal body temperature, pain control, and increased tissue oxygen tension are examples of adjustable variables that support the microcirculation. Anesthetic agents influence the microcirculation of a combination of effects on cardiac output, arterial pressure, and local microvascular changes. The authors examined the role of anesthetic management in optimizing the microcirculation and potentially improving postoperative wound repair in older persons.

Decreased proliferative capacity of aged dermal fibroblasts in a three dimensional matrix is associated with reduced IGF1R expression and activation.

Skin aging results in increased susceptibility to injury and impaired wound healing. Proliferation of fibroblasts is reduced in aged dermis, which contributes to delays in wound closure. Age-associated differences are regulated, in part, by local or systemic factors such as the IGF-1/IGF1R system. The aim of this study was to determine if expression and activation of IGF1R in aged human dermal fibroblasts, when compared to young fibroblasts, is associated with altered proliferative capacity in a 3D collagen matrix that better simulates the dermal extracellular matrix in vivo. The proliferation of young and aged human dermal fibroblasts in 3D collagen and its association with baseline levels of IGF1R expression were measured. The effect of stimulation and inhibition of Erk phosphorylation on the proliferative capacity of fibroblasts in a 3D collagen matrix was defined. Our results show that proliferation and Erk phosphorylation is reduced in aged dermal fibroblasts relative to young fibroblasts. Activation of Erk phosphorylation in aged fibroblasts is associated with a significant increase in fibroblast proliferation in 3D collagen.

Hyaluronan enhances wound repair and increases collagen III in aged dermal wounds.

Age-related changes in the extracellular matrix contribute to delayed wound repair in aging. Hyaluronan, a linear nonsulfated glycosaminoglycan, promotes synthesis and assembly of key extracellular matrix components, such as the interstitial collagens, during wound healing. The biological effects of hyaluronan are mediated, in part, by hyaluronan size. We have previously determined that dermal wounds in aged mice, relative to young mice, have deficits in the generation of lower molecular weight hyaluronan (defined as <300 kDa). Here, we tested the effect of exogenous hyaluronan of 2, 250, or 1,000 kDa sizes on full-thickness excisional wounds in aged mice. Only wounds treated with 250 kDa hyaluronan (HA250) were significantly improved over wounds that received carrier (water) alone. Treatment with HA250 was associated with increased expression of transcripts for the hyaluronan receptors CD44 and RHAMM, as well as collagens III and I. Analyses of dermal protein content by mass spectrometry and Western blotting confirmed significantly increased expression of collagen III in wounds treated with HA250 relative to control wounds. In summary, we find that HA250 improves wound repair and increases the synthesis of collagen III in aged dermal wounds.

Cognitive Prehabilitation: How Can We Counter Neurocognitive Frailty?

Perioperative neurocognitive disorders are common and concerning complications in older adults undergoing surgery that can manifest as acute or chronic cognitive decline. It is hypothesized that cognitive prehabilitation can prepare the brain for the stress of surgery as for any other organ system. In this mini review we discuss the rationale for using cognitive prehabilitation, some of the interventions that have been assessed, and the effects of these interventions on postoperative cognition. PATIENT SUMMARY: Training the brain before surgery can potentially reduce the risk of cognitive decline after surgery in older adults. This mini review discusses some of the trials that examined how to train the brain before surgery and the results from these trials.

Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometrioid and serous papillary endometrial cancer cell lines.

PURPOSE: The role of the insulin-like growth factor (IGF) system in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR signaling pathways. The aim of the present study was to investigate the anti-proliferative activity of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines. METHODS: Type I (ECC-1, Ishikawa) and Type II (USPC-1, USPC-2) endometrial cancer cell lines were treated with NVP-AEW541 in the presence of IGF-I, and the following parameters were measured: IGF-IR, AKT and ERK phosphorylation, apoptosis, proliferation, cell cycle progression and IGF-IR internalization. RESULTS: Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated, whereas it abolished AKT and ERK phosphorylation preferentially in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor. CONCLUSION: Our results suggest that specific IGF-IR inhibition by NVP-AEW541 might be a promising therapeutic tool in endometrial cancer.

Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene.

The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF1R) expression. DNA methylation of CpG islands is an epigenetic mechanism associated with gene silencing. Recent studies have demonstrated that methylation occurs early in prostate carcinogenesis and, furthermore, may contribute to androgen independence. The methylation status of the AR and IGF1R genes was evaluated in a series of prostate cancer cell lines corresponding to early (benign) and advanced (metastatic) stages of the disease. Results of 5-Aza-2'-deoxycytidine (5-Aza) experiments, methylation-specific PCR, and sodium bisulfite-direct DNA sequencing revealed that the AR promoter is hypermethylated in metastatic M12, but not in benign P69, cells. On the other hand, no methylation was seen in the IGF1R promoter at any stage of the disease. We show, however, that 5-Aza treatment, which caused demethylation of the AR promoter, led to a significant increase in IGF1R mRNA levels, whereas addition of the AR inhibitor flutamide decreased the IGF1R mRNA levels to basal values measured prior to the 5-Aza treatment. Given that the IGF1R gene has been identified as a downstream target for AR action, our data is consistent with a model in which the AR gene undergoes methylation during progression of the disease, leading to dysregulation of AR targets, including the IGF1R gene, at advanced metastatic stages.

Liver fibrosis marker is an independent predictor of cardiovascular morbidity and mortality in the general population.

BACKGROUND: A growing body of evidence suggests that Non-alcoholic fatty liver disease (NAFLD) and liver fibrosis are associated with cardiovascular disease (CVD). However, the independent role of liver fibrosis markers in the prediction of CVD in the general population is seldom tested. AIMS: To assess whether a marker of liver fibrosis predicts the first occurrence of a CVD event in a large sample of community-based general population. METHODS: Historical cohort using data from a large health provider that operates a centralized computerized medical record. The level of liver fibrosis was measured by the fibrosis-4 (FIB-4) score, and the association with CVD was adjusted for the European Systematic Coronary Risk Evaluation calculator (SCORE). RESULTS: The study included 8,511 individuals, 3,292 with inconclusive fibrosis and 195 with advanced fibrosis (FIB-4 ≥ 2.67). People with advanced fibrosis had higher risk for CVD, after adjustment for sociodemographic characteristics, the SCORE, use of statins and aspirin (HR [95%CI], 1.63 [1.29-2.06]). The association persisted in both women and men. Using age-specific cut-offs, there was a dose-response association between inconclusive and advanced fibrosis and CVD (HR [95%CI], 1.15 [1.01-1.31]) and HR [95%CI], 1.60 [1.27-2.01], respectively, P for trend<0.001). CONCLUSIONS: A simple fibrosis score is independently associated with CVD, suggesting that fibrosis markers should be considered in primary-care risk assessment.

Nutritional Evaluation and Treatment of the Cirrhotic Patient.

Malnutrition and sarcopenia that lead to functional deterioration, frailty, and increased risk for complications and mortality are common in cirrhosis. Sarcopenic obesity, which is associated with worse outcomes than either condition alone, may be overlooked. Lifestyle intervention aiming for moderate weight reduction can be offered to obese compensated cirrhotic patients, with diet consisting of reduced caloric intake, achieved by reduction of carbohydrate and fat intake, while maintaining high protein intake. Dietary and moderate exercise interventions in patients with cirrhosis are beneficial. Cirrhotic patients with malnutrition should have nutritional counseling, and all patients should be encouraged to avoid a sedentary lifestyle.