Impact of continuous and wireless monitoring of vital signs on clinical outcomes: a propensity-matched observational study of surgical ward patients.

BACKGROUND: Continuous and wireless vital sign monitoring is superior to intermittent monitoring in detecting vital sign abnormalities; however, the impact on clinical outcomes has not been established. METHODS: We performed a propensity-matched analysis of data describing patients admitted to general surgical wards between January 2018 and December 2019 at a single, tertiary medical centre in the USA. The primary outcome was a composite of in-hospital mortality or ICU transfer during hospitalisation. Secondary outcomes were the odds of individual components of the primary outcome, and heart failure, myocardial infarction, acute kidney injury, and rapid response team activations. Data are presented as odds ratios (ORs) with 95% confidence intervals (CIs) and n (%). RESULTS: We initially screened a population of 34,636 patients (mean age 58.3 (Range 18-101) yr, 16,456 (47.5%) women. After propensity matching, intermittent monitoring (n=12 345) was associated with increased risk of a composite of mortality or ICU admission (OR 3.42, 95% CI 3.19-3.67; P<0.001), and heart failure (OR 1.48, 95% CI 1.21-1.81; P<0.001), myocardial infarction (OR 3.87, 95% CI 2.71-5.71; P<0.001), and acute kidney injury (OR 1.32, 95% CI 1.09-1.57; P<0.001) compared with continuous wireless monitoring (n=7955). The odds of rapid response team intervention were similar in both groups (OR 0.86, 95% CI 0.79-1.06; P=0.726). CONCLUSIONS: Patients who received continuous ward monitoring were less likely to die or be admitted to ICU than those who received intermittent monitoring. These findings should be confirmed in prospective randomised trials.

Automated Electronic Frailty Index-Identified Frailty Status and Associated Postsurgical Adverse Events.

Importance: Electronic frailty index (eFI) is an automated electronic health record (EHR)-based tool that uses a combination of clinical encounters, diagnosis codes, laboratory workups, medications, and Medicare annual wellness visit data as markers of frailty status. The association of eFI with postanesthesia adverse outcomes has not been evaluated. Objective: To examine the association of frailty, calculated as eFI at the time of the surgical procedure and categorized as fit, prefrail, or frail, with adverse events after elective noncardiac surgery. Design, Setting, and Participants: This cohort study was conducted at a tertiary care academic medical center in Winston-Salem, North Carolina. The cohort included patients 55 years or older who underwent noncardiac surgery of at least 1 hour in duration between October 1, 2017, and June 30, 2021. Exposure: Frailty calculated by the eFI tool. Preoperative eFI scores were calculated based on available data 1 day prior to the procedure and categorized as fit (eFI score: ≤0.10), prefrail (eFI score: >0.10 to ≤0.21), or frail (eFI score: >0.21). Main Outcomes and Measures: The primary outcome was a composite of the following 8 adverse component events: 90-item Patient Safety Indicators (PSI 90) score, hospital-acquired conditions, in-hospital mortality, 30-day mortality, 30-day readmission, 30-day emergency department visit after surgery, transfer to a skilled nursing facility after surgery, or unexpected intensive care unit admission after surgery. Secondary outcomes were each of the component events of the composite. Results: Of the 33 449 patients (median [IQR] age, 67 [61-74] years; 17 618 females [52.7%]) included, 11 563 (34.6%) were classified as fit, 15 928 (47.6%) as prefrail, and 5958 (17.8%) as frail. Using logistic regression models that were adjusted for age, sex, race and ethnicity, and comorbidity burden, patients with prefrail (odds ratio [OR], 1.24; 95% CI, 1.18-1.30; P < .001) and frail (OR, 1.71; 95% CI, 1.58-1.82; P < .001) statuses were more likely to experience postoperative adverse events compared with patients with a fit status. Subsequent adjustment for all other potential confounders or covariates did not alter this association. For every increase in eFI of 0.03 units, the odds of a composite of postoperative adverse events increased by 1.06 (95% CI, 1.03-1.13; P < .001). Conclusions and Relevance: This cohort study found that frailty, as measured by an automatically calculated index integrated within the EHR, was associated with increased risk of adverse events after noncardiac surgery. Deployment of eFI tools may support screening and possible risk modification, especially in patients who undergo high-risk surgery.

Venous Outflow and Otosclerosis: An Unusual Case of Pulsatile Tinnitus.

We report resolution of right-sided pulsatile tinnitus in a 44-year-old male who underwent stapedectomy for fenestral otosclerosis. Initial workup revealed a mixed hearing loss and absent stapedial reflexes consistent with ossicular fixation. CT angiography demonstrated near complete stenosis of the left-sided transverse and sigmoid sinuses and dominant contralateral venous outflow. We hypothesized that the dominant right cerebral venous outflow tract created turbulent flow that was conducted to cochlea. Successful stapedectomy was performed, and the pulsatile tinnitus resolved. This case report demonstrates evidence that the sound of turbulent blood flow can be conducted through bone and an instance where the perception of vascular tinnitus was eliminated with stapedectomy.

Prepectoral Versus Subpectoral Breast Reconstruction in High-Body Mass Index Patients.

BACKGROUND: The effect of body mass index (BMI) on complication rates in prepectoral implant-based breast reconstruction is not well established. The purpose of this study was to compare complication rates between different BMI groups in subpectoral and prepectoral reconstruction. METHODS: A single-surgeon, 4-year, retrospective review was performed of consecutive prosthetic breast reconstructions. During this time, the senior author's practice shifted from a subpectoral to prepectoral technique. Patients were stratified into BMI subgroups (<25, 25-35, and >35 kg/m2) and complication rates were analyzed. A survey was administered to blinded medical personnel and patients comparing esthetic results. RESULTS: Implant-based reconstructions were performed in 195 patients (103 subpectoral and 92 prepectoral). No significant difference in major complication rate was observed between techniques. Among patients with BMI greater than 35 kg/m2, implant exposure occurred at a significantly higher rate in the prepectoral group (P = 0.04). In patients with BMI greater than 25 kg/m2, minor asymmetry was more prevalent with prepectoral reconstruction (12.3% vs 0%; P = 0.02). Regardless of technique, the odds of reoperation increased by 7% per point increase in BMI, although this did not reach statistical significance (P = 0.07; odds ratio, 1.07; 95% confidence interval, 0.99-1.15).A total of 66 survey responses were received. Physicians rated esthetic results more positively than patients did. Patients with a BMI of less than 25 kg/m2 were rated better than other BMI groups in nearly all categories. The position of submuscular reconstruction was rated significantly better than prepectoral. CONCLUSIONS: There is a trend toward higher complication rates in prepectoral versus subpectoral breast reconstruction with increasing BMI. Nonetheless, the technique appears to be safe, with comparable clinical and cosmetic results.

A Moderate Blast Exposure Results in Dysregulated Gene Network Activity Related to Cell Death, Survival, Structure, and Metabolism.

Blast exposure is common in military personnel during training and combat operations, yet biological mechanisms related to cell survival and function that coordinate recovery remain poorly understood. This study explored how moderate blast exposure influences gene expression; specifically, gene-network changes following moderate blast exposure. On day 1 (baseline) of a 10-day military training program, blood samples were drawn, and health and demographic information collected. Helmets equipped with bilateral sensors worn throughout training measured overpressure in pounds per square inch (psi). On day 7, some participants experienced moderate blast exposure (peak pressure ≥5 psi). On day 10, 3 days post-exposure, blood was collected and compared to baseline with RNA-sequencing to establish gene expression changes. Based on dysregulation data from RNA-sequencing, followed by top gene networks identified with Ingenuity Pathway Analysis, a subset of genes was validated (NanoString). Five gene networks were dysregulated; specifically, two highly significant networks: (1) Cell Death and Survival (score: 42), including 70 genes, with 50 downregulated and (2) Cell Structure, Function, and Metabolism (score: 41), including 69 genes, with 41 downregulated. Genes related to ubiquitination, including neuronal development and repair: UPF1, RNA Helicase and ATPase (UPF1) was upregulated while UPF3 Regulator of Nonsense Transcripts Homolog B (UPF3B) was downregulated. Genes related to inflammation were upregulated, including AKT serine/threonine kinase 1 (AKT1), a gene coordinating cellular recovery following TBIs. Moderate blast exposure induced significant gene expression changes including gene networks involved in (1) cell death and survival and (2) cellular development and function. The present findings may have implications for understanding blast exposure pathology and subsequent recovery efforts.

Elevated Tau in Military Personnel Relates to Chronic Symptoms Following Traumatic Brain Injury.

OBJECTIVE: To understand the relationships between traumatic brain injury (TBI), blood biomarkers, and symptoms of posttraumatic stress disorder (PTSD), depression, and postconcussive syndrome symptoms. DESIGN: Cross-sectional cohort study using multivariate analyses. PARTICIPANTS: One hundred nine military personnel and veterans, both with and without a history of TBI. MAIN MEASURES: PTSD Checklist-Civilian Version (PCL-C); Neurobehavioral Symptom Inventory (NSI); Ohio State University TBI Identification Method; Patient Health Questionnaire-9 (PHQ-9); Simoa-measured concentrations of tau, amyloid-beta (Aß) 40, Aß42, and neurofilament light (NFL). RESULTS: Controlling for age, sex, time since last injury (TSLI), and antianxiety/depression medication use, NFL was trending toward being significantly elevated in participants who had sustained 3 or more TBIs compared with those who had sustained 1 or 2 TBIs. Within the TBI group, partial correlations that controlled for age, sex, TSLI, and antianxiety/depression medication use showed that tau concentrations were significantly correlated with greater symptom severity, as measured with the NSI, PCL, and PHQ-9. CONCLUSIONS: Elevations in tau are associated with symptom severity after TBI, while NFL levels are elevated in those with a history of repetitive TBIs and in military personnel and veterans. This study shows the utility of measuring biomarkers chronically postinjury. Furthermore, there is a critical need for studies of biomarkers longitudinally following TBI.

Mild traumatic brain injuries with loss of consciousness are associated with increased inflammation and pain in military personnel.

Mild traumatic brain injuries (mTBI) are a pervasive concern for military personnel. Determining the impact of injury severity, including loss of consciousness (LOC) may provide important insights into the risk of psychological symptoms and inflammation commonly witnessed in military personnel and veterans following mTBI. US military personnel and veterans were categorized into three groups; TBI with LOC (n = 36), TBI without LOC (n = 25), Controls (n = 82). Participants reported their history of mTBI, psychological symptoms (post-traumatic stress disorder [PTSD] and depression), health-related quality of life (HRQOL), and underwent a blood draw. ANCOVA models which controlled for insomnia status and combat exposure indicated that both mTBI groups (with/without LOC) reported significantly greater depression and PTSD symptoms compared to controls; however, they did not differ from each other. The mTBI with LOC did report greater pain than both controls and mTBI without LOC. The TBI with LOC group also had significantly elevated IL-6 concentrations than both TBI without LOC and control groups. Within the mTBI groups, increased TNFα concentrations were associated with greater PTSD symptoms. These findings indicate that sustaining an mTBI, with or without LOC is detrimental for psychological wellbeing. However, LOC may be involved in perceptions of pain and concentrations of IL-6.

Glial fibrillary acidic protein elevations relate to neuroimaging abnormalities after mild TBI.

OBJECTIVES: To determine whether a panel of blood-based biomarkers can discriminate between patients with suspected mild traumatic brain injury (mTBI) with and without neuroimaging findings (CT and MRI). METHODS: Study participants presented to the emergency department with suspected mTBI (n = 277) with a CT and MRI scan and healthy controls (n = 49). Plasma concentrations of tau, glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and neurofilament light chain (NFL) were measured using the single-molecule array technology. RESULTS: Concentrations of GFAP, tau, and NFL were higher in patients with mTBI, compared with those of controls (p's < 0.01). GFAP yielded an area under the curve (AUC) of 0.93 (95% confidence interval [CI] 0.90-0.96), confirming its discriminatory power for distinguishing mTBI from controls. Levels of GFAP, tau, and NFL were higher in patients with trauma-related intracranial findings on CT compared with those with normal CT, with the only significant predictor being GFAP (AUC 0.77, 95% CI 0.70-0.84). Among patients with mTBI, tau, NFL, and GFAP differentiated subjects with and without MRI abnormalities with an AUC of 0.83, with GFAP being the strongest predictor. Combining tau, NFL, and GFAP showed a good discriminatory power (AUC 0.80, 95% CI 0.69-0.90) for detecting MRI abnormalities, even in patients with mTBI with a normal CT. CONCLUSION: Our study confirms GFAP as a promising marker of brain injury in patients with acute mTBI. A combination of various biomarkers linked to different pathophysiologic mechanisms increases diagnostic subgroup accuracy. This multimarker strategy may guide medical decision making, facilitate the use of MRI scanning, and prove valuable in the stratification of patients with brain injuries in future clinical trials. CLASSIFICATION OF EVIDENCE: Class I evidence that blood concentrations of GFAP, tau, and NFL discriminate patients with mTBI with and without neuroimaging findings.

Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel.

OBJECTIVE: Identify biomarkers in peripheral blood that relate to chronic post-concussive and behavioural symptoms following traumatic brain injuries (TBIs) to ultimately improve clinical management. RESEARCH DESIGN: We compared military personnel with mild TBIs (mTBIs) (n = 42) to those without TBIs (n = 22) in concentrations of tau, amyloid-beta (Aß42) and cytokines (tumour necrosis factor alpha (TNFα, interleukin (IL)-6 and -10) in neuronal-derived exosomes from the peripheral blood. We utilized nanosight technology coupled with ultra-sensitivity immunoassay methods. We also examined the impact of post-concussive and behavioural symptoms including depression and post-traumatic stress disorder (PTSD) on these neuronal-derived markers. RESULTS: We report that concentrations of exosomal tau (F1, 62 = 10.50), Aß42 (F1, 61 = 5.32) and IL-10 (F1, 59 = 4.32) were elevated in the mTBI group compared to the controls. Within the mTBI group, regression models show that post-concussive symptoms were most related to exosomal tau elevations, whereas exosomal IL-10 levels were related to PTSD symptoms. CONCLUSIONS: These findings suggest that chronic post-concussive symptoms following an mTBI relate to altered exosomal activity, and that greater tau pathology may underlie chronic post-concussive symptoms that develop following mTBIs. It also suggests that central inflammatory activity contributes to PTSD symptoms following an mTBI, providing necessary insights into the role of inflammation in chronic PTSD symptoms.

Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury.

OBJECTIVE: The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aß) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms. METHODS: Tau, p-tau, Aß40, and Aß42 were measured by ultrasensitive immunoassay in plasma and exosomes from 195 Veterans enrolled in the Chronic Effects of Neurotrauma Consortium Multicenter Observational Study. Protein biomarkers were compared among groups with and without mTBI with loss of consciousness (LOC) or post-traumatic amnesia (PTA), and also in those with and without repetitive (≥3) mTBI (rTBI) compared to those with 0 (TBI-neg) and 1-2 mTBI. RESULTS: There were no differences in measures of plasma and exosomal protein levels among mTBI with LOC or PTA, mTBI with alteration of consciousness only or TBI-neg. Exosomal tau and exosomal p-tau were elevated in rTBI compared to those with 2 or fewer mTBIs and TBI-neg (p < 0.05). Elevations of exosomal tau and p-tau significantly correlated with post-traumatic and post-concussive symptoms, with exosomal tau also relating specifically to cognitive, affective, and somatic post-concussive symptoms (p < 0.05). CONCLUSION: rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

Exosomes in Acquired Neurological Disorders: New Insights into Pathophysiology and Treatment.

Exosomes are endogenous nanovesicles that play critical roles in intercellular signaling by conveying functional genetic information and proteins between cells. Exosomes readily cross the blood-brain barrier and have promise as therapeutic delivery vehicles that have the potential to specifically deliver molecules to the central nervous system (CNS). This unique feature also makes exosomes attractive as biomarkers in diagnostics, prognostics, and therapeutics in the context of multiple significant public health conditions, including acquired neurological disorders. The purpose of this review is to summarize the state of the science surrounding the relevance of extracellular vesicles (EVs), particularly exosomes, to acquire neurological disorders, specifically traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. In total, ten research articles were identified that examined exosomes in the context of TBI, SCI, or stroke; these manuscripts were reviewed and synthesized to further understand the current role of exosomes in the context of acquired neurological disorders. Of the ten published studies, four focused exclusively on TBI, one on both TBI and SCI, and five on ischemic stroke; notably, eight of the ten studies were limited to pre-clinical samples. The present review is the first to discuss the current body of knowledge surrounding the role of exosomes in the pathophysiology, diagnosis, and prognosis, as well as promising therapeutic strategies in TBI, SCI, and stroke research.

Nightmares in United States Military Personnel With Sleep Disturbances.

STUDY OBJECTIVES: Sleep disturbances are common in United States military personnel. Despite their exposure to combat and trauma, little is known about nightmares in this population. The purpose of this study was to describe the prevalence and associated clinical and polysomnographic characteristics of nightmares in United States military personnel with sleep disturbances. METHODS: Retrospective review of 500 active duty United States military personnel who underwent a sleep medicine evaluation and polysomnography at our sleep center. The Pittsburgh Sleep Quality Index and the Pittsburgh Sleep Quality Index-Addendum were used to characterize clinically significant nightmares. Subjective and objective sleep attributes were compared between groups. RESULTS: At least weekly nightmares were present in 31.2%; yet, only 3.9% reported nightmares as a reason for evaluation. Trauma-related nightmares occurred in 60% of those patients with nightmares. Patients with nightmares had increased sleep onset latency (SOL) and rapid eye movement (REM) sleep latency (mean SOL/REM sleep latency 16.6/145 minutes, P = .02 and P = .01 respectively) compared to those without (mean SOL/REM sleep latency 12.5/126 minutes). The comorbid disorders of depression (P ≤ .01, relative risk [RR] 3.55 [95% CI, 2.52-4.98]), anxiety (P ≤ .01, RR 2.57 [95% CI, 1.93-3.44]), posttraumatic stress disorder (P ≤ .01, RR 5.11 [95% CI, 3.43-7.62]), and insomnia (P ≤ .01, RR 1.59 [95% CI, 1.42-1.79]) were all associated with nightmares. CONCLUSIONS: Clinically significant nightmares are highly prevalent in United States military personnel with sleep disturbances. Nightmares are associated with both subjective and objective sleep disturbances and are frequently comorbid with other sleep and mental health disorders. COMMENTARY: A commentary on this article appears in this issue on page 303.

Elevated tau and interleukin-6 concentrations in adults with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by apneas and hypopneas that result in hypoxia, cerebral hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress. These pathophysiologic processes likely contribute to neuronal damage. Tau is a protein that stabilizes microtubules and, along with amyloid beta (Aß), is associated with neurodegenerative processes. We sought to determine if tau and other biomarkers of inflammation were related to OSA severity. Concentrations of tau, Aß40, Aß42, c-reactive protein (CRP), TNF-α, interleukin (IL)-6, and IL-10 were measured in blood and compared between participants with moderate-severe OSA (n = 28), those with mild OSA (n = 22), and healthy controls (n = 24). The cohort included relatively young, primarily male active duty military personnel without a history of traumatic brain injury or neurodegenerative disease. Total biomarker concentrations were determined from plasma samples using an ultra-sensitive detection method, Simoa™, and CRP was assayed by ELISA. Total tau and IL-6 concentrations were elevated in participants with moderate-severe OSA, with a mean apnea-hypopnea index (AHI) of 26.1/h, compared to those with mild OSA (mean AHI 8.6/h) and healthy controls (mean AHI 2.1/h). Tau concentrations were also significantly correlated with the AHI (r = 0.342, p = 0.004). Our findings show that tau is elevated in the blood of young patients with moderate-severe OSA, suggesting that this degree of sleep-disordered breathing is a contributing factor in the development of neurodegenerative disorders. The finding of increased IL-6 further suggests that inflammatory biomarkers are present early in the course of this chronic disease.

Moderate blast exposure alters gene expression and levels of amyloid precursor protein.

OBJECTIVE: To explore gene expression after moderate blast exposure (vs baseline) and proteomic changes after moderate- (vs low-) blast exposure. METHODS: Military personnel (N = 69) donated blood for quantification of protein level, and peak pressure exposures were detected by helmet sensors before and during a blast training program (10 days total). On day 7, some participants (n = 29) sustained a moderate blast (mean peak pressure = 7.9 psi) and were matched to participants with no/low-blast exposure during the training (n = 40). PAXgene tubes were collected from one training site at baseline and day 10; RNA-sequencing day 10 expression was compared with each participant's own baseline samples to identify genes and pathways differentially expressed in moderate blast-exposed participants. Changes in amyloid precursor protein (APP) from baseline to the day of blast and following 2 days were evaluated. Symptoms were assessed using a self-reported form. RESULTS: We identified 1,803 differentially expressed genes after moderate blast exposure; the most altered network was APP. Significantly reduced levels of peripheral APP were detected the day after the moderate blast exposure and the following day. Protein concentrations correlated with the magnitude of the moderate blast exposure on days 8 and 9. APP concentrations returned to baseline levels 3 days following the blast, likely due to increases in the genetic expression of APP. Onset of concentration problems and headaches occurred after moderate blast. CONCLUSIONS: Moderate blast exposure results in a signature biological profile that includes acute APP reductions, followed by genetic expression increases and normalization of APP levels; these changes likely influence neuronal recovery.

Moderate blast exposure results in increased IL-6 and TNFα in peripheral blood.

A unique cohort of military personnel exposed to isolated blast was studied to explore acute peripheral cytokine levels, with the aim of identifying blast-specific biomarkers. Several cytokines, including interleukin (IL) 6, IL-10 and tumor necrosis factor alpha (TNFα) have been linked to pre-clinical blast exposure, but remained unstudied in clinical blast exposure. To address this gap, blood samples from 62 military personnel were obtained at baseline, and daily, during a 10-day blast-related training program; changes in the peripheral concentrations of IL-6, IL-10 and TNFα were evaluated using an ultrasensitive assay. Two groups of trainees were matched on age, duration of military service, and previous history of blast exposure(s), resulting in moderate blast cases and no/low blast controls. Blast exposures were measured using helmet sensors that determined the average peak pressure in pounds per square inch (psi). Moderate blast cases had significantly elevated concentrations of IL-6 (F1,60=18.81, p<0.01) and TNFα (F1,60=12.03, p<0.01) compared to no/low blast controls; levels rebounded to baseline levels the day after blast. On the day of the moderate blast exposure, the extent of the overpressure (psi) in those exposed correlated with IL-6 (r=0.46, p<0.05) concentrations. These findings indicate that moderate primary blast exposure results in changes, specifically acute and transient increases in peripheral inflammatory markers which may have implications for neuronal health.