Photoacoustic monitoring of angiogenesis predicts response to therapy in healing wounds.

Chronic wounds are a major health problem that cause the medical infrastructure billions of dollars every year. Chronic wounds are often difficult to heal and cause significant discomfort. Although wound specialists have numerous therapeutic modalities at their disposal, tools that could three dimensional-map wound bed physiology and guide therapy do not exist. Visual cues are the current standard but are limited to surface assessment; clinicians rely on experience to predict response to therapy. Photoacoustic (PA) ultrasound (US) is a non-invasive, hybrid imaging modality that can solve these major limitations. PA relies on the contrast generated by haemoglobin in blood which allows it to map local angiogenesis, tissue perfusion and oxygen saturation-all critical parameters for wound healing. This work evaluates the use of PA-US to monitor angiogenesis and stratify patients responding versus not-responding to therapy. We imaged 19 patients with 22 wounds once a week for at least 3 weeks. Our findings suggest that PA imaging directly visualises angiogenesis. Patients responding to therapy showed clear signs of angiogenesis and an increased rate of PA increase (p = 0.002). These responders had a significant and negative correlation between PA intensity and wound size. Hypertension was correlated to impaired angiogenesis in non-responsive patients. The rate of PA increase and hence the rate of angiogenesis was able to predict healing times within 30 days from the start of monitoring (power = 88%, alpha = 0.05). This early response detection system could help inform management and treatment strategies while improving outcomes and reducing costs.

Microglial reduction of colony stimulating factor-1 receptor expression is sufficient to confer adult onset leukodystrophy.

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a dementia resulting from dominantly inherited CSF1R inactivating mutations. The Csf1r+/- mouse mimics ALSP symptoms and pathology. Csf1r is mainly expressed in microglia, but also in cortical layer V neurons that are gradually lost in Csf1r+/- mice with age. We therefore examined whether microglial or neuronal Csf1r loss caused neurodegeneration in Csf1r+/- mice. The behavioral deficits, pathologies and elevation of Csf2 expression contributing to disease, previously described in the Csf1r+/- ALSP mouse, were reproduced by microglial deletion (MCsf1rhet mice), but not by neural deletion. Furthermore, increased Csf2 expression by callosal astrocytes, oligodendrocytes, and microglia was observed in Csf1r+/- mice and, in MCsf1rhet mice, the densities of these three cell types were increased in supraventricular patches displaying activated microglia, an early site of disease pathology. These data confirm that ALSP is a primary microgliopathy and inform future therapeutic and experimental approaches.

Low Thyroid Function in Nonalcoholic Fatty Liver Disease Is an Independent Predictor of All-Cause and Cardiovascular Mortality.

INTRODUCTION: Higher levels of thyroid-stimulating hormone (TSH) in the euthyroid state can negatively affect the metabolic health, including nonalcoholic fatty liver disease (NAFLD). We studied the effect of TSH levels in the setting of normal levels of thyroid hormone on all-cause and cause-specific mortality stratified by NAFLD status. METHODS: The National Health and Nutrition Examination Survey (NHANES) III from 1988 to 1994 and NHANES III-linked mortality data through 2015 were used. NAFLD was defined as ultrasonographically diagnosed hepatic steatosis without coexisting liver diseases. Subclinical hypothyroidism was defined as a TSH level over 4.5 mIU/L and "low-normal" thyroid function as higher TSH level (2.5-4.5 mIU/L) within the euthyroid reference range. The Cox proportional hazard model analyzed the all-cause mortality and cause-specific mortality. RESULTS: In a multivariate logistic regression analysis, individuals with low thyroid function demonstrated an association with NAFLD in a dose-dependent manner. During a median follow-up of 23 years, low thyroid function was associated with increased all-cause mortality only in the univariate model. Low thyroid function was associated with a higher risk for all-cause mortality in individuals with NAFLD and not in those without NAFLD. Furthermore, low thyroid function was associated with a higher risk for cardiovascular mortality in the entire population and among those with NAFLD but demonstrated no association with the non-NAFLD group. DISCUSSION: In this large nationally representative sample of American adults, low thyroid function was associated with NAFLD and a predictor of higher risk for all-cause and cardiovascular mortality in individuals with NAFLD.

Diet quality and its association with nonalcoholic fatty liver disease and all-cause and cause-specific mortality.

BACKGROUND & AIMS: Healthy diet has been recommended for nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent mortality. We aim to assess the impact of quality of diet on NAFLD and mortality in subjects with and without NAFLD. METHODS: We performed cohort study using the Third National Health and Nutrition Examination Survey from 1988 to 1994 and linked mortality data through 2015. We used the Healthy Eating Index (HEI) scores to define diet quality, with higher HEI scores (Q4) indicating better adherence to dietary recommendations. NAFLD was defined as ultrasonographic hepatic steatosis. RESULTS: Multivariate analysis showed that subjects with higher diet quality were inversely associated with NAFLD in a dose-dependent manner. During the median follow-up of 23 years, having a higher diet quality was associated with reduction in risk of all-cause mortality in the age, sex, Race/ethnicity-adjusted hazard ratio (HR) (Q4, HR: 0.60, 95% CI: 0.52-0.68) and the multivariate model (Q4, HR: 0.81, 95% CI: 0.71-0.92). Higher diet quality was associated with a lower risk for all-cause mortality in subjects without NAFLD; however, this protective association with diet quality was not noted in those with NAFLD. Furthermore, a high diet quality was associated with a lower risk for cancer-related mortality in the total population and among those without NAFLD. This association was not noted in those with NAFLD. CONCLUSIONS: High diet quality was inversely associated with NAFLD and was positively associated with a lower risk for cancer-related and all-cause mortality in those without NAFLD.

Low-Normal Thyroid Function Is Associated With Advanced Fibrosis Among Adults in the United States.

The pathogenetic pathways leading to increasing prevalence of advanced fibrosis in the setting of nonalcoholic fatty liver disease (NAFLD) and resulting in higher rates of liver-related and cardiovascular morbidity and mortality in the United States are multifactorial.1 The negative health impact of "low-normal" thyroid function, which is defined as a higher level of thyroid-stimulating hormone (TSH) within the euthyroid reference range, may be comparable with overt and subclinical hypothyroidism.2-4 We reported a strong association between biopsy-proven advanced fibrosis in NAFLD with increasing TSH levels in a dose-dependent manner even within the euthyroid reference range.5 To generalize our findings across all ethnicities, we examined the association of both low-normal thyroid function and subclinical hypothyroidism with advanced fibrosis in the US general population.

Implementing an obstetric triage acuity scale: interrater reliability and patient flow analysis.

A 5-category Obstetric Triage Acuity Scale (OTAS) was developed with a comprehensive set of obstetrical determinants. The objectives of this study were as follows: (1) to test the interrater reliability of OTAS and (2) to determine the distribution of patient acuity and flow by OTAS level. To test the interrater reliability, 110 triage charts were used to generate vignettes and the consistency of the OTAS level assigned by 8 triage nurses was measured. OTAS performed with substantial (Kappa, 0.61 - 0.77, OTAS 1-4) and near perfect correlation (0.87, OTAS 5). To assess patient flow, the times to primary and secondary health care provider assessments and lengths of stay stratified by acuity were abstracted from the patient management system. Two-thirds of triage visits were low acuity (OTAS 4, 5). There was a decrease in length of stay (median [interquartile range], minutes) as acuity decreased from OTAS 1 (120.0 [156.0] minutes) to OTAS 3 (75.0 [120.8]). The major contributor to length of stay was time to secondary health care provider assessment and this did not change with acuity. The percentage of patients admitted to the antenatal or birthing unit decreased from 80% (OTAS 1) to 12% (OTAS 5). OTAS provides a reliable assessment of acuity and its implementation has allowed for triaging of obstetric patients based on acuity, and a more in-depth assessment of the patient flow. By standardizing assessment, OTAS allows for opportunities to improve performance and make comparisons of patient care and flow across organizations.

Orthostatic hypotension as the initial presentation of disseminated cryptococcosis in a kidney transplant recipient.

Background: Solid organ transplant recipients are immunocompromised and at risk for invasive viral, fungal, and bacterial pathogens. Cryptococcus neoformans is the third most common invasive fungal infection in transplant recipients, and the clinical presentation of Cryptococcus neoformans infection can vary widely. Cryptococcal disease can affect the brain, lungs, skin, or vasculature, and it is frequently disseminated. Meningitis typically presents with fever, headache, and altered mental status. Solid organ transplant recipients with cryptococcosis tend to have poorer outcomes than HIV patients with cryptococcosis. Case presentation: In this case report, we describe the case of a 69 year-old man with a past medical history of a deceased donor kidney transplant who presented with severe orthostatic hypotension and was found to have disseminated cryptococcosis. Conclusions: This case report emphasizes the importance of broadening the differential diagnosis in transplant recipients who present with non-specific chief concerns. Availability of data and materials: No datasets were used in the preparing of this manuscript. All patient information comes from the electronic health record and authors personal care of this patient.

Treatment of inoperable hepatocellular carcinoma with immunotherapy.

In the USA, mortality associated with hepatocellular carcinoma (HCC) continues to rise. Globally, HCC is the third most common cause of cancer-related death. In early stages of HCC, hepatic resection or liver transplantation are the preferred treatment options with a high probability of recurrence-free postoperative course. However, ineffective screening of chronic liver diseases in high-risk populations, poor linkage to care and suboptimal HCC surveillance has led to increasing rates of late-stage HCC at clinical presentation or diagnosis amenable only to palliative and experimental treatment options. Our case is a 66-year-old man with chronic hepatitis C virus infection complicated by cirrhosis and inoperable HCC which was non-responsive to selective intrahepatic trans-arterial chemoembolisation by interventional radiology. Therefore, he was treated with nivolumab immunotherapy and demonstrated normalisation of previously elevated alpha-fetoprotein levels suggestive of at least a partial response to immunotherapy. No adverse events related to nivolumab immunotherapy were encountered.

Kratom-Induced Cholestatic Liver Injury and Its Conservative Management.

Drug-induced liver injury (DILI) is a common cause of hepatotoxicity associated with prescription-based and over-the-counter exposure to medications and herbal supplements. Use of unapproved and inadequately tested herbal supplements can cause DILI. Therefore, thorough history-taking on exposure to herbal supplements must be an integral part of clinical evaluation of DILI. Kratom is an herbal supplement or remedy that has been known for its analgesic effects and has also been used for self-treatment of opiate withdrawals. A 52-year-old man was seen for evaluation of yellow discoloration of the eyes and skin. He reported taking kratom for right shoulder strain for at least a couple of months. On workup, his total bilirubin was noted to be 23.2 mg/dL, which peaked at 28.9 mg/dL. He was noted to have mild elevation of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Extensive laboratory tests were ordered and known causes of chronic liver disease ruled out. Magnetic resonance imaging of the abdomen was unremarkable without stigmata of portal hypertension or signs of chronic liver disease. He demonstrated no evidence of coagulopathy or hepatic encephalopathy during his illness. He underwent liver biopsy, which demonstrated histologic evidence of acute cholestatic hepatitis highly suspicious of DILI. He was advised to avoid kratom or other herbal supplements in future and prescribed ursodeoxycholic acid with significant improvement in his liver chemistries. Kratom is associated with significant liver enzymes derangements leading to DILI. Kratom is not approved for use in the United States and should be avoided.

The molecular determinants of R-roscovitine block of hERG channels.

Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (IKr) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K+channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine is a cyclin-dependent kinase (CDK) inhibitor that induces apoptosis in colorectal, breast, prostate, multiple myeloma, other cancer cell lines, and tumor xenografts, in micromolar concentrations. It is well tolerated in phase II clinical trials. R-roscovitine inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or hERG pore mutant channels (T623A, S624A, Y652A, F656A) demonstrated that compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 µM R-roscovitine was ~ 48%, 29%, and 73% weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with a ~ 34% stronger inhibition. These findings were further supported by the IC50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be. Docking studies further support our findings. Thus, R-roscovitine's relatively unique features, coupled with its tolerance in clinical trials, could guide future drug screens.

Anaphylactoid reaction to recombinant tissue plasminogen activator.

Anaphylactoid reaction to recombinant tissue plasminogen activator for the thrombolytic treatment of acute ischemic stroke is an uncommon complication. An increased risk of anaphylaxis may be found in patients concomitantly being treated with angiotensin-converting enzyme inhibitors, as illustrated by this case report describing a patient who experienced an urticaric rash, hypotension, tachycardia, orolingual angioedema, and airway obstruction following intravenous administration of alteplase. Possible pharmacologic interactions resulting in excessive serum bradykinin and subsequent systemic hypersensitivity responses are discussed.

Predictive validity comparison of two five-level triage acuity scales.

INTRODUCTION: Each of the two most commonly used five-level triage tools in North America, the Emergency Severity Index and the Canadian Triage and Acuity Scale have been used as a measure of emergency department resource utilization in addition to acuity. In both cases, it is believed that patients triaged as having a higher level of acuity require a greater number of emergency department resources. We compared the ability of each tool to predict the emergency department resources for each emergency department visit and associated hospital admission and in-hospital mortality rates. METHODS: This is an observational, cohort study of a population-based random sample of patients triaged at two emergency departments over a 4-month period. Correlational analyses were performed to examine the relationship between the triage assessment and: (i) resource utilization, (ii) hospital admission, and (iii) in-hospital mortality. RESULTS: From 486 patients, analyses revealed the greatest correlation was between Emergency Severity Index and diagnostic resources [-0.54 (95% confidence intervals: -0.58, -0.50)] and the poorest correlation was between Canadian Triage and Acuity Scale and mortality [-0.16 (95% confidence intervals: -0.20, -0.12)]. No statistically significant differences (P<0.005) were observed between each tool 's ability to predict any of the outcomes measured. CONCLUSION: No statistically significant difference was observed in the ability of Emergency Severity Index v. 3 and Canadian Triage and Acuity Scale to predict emergency department resource utilization or immediate patient outcomes. This ability is, at best, only moderate indicating that other, more accurate tools than measures of triage acuity are required for this purpose.

How does fast track affect quality of care in the emergency department?

STUDY OBJECTIVES: Use of fast track has been shown to improve the emergency department flow of less urgent patients. It has been speculated, however, that this could negatively affect the care of urgent patients. The objective of this study was to determine whether a dedicated fast track for less urgent patients [Canadian Triage and Acuity scale category 4/5 (CTAS 4/5)] affected (1) the time to assessment for urgent patients (CTAS 3), (2) the length of stay for less urgent patients (CTAS 4 and 5), and (3) the left-without-being-seen rate. METHODS: In June 2003, fast track was opened in our emergency department from 13:00 to 19:00 h. A before-after intervention comparison analysis was completed for 1 week in Aug 2002 and the same week in Aug 2003. Data collected included (1) time to assessment of CTAS 3 patients, (2) the length of stay for CTAS 4/5 patients, and (3) percentage of patients who left without being seen. RESULTS: A total of 368 patients were reviewed for 2002 and 380 patients were reviewed for 2003. Median time to assessment of CTAS 3 patients presenting from 13:00 to 19:00 h was reduced from 66 min (Interquartile range: 40, 94 min) in 2002 to 60 min (IQR: 38, 108 min) after fast track was open in 2003 (P = 0.95). Median length of stay of CTAS 4 and 5 patients was reduced from 170 min (IQR: 111, 256 min) to 110 min (IQR: 69, 185 min) (P < 0.001). The overall left-without-being-seen rate decreased from 5% (20/368) to 2% (9/380). CONCLUSION: A dedicated fast track for CTAS 4/5 patients can reduce the length of stay and the left-without-being-seen rate with no impact on CTAS 3 patients seen in the main emergency department.

The impact of computerized provider order entry on emergency department flow.

OBJECTIVES: Computerized provider order entry (CPOE) has been established as a method to improve patient safety by avoiding medication errors; however, its effect on emergency department (ED) flow remains undefined. We examined the impact of CPOE implementation on three measures of ED throughput: wait time (WT), length of stay (LOS), and the proportion of patients that left without being seen (LWBS). METHODS: We conducted a retrospective cohort study of all ED patients of 18 years and older presenting to London Health Sciences Centre during July and August 2013 and 2014, before and after implementation of a CPOE system. The three primary variables were compared between time periods. Subgroup analyses were also conducted within each Canadian Triage and Acuity Scale (CTAS) level (1-5) individually, as well as for admitted patients only. RESULTS: A significant increase in WT of 5 minutes (p=0.036) and LOS of 10 minutes (p=0.001), and an increase in LWBS from 7.2% to 8.1% (p=0.002) was seen after CPOE implementation. Admitted patients' LOS increased by 63 minutes (p<0.001), the WT of CTAS 3 and 5 patients increased by 6 minutes (p=0.001) and 39 minutes (p=0.005), and LWBS proportion increased significantly for CTAS 3-5 patients, from 24.3% to 42.0% (p<0.001) for CTAS 5 patients specifically. CONCLUSIONS: CPOE implementation detrimentally impacted all patient flow throughput measures that we examined. The most striking clinically relevant result was the increase in LOS of 63 minutes for admitted patients. This raises the question as to whether the potential detrimental effects to patient safety of CPOE implementation outweigh its benefits.

Reassessing the methods of medical record review studies in emergency medicine research.

STUDY OBJECTIVE: An assessment of the methods of medical record review studies published in emergency medicine journals during a 5-year period ending in 1993 provided strategies for improvements. We assess and quantify the current methodologic quality of medical record review studies in emergency medicine journals using published guidelines and compare these results among journals and with those of 10 years previously. METHODS: Independent, systematic searches of emergency medicine journals identified all medical record review studies published in 2003. Methodology assessments of each selected study were conducted independently by 2 other researchers, and disagreements were resolved by arbitration. RESULTS: We identified 79 (14%) medical record review studies in 563 original research articles in 6 emergency medicine journals. The highest adherence to methodologic standards was found for sampling method (99%; 95% confidence interval [CI] 93% to 100%), and the lowest was for abstractor blinding to hypothesis (4%; 95% CI 1% to 11%). Interobserver agreement for the 12 criteria ranged from 57% to 95%. A comparison of these results with those of 10 years ago revealed significant improvements in 3 of the 8 original criteria assessed: data abstraction forms, mentioning interobserver performance, and testing interobserver performance. CONCLUSION: Medical record review studies continue to comprise a substantial proportion of original research in the emergency medicine literature. Important improvements are noted in some criteria, but adherence remains below 50% for 7 of the 12 criteria assessed.

Understanding the role of nurse practitioners in Canada.

The practice of medicine and nursing continues to evolve as a result of changes in knowledge, technology and health care needs. New areas of specialization have developed and, in particular, the roles and duties of registered nurses have been expanded. This expansion has enabled nurses with advanced education and skills to function as independent and interdependent clinicians who practise in partnership with physicians and other health care professionals.

Spinal epidural abscess.

Spinal epidural abscess is an uncommon condition. Predisposing factors include spinal surgery, recent trauma, immunosuppression, a distal site of infection and intravenous drug use; however, these are not always present, as illustrated by this case report describing a patient who had repeated emergency department visits and delayed diagnosis that was ultimately confirmed via magnetic resonance imaging.

Adult epiglottitis: a five-year retrospective chart review in a major urban centre.

OBJECTIVE: There is an increasing awareness of unvaccinated adults presenting with epiglottitis to the emergency department. This study examines the clinical presentations and outcomes of diagnosed cases of adult epiglottitis presenting to all emergency departments in Hamilton, Ont., between 1999 and 2003. METHODS: We employed explicit protocols with defined variables, trained abstractors and standardized abstraction forms, and reviewed all diagnosed cases of adult epiglottitis during a 5-year period. Inter-rater agreement was measured using a kappa statistic. RESULTS: Inter-rater reliability for data abstraction was kappa = 1. From a total of 1 million emergency department admissions, 54 cases of epiglottitis were identified. The mean age was 49, and 69% of the patients were male. The 3 most frequently documented symptoms were sore throat (100%) odynophagia (94%) and inability to swallow secretions (63%). The 2 most frequently documented signs were swelling of the epiglottis/supraglottis (100%), and tachycardia (53%). Organisms were isolated from blood in 11% of the cases. There was a white blood cell count >20 x 10(9)/L in 4 of the cases (7.4%). From the 54 cases, 9 of the patients were intubated and all patients were safely discharged from hospital. CONCLUSION: Adults presenting with epiglottitis to the emergency department in Hamilton have good outcomes, with less airway management required than previously reported in children. Further study is needed to see if these conclusions are similar in other populations.

Root cause analysis of laboratory turnaround times for patients in the emergency department.

INTRODUCTION: Laboratory investigations are essential to patient care and are conducted routinely in emergency departments (EDs). This study reports the turnaround times at an academic, tertiary care ED, using root cause analysis to identify potential areas of improvement. Our objectives were to compare the laboratory turnaround times with established benchmarks and identify root causes for delays. METHODS: Turnaround and process event times for a consecutive sample of hemoglobin and potassium measurements were recorded during an 8-day study period using synchronized time stamps. A log transformation (ln [minutes + 1]) was performed to normalize the time data, which were then compared with established benchmarks using one-sample t tests. RESULTS: The turnaround time for hemoglobin was significantly less than the established benchmark (n = 140, t = -5.69, p < 0.001) and that of potassium was significantly greater (n = 121, t = 12.65, p < 0.001). The hemolysis rate was 5.8%, with 0.017% of samples needing recollection. Causes of delays included order-processing time, a high proportion (43%) of tests performed on patients who had been admitted but were still in the ED waiting for a bed, and excessive laboratory process times for potassium. CONCLUSIONS: The turnaround time for hemoglobin (18 min) met the established benchmark, but that for potassium (49 min) did not. Root causes for delay were order-processing time, excessive queue and instrument times for potassium and volume of tests for admitted patients. Further study of these identified causes of delays is required to see whether laboratory TATs can be reduced.

Assessment of inter-observer reliability of two five-level triage and acuity scales: a randomized controlled trial.

INTRODUCTION: The Emergency Severity Index (ESI) is an initial measure of patient assessment in the emergency department (ED). It rates patients based on acuity and predicted resource intensity from Level 1 (most ill) to Level 5 (least resource intensive). Already implemented and evaluated in several US hospitals, ESI has yet to be evaluated in a Canadian setting or compared with the five-level Canadian Emergency Department Triage and Acuity Scale (CTAS). OBJECTIVE: To compare the inter-observer reliability of 2 five-level triage and acuity scales. METHODS: Ten triage nurses, who had all been trained in the use of CTAS, from 4 urban, academic Canadian EDs were randomly assigned either to training in ESI version 3 (ESI v.3) or to refresher training in CTAS. They independently assigned triage scores to 200 emergency cases, unaware of the rating by the other nurses. RESULTS: Number of years of nursing practice was the only significant demographic difference found between the 2 groups (p = 0.014). A quadratically weighted kappa to measure the inter-observer reliability of the CTAS group was 0.91 (0.90, 0.99) and not significantly different from that of the ESI group 0.89 (0.88, 0.99). An inter-test generalizability (G) study performed on the variance components derived from an analysis of variance (ANOVA) revealed G(5) = 0.90 (0.82, 0.99). CONCLUSIONS: After 3 hours of training, experienced triage nurses were able to perform triage assessments using ESI v.3 with the same inter-observer reliability as those with experience and refresher training in using the CTAS.