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1.
Psychol Assess ; 2024 May 06.
Article in English | MEDLINE | ID: mdl-38709629

ABSTRACT

Recent changes to diagnostic criteria for serious conduct problems in children and adolescents have included the presence of elevated callous-unemotional traits to define etiologically and clinically important subgroups of youth with a conduct problem diagnosis. The Clinical Assessment of Prosocial Emotions (CAPE) is an intensive assessment of the symptoms of this limited prosocial emotions specifier that uses a structured professional judgment method of scoring, which may make it useful in clinical settings when diagnoses may require more information than that provided by behavior rating scales. The present study adds to the limited tests of the CAPE's reliability and validity, using a sample of clinic-referred children ages 6-17 years of age, who were all administered the CAPE by trained clinicians. The mean age of the sample was 10.13 years (SD = 2.64); 54% of the sample identified as male and 46% identified as female; and 67% of participants identified as White, 29% identified as Black, and 52% identified as another race/ethnicity (i.e., Asian, Hispanic/Latinx, or other). The findings indicated that CAPE scores demonstrated strong interrater reliability. The scores also were associated with measures of conduct problems and aggression, even when controlling for behavior ratings of callous-unemotional traits. Further, when children with conduct problem diagnoses were divided into groups based on the presence of the limited prosocial emotions specifier from the CAPE, the subgroup with the specifier showed more severe conduct problems and aggression. The results support cautious clinical use of the CAPE, its further development and testing, and research into ways to make its use feasible in many clinical settings. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

2.
bioRxiv ; 2024 Jan 23.
Article in English | MEDLINE | ID: mdl-38328115

ABSTRACT

KRAS is a small GTPase, ubiquitously expressed in mammalian cells, that functions as a molecular switch to regulate cell proliferation and differentiation. Oncogenic mutations that render KRAS constitutively active occur frequently in human cancers. KRAS must localize to the plasma membrane (PM) for biological activity. KRAS PM binding is mediated by interactions of the KRAS membrane anchor with phosphatidylserine (PtdSer), therefore, depleting PM PtdSer content abrogates KRAS PM binding and oncogenic function. From a genome-wide siRNA screen to search for genes that regulate KRAS PM localization, we identified a set of phosphatidylinositol (PI) 3-phosphatase family members: myotubularin-related (MTMR) proteins 2, 3, 4 and 7. Here we show that knockdown of MTMR 2/3/4/7 expression disrupts KRAS PM interactions. The molecular mechanism involves depletion of PM PI 4-phosphate (PI4P) levels, which in turn disrupts the subcellular localization and operation of oxysterol-binding protein related protein (ORP) 5, a PtdSer lipid transfer protein that maintains PM PtdSer content. Concomitantly, silencing MTMR 2/3/4/7 expression elevates PM levels of PI3P and reduces PM and total cellular levels of PtdSer. In summary we propose that the PI 3-phosphatase activity provided by MTMR proteins is required to generate PM PI for the synthesis of PM PI4P, which in turn, promotes the PM localization of PtdSer and KRAS.

3.
J Emerg Med ; 66(2): 109-132, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38262782

ABSTRACT

BACKGROUND: Firearm injury poses a significant public health burden in the United States. OBJECTIVES: The purpose of this systematic review was to provide a comprehensive accounting of the medical costs of firearm injuries in the United States. METHODS: A systematic literature review was conducted to identify studies published between January 1, 2000 and July 13, 2022 that reported medical costs of firearm injuries. A search of Embase, PubMed, and the Cochrane Library databases was performed by a medical librarian. The National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was used to evaluate for risk of bias. Health care-related charges and costs per firearm injury were presented and trends were identified. RESULTS: Sixty-four studies were included in the analysis. Study sample sizes ranged from 18 to 868,483 patients. Reported costs per injury ranged from $261 to $529,609. The median cost reported was $27,820 (interquartile range [IQR] $15,133-$40,124) and median charge reported was $53,832 (IQR $38,890-$98,632). Studies that divided initial hospitalization costs and follow-up medical costs identified that initial hospitalization accounts for about 60% of total costs. CONCLUSIONS: We found a significant volume of literature about the medical costs of firearm injury, which identified a highly heterogeneous cost burden. A significant amount of cost burden occurs after the index hospitalization, which is the only cost reported in most studies. Limitations of this study include reporting bias that favors hospitalized patients as well as a large focus on hospital charges as measurements of cost identified in the literature.


Subject(s)
Firearms , Health Care Costs , Wounds, Gunshot , Humans , Cross-Sectional Studies , Hospitalization , Hospitals , United States/epidemiology , Wounds, Gunshot/economics , Wounds, Gunshot/epidemiology
4.
Plant Dis ; : PDIS04230632RE, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38127637

ABSTRACT

Phytophthora nicotianae causes devastating disease in a range of hosts, including tobacco (N. tabacum L.), tomato, citrus, strawberry, and numerous ornamentals. Black shank, caused by P. nicotianae, is the most economically important disease to tobacco production in Tennessee and North Carolina. Black shank management includes the use of resistant cultivars, crop rotation, and fungicides. Fungicide resistance is a concern for black shank management due to the limited number of active ingredients available and the repeated exposure of pathogen populations to these products. In vitro fungicide sensitivity assays were conducted on 155 P. nicotianae isolates collected in Tennessee and North Carolina in 2021 and 2022 to determine their EC50 values for oxathiapiprolin, mandipropamid, and fluopicolide. The P. nicotianae was isolated predominantly from burley, dark, and flue-cured tobacco showing symptoms of black shank as well as tomato with buckeye rot symptoms. A discriminatory dose was used to determine each isolate's sensitivity to mefenoxam in 2021 and 2022. In 2021, EC50 values were determined for oxathiapiprolin, mandipropamid, and fluopicolide. In 2022, discriminatory doses based on EC75 values were used to determine each isolate's sensitivity to these fungicides. All isolates from the 2 years were sensitive to mefenoxam, mandipropamid, and fluopicolide. One isolate in 2022 was moderately sensitive to oxathiapiprolin, while all other isolates were sensitive.

5.
J Vector Ecol ; 49(1): 44-52, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38147300

ABSTRACT

In the United States, there has been a steady increase in diagnosed cases of tick-borne diseases in people, most notably Lyme disease. The pathogen that causes Lyme disease, Borrelia burgdorferi, is transmitted by the blacklegged tick (Ixodes scapularis). Several small mammals are considered key reservoirs of this pathogen and are frequently-used hosts by blacklegged ticks. However, limited studies have evaluated between-species host use by ticks. This study compared I. scapularis burdens and tick-associated pathogen presence in wild-caught Clethrionomys gapperi (southern red-backed voles) and Peromyscus spp. (white-footed mice) in forested areas where the habitat of both species overlapped. Rodent trapping data collected over two summers showed a significant difference in the average tick burden between species. Adult Peromyscus spp. had an overall mean of 4.03 ticks per capture, while adult C. gapperi had a mean of 0.47 ticks per capture. There was a significant association between B. burgdorferi infection and host species with more Peromyscus spp. positive samples than C. gapperi (65.8% and 10.2%, respectively). This work confirms significant differences in tick-host use and pathogen presence between sympatric rodent species. It is critical to understand tick-host interactions and tick distributions to develop effective and efficient tick control methods.


Subject(s)
Ixodes , Lyme Disease , Humans , Animals , Adult , Rodentia , Peromyscus , Arvicolinae
6.
POCUS J ; 8(1): 88-92, 2023.
Article in English | MEDLINE | ID: mdl-37152335

ABSTRACT

Emergency and critical care physicians frequently encounter patients presenting with dyspnea and normal left ventricular systolic function who may benefit from early diastolic evaluation to determine acute patient management. The current American Society of Echocardiography Guidelines approach to diastolic evaluation is often impractical for point of care ultrasound (POCUS) evaluation, and few studies have evaluated the potential use of a simplified approach. This article reviews the literature on the use of a simplified diastolic evaluation to assist in determining acute patient management.

8.
Phlebology ; 37(9): 678-685, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36114157

ABSTRACT

BACKGROUND: Despite socioeconomic disparities, no association between clinical presentation and poor outcomes explains a higher mortality in African Americans with pulmonary embolism (PE). The objective is to identify the co-morbidities and echocardiographic characteristics associated with increased mortality in African American patients. METHODS: This is a cross-sectional study of Caucasian or African American patients with PE diagnosed between October 2015 and December 2017 at University of Maryland Medical Center. The outcomes were in-hospital death, length of stay, and bleeding. RESULTS: There were 303 African Americans and 343 Caucasians. Caucasians were older (p = 0.007), males (p = 0.01) with history of coronary artery revascularization (CABG (p = 0.001), coronary stents (p = 0.001)), trauma (p = 0.007), and/or recent surgeries (p = 0.0001). African Americans exhibited higher rates of diabetes (p = 0.01), chronic kidney disease (p = 0.0005), and smoking (p = 0.04). Severity of PE was similar between groups and there was no difference in clot burden size. African Americans had more right ventricular strain on Computer Tomography (p = 0.001) and echocardiogram (p = 0.004); also, underfilled left ventricles (p = 0.02) and higher right ventricular systolic pressures (p = 0.001). There was no difference in hospital mortality (7.1% vs. 7.9%, p = 0.71), length of stay (13.1 ± 16.7 vs 12.8 ± 14.9, p = 0.80) and bleeding (9.0% vs.8.3%. p = 0.72). Mortality was higher in African Americans who received advanced therapies (3.8% vs. 18.8%, p = 0.02). The risk of death increased with age (OR 1.04; 95%CI 1.020-1.073) and with advanced therapies (OR 2.43; 95%CI 1.029-5.769). CONCLUSIONS: Differences in co-morbidities, radiologic findings, and echocardiographic characteristics that may contribute to higher mortality in African American patients, specifically those receiving advanced therapies.


Subject(s)
Black or African American , Pulmonary Embolism , Acute Disease , Cross-Sectional Studies , Echocardiography , Hospital Mortality , Humans , Male , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/therapy
9.
Am J Emerg Med ; 60: 96-100, 2022 10.
Article in English | MEDLINE | ID: mdl-35930997

ABSTRACT

INTRODUCTION: Patients who present in shock have high expected mortality and early resuscitation is crucial to improve their outcomes. The Critical Care Resuscitation Unit (CCRU) is a specialized unit at the University of Maryland Medical Center (UMMC) that prioritizes early resuscitation of critically ill patients. We hypothesized that lactate clearance and reduction of Sequential Organ Failure Assessment (SOFA) score during CCRU stay would be associated with lower in-hospital mortality. METHODS: We performed a retrospective analysis of adult patients who were admitted to the CCRU between 01/01/2018-12/31/2018 and had a diagnosis of severe shock, determined by serum lactate ≥4 mmol/L. We excluded patients who died during CCRU stay. We used multivariable logistic regression to evaluate the association between lactate clearance and reduction in SOFA scores during CCRU stay and in-hospital mortality. RESULTS: Out of 1740 patients admitted to the CCRU in 2018, 172 (10%) had serum lactate ≥4 mmol/L. Twenty-two (13%) patients died during their CCRU stay. Our primary analysis included 129 patients with lactate clearance data and 136 patients with SOFA data. Average patients' age was 54 years, and median length of stay in the CCRU was 6 h 55 min. The average lactate and SOFA score on admission were 7.4 (3.8) mmol/L and 8.3 (4.7), respectively. Average lactate clearance was 1.9 (3.1) and average SOFA score reduction was 0.2 (2.9). In multivariable logistic regressions evaluating SOFA score and lactate separately, SOFA score reduction during CCRU stay was associated with lower in-hospital mortality (OR 0.83, 95% CI: 0.70-0.97) but lactate clearance was not (OR 0.90, 95% CI 0.78-1.03). In forward stepwise multivariable analysis containing both SOFA score and lactate values, SOFA score clearance during CCRU stay was still associated with decreased in-hospital mortality (OR 0.84, 95% CI 0.72-0.98). CONCLUSIONS: Care in the CCRU is more effective at reducing lactate than SOFA scores in patients with severe shock. However, SOFA score reduction in the resuscitation phase during the CCRU stay was associated with decreased odds of in-hospital mortality in this group of patients. Further studies are necessary to confirm our observations.


Subject(s)
Intensive Care Units , Organ Dysfunction Scores , Adult , Critical Care , Hospital Mortality , Humans , Lactic Acid , Middle Aged , Prognosis , Retrospective Studies
10.
Sci Rep ; 11(1): 19719, 2021 10 05.
Article in English | MEDLINE | ID: mdl-34611201

ABSTRACT

Many pheromone sensing bacteria produce and detect more than one chemically distinct signal, or autoinducer. The pathways that detect these signals are typically noisy and interlocked through crosstalk and feedback. As a result, the sensing response of individual cells is described by statistical distributions that change under different combinations of signal inputs. Here we examine how signal crosstalk reshapes this response. We measure how combinations of two homoserine lactone (HSL) input signals alter the statistical distributions of individual cell responses in the AinS/R- and LuxI/R-controlled branches of the Vibrio fischeri bioluminescence pathway. We find that, while the distributions of pathway activation in individual cells vary in complex fashion with environmental conditions, these changes have a low-dimensional representation. For both the AinS/R and LuxI/R branches, the distribution of individual cell responses to mixtures of the two HSLs is effectively one-dimensional, so that a single tuning parameter can capture the full range of variability in the distributions. Combinations of crosstalking HSL signals extend the range of responses for each branch of the circuit, so that signals in combination allow population-wide distributions that are not available under a single HSL input. Dimension reduction also simplifies the problem of identifying the HSL conditions to which the pathways and their outputs are most sensitive. A comparison of the maximum sensitivity HSL conditions to actual HSL levels measured during culture growth indicates that the AinS/R and LuxI/R branches lack sensitivity to population density except during the very earliest and latest stages of growth respectively.


Subject(s)
Bacterial Physiological Phenomena , Quorum Sensing , Signal Transduction , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Environmental Microbiology , Gene Expression Regulation, Bacterial , Genes, Reporter , Microscopy, Fluorescence
11.
MMWR Morb Mortal Wkly Rep ; 70(17): 639-643, 2021 Apr 30.
Article in English | MEDLINE | ID: mdl-33914720

ABSTRACT

Although COVID-19 mRNA vaccines demonstrated high efficacy in clinical trials (1), they were not 100% efficacious. Thus, some infections postvaccination are expected. Limited data are available on effectiveness in skilled nursing facilities (SNFs) and against emerging variants. The Kentucky Department for Public Health (KDPH) and a local health department investigated a COVID-19 outbreak in a SNF that occurred after all residents and health care personnel (HCP) had been offered vaccination. Among 83 residents and 116 HCP, 75 (90.4%) and 61 (52.6%), respectively, received 2 vaccine doses. Twenty-six residents and 20 HCP received positive test results for SARS-CoV-2, the virus that causes COVID-19, including 18 residents and four HCP who had received their second vaccine dose >14 days before the outbreak began. An R.1 lineage variant was detected with whole genome sequencing (WGS). Although the R.1 variant has multiple spike protein mutations, vaccinated residents and HCP were 87% less likely to have symptomatic COVID-19 compared with those who were unvaccinated. Vaccination of SNF populations, including HCP, is critical to reduce the risk for SARS-CoV-2 introduction, transmission, and severe outcomes in SNFs. An ongoing focus on infection prevention and control practices is also essential.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/epidemiology , COVID-19/virology , Disease Outbreaks , SARS-CoV-2/genetics , Skilled Nursing Facilities , Aged , COVID-19/prevention & control , Humans , Immunization Programs , Kentucky/epidemiology , SARS-CoV-2/isolation & purification
12.
J Intensive Care Med ; 36(7): 808-817, 2021 Jul.
Article in English | MEDLINE | ID: mdl-32578468

ABSTRACT

BACKGROUND: Reduced cholesterol levels are associated with increased organ failure and mortality in sepsis. Cholesterol levels may vary by infection type (gram negative vs positive), possibly reflecting differences in cholesterol-mediated bacterial clearance. METHODS: This was a secondary analysis of a combined data set of 2 prospective cohort studies of adult patients meeting Sepsis-3 criteria. Infection types were classified as gram negative, gram positive, or culture negative. We investigated quantitative (levels) and qualitative (dysfunctional high-density lipoprotein [HDL]) cholesterol differences. We used multivariable logistic regression to control for disease severity. RESULTS: Among 171 patients with sepsis, infections were gram negative in 67, gram positive in 46, and culture negative in 47. Both gram-negative and gram-positive infections occurred in 11 patients. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels were lower for culture-positive sepsis at enrollment (TC, P < .001; LDL-C, P < .001; HDL-C, P = .011) and persisted after controlling for disease severity. Similarly, cholesterol levels were lower among culture-positive patients at 48 hours (TC, P = .012; LDL-C, P = .029; HDL-C, P = .002). Triglyceride (TG) levels were lower at enrollment (P =.033) but not at 48 hours (P = .212). There were no differences in dysfunctional HDL. Among bacteremic patients, cholesterol levels were lower at enrollment (TC, P = .010; LDL-C, P = .010; HDL-C, P ≤ .001; TG, P = .005) and at 48 hours (LDL-C, P = .027; HDL-C, P < .001; TG, P = .020), except for 48 hour TC (P = .051). In the bacteremia subgroup, enrollment TC and LDL-C were lower for gram-negative versus gram-positive infections (TC, P = .039; LDL-C, P = .023). CONCLUSION: Cholesterol levels are significantly lower among patients with culture-positive sepsis and bacteremia.


Subject(s)
Bacteremia , Sepsis , Shock, Septic , Adult , Cholesterol , Humans , Prospective Studies , Triglycerides
13.
J Am Coll Emerg Physicians Open ; 1(3): 222-230, 2020 Jun.
Article in English | MEDLINE | ID: mdl-33000037

ABSTRACT

OBJECTIVE: Research evaluating the relationship between vasopressor initiation timing and clinical outcomes is limited and conflicting. We investigated the association between time to vasopressors, worsening organ failure, and mortality in patients with septic shock. METHODS: This was a retrospective study of patients with septic shock (2013-2016) within 24 hours of emergency department (ED) presentation. The primary outcome was worsening organ failure, defined as an increase in Sequential Organ Failure Assessment (SOFA) score ≥2 at 48 hours compared to baseline, or death within 48 hours. The secondary outcome was 28-day mortality. Time to vasopressor initiation was categorized into 6, 4-hour intervals from time of ED triage. Multiple logistic regression was used to identify predictors of worsening organ failure. RESULTS: We analyzed data from 428 patients with septic shock. There were 152 patients with the composite primary outcome (SOFA increase ≥2 or death at 48 hours). Of these, 77 patients died in the first 48 hours and 75 patients had a SOFA increase ≥2. Compared to the patients who received vasopressors in the first 4 hours, those with the longest time to vasopressors (20-24 hours) had increased odds of developing worsening organ failure (odds ratios [OR] = 4.34, 95% confidence intervals [CI] = 1.47-12.79, P = 0.008). For all others, the association between vasopressor timing and worsening organ failure was non-significant. There was no association between time to vasopressor initiation and 28-day mortality. CONCLUSIONS: Increased time to vasopressor initiation is an independent predictor of worsening organ failure for patients with vasopressor initiation delays >20 hours.

14.
J Natl Med Assoc ; 112(2): 176-185, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32178886

ABSTRACT

OBJECTIVE: In this report, we used a qualitative descriptive design to explore young African American adults' intergenerationally influenced strategies to experienced racial discrimination. METHODS: The study was guided by a qualitative descriptive design using criterion and snowball sampling, and semi-structured interview questions. We also explored, quantitatively, gender differences among the racial discrimination experiences encountered and the strategies used. FINDINGS: Forty-nine participants included in this report were an average age of 29.5 (SD = 10.1). Racial discrimination experiences included daily microaggressions such as insensitive comments, stereotyping, exclusion from work and school activities, perceived low expectations, inequities in employment, and police profiling. Intergenerationally influenced strategies used in response to these experiences included religious beliefs and practices, positive reframing, and modeling behaviors used by previous generations. These intergenerationally influenced strategies enabled participants to remain calm, to express goodwill toward others, and to be patient and hopeful for a better future. CONCLUSION: Since intergenerationally influenced strategies are likely potential sources of strength and resilience for young African Americans, knowledge of these strategies might be useful to health care practitioners seeking to improve the mental health care of this population.


Subject(s)
Black or African American , Historical Trauma , Intergenerational Relations/ethnology , Mental Health Services/standards , Racism , Resilience, Psychological , Adult , Black or African American/ethnology , Black or African American/psychology , Female , Historical Trauma/psychology , Historical Trauma/rehabilitation , Humans , Male , Needs Assessment , Quality Improvement/organization & administration , Racism/ethnology , Racism/psychology , Social Discrimination/prevention & control , Social Interaction/ethnology , Spirituality , United States/epidemiology
15.
J Am Coll Emerg Physicians Open ; 1(6): 1332-1340, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33392541

ABSTRACT

OBJECTIVES: Cholesterol may be protective in sepsis. Patients with early sepsis may have critically low cholesterol levels that are associated with poor outcomes. The study objective was to test the safety of a fish oil-containing lipid injectable emulsion for stabilizing early cholesterol levels in sepsis. METHODS: Phase I Bayesian optimal interval design trial of adult patients with septic shock (Sequential Organ Failure Assessment score ≥4 or vasopressor dependence). Using sequential dose escalation, participants received 2 doses of 1.0 to 1.6 g/kg of lipid emulsion (Smoflipid 20% lipid emulsion) within 48 hours of enrollment. Cholesterol levels, function, and organ failure were assessed serially during the first 7 days of hospital admission. MEASUREMENTS AND MAIN RESULTS: A total of 10 patients with septic shock were enrolled. One patient withdrew for social reasons. Another patient had an unrelated medical complication and received 1 drug dose. Of 9 patients, mean age was 58 years (SD 16), median Sequential Organ Failure Assessment was 8, and 28-day mortality was 30%. No serious adverse events related to lipid infusion occurred. The six occurrences of non-serious adverse events possibly related to lipid infusion included hyperglycemia (1), elevated triglycerides (3), anemia (1), and vascular access redness/pain (1) for all doses. The mean change in total cholesterol levels from enrollment was -7 (SD 16.6) at 48 hours and 14 (SD 25.2) at 7 days. CONCLUSIONS: Fish oil-containing lipid emulsion administration during early septic shock was safe. Further studies are needed to assess effects on cholesterol levels, function, and organ failure. CLINICAL TRIAL REGISTRATION: NCT03405870.

16.
Sports Biomech ; 19(1): 76-89, 2020 Feb.
Article in English | MEDLINE | ID: mdl-29902127

ABSTRACT

A potential challenge associated with sports is that athletes must often perform the cognitive processing associated with decision-making (i.e., movement selection) when fatigued. The purpose of this systematic review was to summarise studies that have analysed the extent to which fatigue influences the effects of decision-making on lower extremity mechanics during execution of common sports manoeuvres. We specifically focused on mechanics associated with ACL injury risk. Reviewers searched the PubMed, SPORTDiscus, CINAHL and Web of Science databases. The search identified 183 unique articles. Five of these articles met our eligibility criteria. Two of the studies incorporated fatigue protocols where athletes progressed to exhaustion and found that the effects of decision-making on mechanics were more pronounced with fatigue. The nature of the results appears to indicate that fatigue may compromise an athlete's cognitive processing in a manner that diminishes their ability to control movement when rapid decision-making is required. However, three subsequent studies utilised fatigue protocols designed to mimic sports participation and found that fatigue did not influence the effects of decision-making on mechanics. In general, these findings appear to indicate that fatigue may only affect the cognitive processing associated with decision-making when athletes approach a state of exhaustion.


Subject(s)
Athletes/psychology , Decision Making , Fatigue/psychology , Anterior Cruciate Ligament Injuries/physiopathology , Anticipation, Psychological , Athletic Injuries/physiopathology , Humans , Lower Extremity/physiology , Movement/physiology , Muscle Fatigue/physiology , Risk Factors
17.
BMJ Open ; 9(9): e029348, 2019 09 18.
Article in English | MEDLINE | ID: mdl-31537565

ABSTRACT

INTRODUCTION: Sepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis. METHODS AND ANALYSIS: This is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours - enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function. ETHICS AND DISSEMINATION: Investigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial. TRIAL REGISTRATION NUMBER: NCT03405870.


Subject(s)
Cholesterol/blood , Fat Emulsions, Intravenous/therapeutic use , Sepsis/therapy , Shock, Septic/therapy , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Humans , Sepsis/blood , Shock, Septic/blood
18.
J Cell Sci ; 132(16)2019 08 22.
Article in English | MEDLINE | ID: mdl-31331963

ABSTRACT

Ras proteins are small GTPases localized to the plasma membrane (PM), which regulate cellular proliferation, apoptosis and differentiation. After a series of post-translational modifications, H-Ras and N-Ras traffic to the PM from the Golgi via the classical exocytic pathway, but the exact mechanism of K-Ras trafficking to the PM from the ER is not fully characterized. ATP5G1 (also known as ATP5MC1) is one of the three proteins that comprise subunit c of the F0 complex of the mitochondrial ATP synthase. In this study, we show that overexpression of the mitochondrial targeting sequence of ATP5G1 perturbs glucose metabolism, inhibits oncogenic K-Ras signaling, and redistributes phosphatidylserine (PtdSer) to mitochondria and other endomembranes, resulting in K-Ras translocation to mitochondria. Also, it depletes phosphatidylinositol 4-phosphate (PI4P) at the Golgi. Glucose supplementation restores PtdSer and K-Ras PM localization and PI4P at the Golgi. We further show that inhibition of the Golgi-localized PI4-kinases (PI4Ks) translocates K-Ras, and PtdSer to mitochondria and endomembranes, respectively. We conclude that PI4P at the Golgi regulates the PM localization of PtdSer and K-Ras.This article has an associated First Person interview with the first author of the paper.


Subject(s)
Golgi Apparatus/metabolism , Mitochondria/metabolism , Phosphatidylinositol Phosphates/metabolism , Proto-Oncogene Proteins p21(ras)/metabolism , Animals , Cricetinae , Dogs , Golgi Apparatus/genetics , HEK293 Cells , Humans , Madin Darby Canine Kidney Cells , Mitochondria/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Mitochondrial Proton-Translocating ATPases/metabolism , Phosphatidylinositol Phosphates/genetics , Protein Transport/genetics , Proto-Oncogene Proteins p21(ras)/genetics
19.
Sports Biomech ; 18(2): 163-173, 2019 Apr.
Article in English | MEDLINE | ID: mdl-31042140

ABSTRACT

Training to reduce landing forces is a common component of anterior cruciate ligament injury prevention programmes. The purpose of this study was to compare the effects of training incorporating instructions promoting an internal versus external attentional focus on landing forces in adolescent rugby athletes. Twenty-two rugby athletes were randomly allocated to groups that received instructions promoting an internal versus an external focus during a two week training programme. Landing forces were recorded before and after completion of the programme. During follow-up testing, landings were performed with and without a secondary cognitive task. Both groups exhibited a similar reduction in landing forces following training for trials performed without the secondary cognitive task. However, the groups responded differently when the secondary cognitive task was imposed. Athletes who were trained with an internal focus demonstrated a prominent increase in landing forces for trials that included the secondary cognitive task (vs. trials performed without the secondary cognitive task), whereas the secondary cognitive task had minimal influence for athletes who were trained with an external focus. It appears that training with an external focus may promote adaptations in landing mechanics that can be implemented more automatically.


Subject(s)
Adaptation, Physiological , Attention , Football/physiology , Football/psychology , Lower Extremity/physiology , Physical Conditioning, Human/methods , Adolescent , Anterior Cruciate Ligament Injuries/prevention & control , Biomechanical Phenomena , Cognition , Female , Humans , Male , Movement
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