scholarly journals Application of a 27-protein candidate cardiovascular surrogate endpoint to track risk ascendancy and resolution in COVID-19

2021 ◽  
Author(s):  
Clare Paterson ◽  
Yolanda Hagar ◽  
Michael A. Hinterberg ◽  
Alexander W. Charney ◽  
Diane M. Del Valle ◽  
...  
Keyword(s):  
Surrogate Endpoint ◽  
Blood Draw ◽  
Sequential Samples ◽  
The Mean ◽  
Cv Disease ◽  
Poor Outcomes ◽  
Risk Biomarkers ◽  
Risk Predictors ◽  
Increases In Risk ◽  
Independent Cohort

ABSTRACTBackgroundThere is an urgent need for tools allowing the early prognosis and subsequent monitoring of individuals with heterogeneous COVID-19 disease trajectories. Pre-existing cardiovascular (CV) disease is a leading risk factor for COVID-19 susceptibility and poor outcomes, and cardiac involvement is prevalent in COVID-19 patients both during the acute phase as well as in convalescence. The utility of traditional CV risk biomarkers in mild COVID-19 disease or across disease course is poorly understood. We sought to determine if a previously validated 27-protein predictor of CV outcomes served a purpose in COVID-19.MethodsThe 27-protein test of residual CV (RCV) risk was applied without modification to n=860 plasma samples from hospitalized and non-hospitalized SARS-CoV-2 infected individuals at disease presentation from three independent cohorts to predict COVID-19 severity and mortality. The same test was applied to an additional n=991 longitudinal samples to assess sensitivity to change in CV risk throughout the course of infection into convalescence.ResultsIn each independent cohort, RCV predictions were significantly related to maximal subsequent COVID-19 severity and to mortality. At the baseline blood draw, the mean protein-predicted likelihood of an event in subjects who died during the study period ranged from 88-99% while it ranged from 8-36% in subjects who were not admitted to hospital. Additionally, the test outperformed existing risk predictors based on commonly used laboratory chemistry values or presence of comorbidities. Application of the RCV test to sequential samples showed dramatic increases in risk during the first few days of infection followed by risk reduction in the survivors; a period of catastrophically high cardiovascular risk (above 50%) typically lasted 8-12 days and had not resolved to normal levels in most people within that timescale.ConclusionsThe finding that a 27-protein candidate CV surrogate endpoint developed in multi-morbid patients prior to the pandemic is both prognostic and acutely sensitive to the adverse effects of COVID-19 suggests that this disease activates the same biologic risk-related mechanisms. The test may be useful for monitoring recovery and drug response.

Quantification of small-scale heterogeneity in aquatic aminopeptidase activity

2020 ◽  
Vol 84 ◽  
pp. 127-140
Author(s):  
BM Gaas ◽  
JW Ammerman
Keyword(s):  
Chlorophyll Fluorescence ◽  
Leucine Aminopeptidase ◽  
Hudson River ◽  
Aminopeptidase Activity ◽  
Small Scale ◽  
Analysis Instrument ◽  
Sequential Samples ◽  
Degree Of Confidence ◽  
The Mean ◽  
Hydrolysis Of

Leucine aminopeptidase (LAP) is one of the enzymes involved in the hydrolysis of peptides, and is sometimes used to indicate potential nitrogen limitation in microbes. Small-scale variability has the potential to confound interpretation of underlying patterns in LAP activity in time or space. An automated flow-injection analysis instrument was used to address the small-scale variability of LAP activity within contiguous regions of the Hudson River plume (New Jersey, USA). LAP activity had a coefficient of variation (CV) of ca. 0.5 with occasional values above 1.0. The mean CVs for other biological parameters—chlorophyll fluorescence and nitrate concentration—were similar, and were much lower for salinity. LAP activity changed by an average of 35 nmol l-1 h-1 at different salinities, and variations in LAP activity were higher crossing region boundaries than within a region. Differences in LAP activity were ±100 nmol l-1 h-1 between sequential samples spaced <10 m apart. Variogram analysis indicated an inherent spatial variability of 52 nmol l-1 h-1 throughout the study area. Large changes in LAP activity were often associated with small changes in salinity and chlorophyll fluorescence, and were sensitive to the sampling frequency. This study concludes that LAP measurements in a sample could realistically be expected to range from zero to twice the average, and changes between areas or times should be at least 2-fold to have some degree of confidence that apparent patterns (or lack thereof) in activity are real.

scholarly journals A PROSPECTIVE ANALYSIS OF GUSTILLO-ANDERSON OPEN TYPE II AND TYPE III TIBIAL DIAPHYSEAL FRACTURES OF AO TYPE 42C1 AND 42C2; THAT WERE SURGICALLY INTERVENED UPON.

2021 ◽  
pp. 1-8
Author(s):  
Umale Rushikesh Hari ◽  
R K Guhan ◽  
Janhavi Thanigaivelu ◽  
Venkatachalam. K
Keyword(s):  
Tibial Fracture ◽  
Tibial Fractures ◽  
Soft Tissue Coverage ◽  
Type Ii ◽  
Open Type ◽  
Type Iii ◽  
Bone Trauma ◽  
Diaphyseal Fractures ◽  
The Mean ◽  
Poor Outcomes

Introduction: Segmental tibial fracture is characterized, as a distinguished kind of fracture type. They are portrayed by at least, two distinctive fracture lines, with a totally separate, inter-calary osseous section, either with intact cortical tubular or as a comminuted segment. AO type 42 C1 and C2 fractures of the tibia are generally, brought about by a high- velocity RTA. They have a high “taux de” of complications. AO type 42 C1 and C2 tibial fractures are considered, as a discrete clinico-surgical bone trauma and are in deep contrast, with the other variants of tibial fractures. Aim: To analyze the functional outcome of Gustillo- Anderson open type II and type III Tibial Diaphyseal fractures of AO Type 42C1 and 42C2; that were surgically intervened upon. Materials and Methods: 62 adult patients in the age bracket of 26-55 years having Gustillo-Anderson open type II and type III Tibial Diaphyseal fractures of AO Type 42C1 and 42C2, were surgically intervened in the form of reamed IMIL nailing. Results: We achieved 62.36% Excellent, 13.98% Good, 15.05% Fair and 4.84% Poor outcomes calculated by the mean of mean scores of Johner AND Wruhs Criteria, Modified Knee Society Score, Yokoyama Criteria scores. Conclusion: This study concludes that Gustillo- Anderson open type II and type III Tibial Diaphyseal fractures of AO Type 42C1 and 42C2 can be managed satisfactorily with IMIL nailing without the need of external fixator application, provided appropriate soft tissue coverage is given at the appropriate time.

Abstract 3086: Safety of Induced Hypertension in Acute Ischemic Stroke Patients with Suboptimal Recanalization after Endovascular Thrombolysis.

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Steve M Cordina ◽  
Shahram Majidi ◽  
Saqib A Chaudhry ◽  
Ameer E Hassan ◽  
Gustavo J Rodriguez ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Endovascular Treatment ◽  
Acute Ischemic Stroke ◽  
Odds Ratio ◽  
Multivariate Logistic Regression Analysis ◽  
Norepinephrine Infusion ◽  
Induced Hypertension ◽  
The Mean ◽  
Poor Outcomes ◽  
Similar Risk

Background: Induced hypertension is feasible, likely safe and can improve neurologic deficits in patients who are not candidates for thrombolysis. The safety of inducing hypertension in post-thrombolytic patients with suboptimal recanalization after endovascular thrombolysis is not currently known. Objective: To determine the feasibility and safety of inducing hypertension in patients in the acute post thrombolytic phase. Methods: We analyzed retrospectively collected data from a database of patients who presented with acute ischemic stroke and who received endovascular treatment with or without intravenous (IV) r-tPA . Patients with suboptimal recanalization after endovascular thrombolysis underwent induction of hypertension (systolic blood pressure [SBP] target 140-180 mmHg) for a 24 hour period after an immediate post-procedure CT scan did not demonstrate any intracerebral hemorrhage (ICH). We determined the rate of symptomatic ICH (sICH), and outcome based on modified Rankin score (mRS) at the time of discharge and compared these data to those observed in patients with non-induced hypertension and normotension. Multivariate logistic regression analysis was used to identify the odds ratio of neurological worsening and/or death after adjusting for initial National Institute of Health Stroke Scale (NIHSS) score and success of hypertension induction, which was defined as a sustained mean BP of ≥ 30% above the admission BP over the first 24 hours. Results: A total of 16 patients (12%, mean age 66) underwent post-thrombolytic induced hypertension among 138 patients who were treated with endovascular treatment. The mean age (± standard deviation [SD]) of treated patients was 68 (± 15.3) years and 52 (46%) were women. Hypertension was induced using intravenous phenylephrine or norepinephrine infusion in 9 and 7 patients, respectively. The mean (±SD) increase in SBP was 140 (±16.4) mmHg. In multivariate analysis, patients with post-thrombolytic induced hypertension had similar risk of sICH (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.11-8.55) and similar discharge mRS (OR 1.85, 95% CI 0.50-6.84). Conclusion: There was no observed increase in sICH or poor outcomes associated with induced hypertension in patients with suboptimal recanalization after endovascular thrombolysis supporting safety. Further trials directed towards assessing efficacy of this approach are needed.

scholarly journals Therapeutic and Prognostic Implications of BRAF V600E in Pediatric Low-Grade Gliomas

2017 ◽  
Vol 35 (25) ◽  
pp. 2934-2941 ◽  
Author(s):  
Alvaro Lassaletta ◽  
Michal Zapotocky ◽  
Matthew Mistry ◽  
Vijay Ramaswamy ◽  
Marion Honnorat ◽  
...  
Keyword(s):  
Quantitative Imaging ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Braf V600e ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Molecular Stratification ◽  
Treatment Data ◽  
Poor Outcomes ◽  
Independent Cohort

Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180). Results BRAF V600E mutation was detected in 69 of 405 patients (17%) with PLGG across a broad spectrum of histologies and sites, including midline locations, which are not often routinely biopsied in clinical practice. Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively ( P < .001). Additional multivariable clinical and molecular stratification revealed that the extent of resection and CDKN2A deletion contributed independently to poor outcome in BRAF V600E PLGG. A similar independent role for CDKN2A and resection on outcome were observed in the independent cohort. Quantitative imaging analysis revealed progressive disease and a lack of response to conventional chemotherapy in most patients with BRAF V600E PLGG. Conclusion BRAF V600E PLGG constitutes a distinct entity with poor prognosis when treated with current adjuvant therapy.

scholarly journals Lateral skull base malignancies

2002 ◽  
Vol 12 (5) ◽  
pp. 1-4 ◽  
Author(s):  
Benjamin M. McGrew ◽  
C. Gary Jackson ◽  
Raquel A. Redtfeldt
Keyword(s):  
Skull Base ◽  
Postoperative Radiotherapy ◽  
Survival Rates ◽  
Tumor Resection ◽  
Surgical Techniques ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Lateral Skull Base ◽  
The Mean ◽  
Poor Outcomes

Object Historically poor outcomes have been characteristic in patients with lateral skull base malignancies. As advances in skull base surgical techniques have been made, complete resection has increasingly been achieved. This has resulted in improved survival rates and local tumor control. Methods The authors performed a retrospective review of 95 patients treated for lateral skull base malignancies. The mean age of the patients was 49.4 years. There were 44 females and 51 males. The mean follow-up period was 50 months. Resection was performed in all patients, and postoperative radiotherapy was undertaken in 54% of the cases. Local disease control was maintained in 73% of the patients. Tumor involvement of the facial nerve and intracranial tumor extension did not jeopardize the rate of local control. Conclusions Despite the fact that technical advances in skull base surgery have resulted in a higher incidence of complete tumor resection and improved survival rates, a respect for the poor prognosis historically associated with lateral skull base malignancies should be maintained and treatment should be appropriately aggressive.

Surgical Treatment of Spinal Extradural Arachnoid Cysts in the Thoracolumbar Spine

Neurosurgery ◽  
2012 ◽  
Vol 71 (2) ◽  
pp. 278-284 ◽  
Author(s):  
Haruki Funao ◽  
Masaya Nakamura ◽  
Naobumi Hosogane ◽  
Kota Watanabe ◽  
Takashi Tsuji ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Surgical Procedure ◽  
Thoracolumbar Spine ◽  
Neurological Recovery ◽  
Dural Defect ◽  
Total Resection ◽  
Duration Of Symptoms ◽  
Significant Difference ◽  
The Mean ◽  
Poor Outcomes

Abstract BACKGROUND: Because an idiopathic spinal extradural arachnoid cyst (SEAC) is rare, its optimal surgical treatment remains controversial. OBJECTIVE: To evaluate the results of surgical treatments for SEACs and to clarify features of the disease associated with poor outcomes. METHODS: Twelve patients with SEACs who underwent surgery at our hospital between 1988 and 2008 were examined retrospectively. The mean follow-up period was 4.7 years. Total resection of the cyst was performed in 7 patients and closure of the dural defect without cyst resection in 5 patients. Surgical outcomes were evaluated with regard to the duration of symptoms, the size of the cyst, and the surgical procedure used. RESULTS: Neurological recovery was observed in all patients, and there was no recurrence. Poor outcomes were observed in patients with a long duration of symptoms (&gt;1 year, P &lt; .01) and large cyst size (&gt;5 vertebrae, P &lt; .05). The surgical procedure had no significant association with the postoperative neurological recovery. However, there was a significant difference in the degree of the mean postoperative kyphotic angle between the patients treated by total resection of the cyst (9.7 degrees) and those treated by closure of the dural defect without cyst resection through selective laminectomy (2.2 degrees) (P &lt; .01). CONCLUSION: There was no significant difference in postoperative neurological recovery between the 2 surgical procedures. However, closure of the dural defect without cyst resection was less invasive, preventing postoperative kyphotic deformity of the thoracolumbar spine.

Long-term effect of natalizumab in patients with RRMS: TYSTEN cohort

2020 ◽  
pp. 135245852093623
Author(s):  
Kévin Bigaut ◽  
Thibaut Fabacher ◽  
Laurent Kremer ◽  
Jean-Claude Ongagna ◽  
Arnaud Kwiatkowski ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Predictive Factors ◽  
Term Effect ◽  
Cumulative Probability ◽  
Secondary Progressive ◽  
Long Term Effect ◽  
The Mean ◽  
Poor Outcomes

Background: Data are needed on long-term effect of natalizumab (NTZ) in relapsing-remitting multiple sclerosis (RRMS). Objectives: To evaluate the time of onset of secondary progressive phase in patients with an RRMS treated with NTZ and to investigate predictive factors. Methods: TYSTEN is an observational study. Patients starting NTZ between 2007 and 2012 were included and followed up until October 2018. Relapses, Expanded Disability Status Scale (EDSS) scores, and results of brain magnetic resonance imaging (MRI) were collected each year. Data were used to estimate the cumulative probability of several poor outcomes such as secondary progressive multiple sclerosis (SPMS) conversion, EDSS worsening, EDSS 4.0, and EDSS 6.0. Results: 770 patients were included. The mean follow-up duration was 97 months and the mean time exposure to NTZ was 66 months. At 10 years, the cumulative probability of SPMS was 27.7%. Predictive factors for poor outcomes were a ⩾1-point increase in EDSS score from baseline, new T2 lesion or T1 gadolinium-enhancing lesion, the occurrence of relapse at 1 or 2 years and No Evidence of Disease Activity (NEDA-3; no relapse, no new T2 or T1 gadolinium-enhancing lesions, no progression) was a protective factor. Conclusion: In our cohort of patients treated with NTZ, poor outcomes were infrequent and are driven by disease activity.

Pharmacokinetic Evaluation of a Fibrinogen Concentrate in Patients with Congenital Fibrinogen Deficiency.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2268-2268 ◽  
Author(s):  
Marilyn J. Manco-Johnson ◽  
Giancarlo Castaman ◽  
Sandra Fremann ◽  
Sigurd Knaub ◽  
Gavino Piseddu ◽  
...  
Keyword(s):  
Body Weight ◽  
Limit Of Detection ◽  
Secondary Analysis ◽  
Surrogate Endpoint ◽  
Activity Levels ◽  
Fibrinogen Concentrate ◽  
Relevant Effect ◽  
Efficacy Parameter ◽  
Post Infusion ◽  
The Mean

Abstract BACKGROUND: Congenital fibrinogen deficiency is a rare bleeding disorder and comprises fibrinogen abnormalities that result in either reductions in the quantity (hypofibrinogenemia and afibrinogenemia) or structure and functionality (dysfibrinogenemia) of fibrinogen. The pharmacokinetics (PK) and surrogate efficacy of a plasma-derived fibrinogen concentrate was studied in a prospective, open, non-controlled, multinational clinical study in patients with confirmed afibrinogenemia. METHODS: Patients had to have &lt; 0.20 g/L plasma fibrinogen activity, be in a non-bleeding state and receive a single dose of 70 mg/kg body weight. Maximum clot firmness (MCF), determined via validated thrombelastography (TEG), was used as a surrogate endpoint for hemostatic efficacy. Standard PK parameters were analyzed in a central laboratory with a validated Clauss assay and an ELISA. RESULTS: A total of 15 patients were treated at 10 centers in the US and Italy. Of these, 5 (33.3%) were female. The mean age was 30 years, with 11 subjects (73.3%) in the age group of 16 to &lt;65 years and the remaining between 8 and 14 years. PK RESULTS: Both median fibrinogen plasma antigen and activity levels reached a maximum within 30 minutes to 1 h post-infusion and decreased continuously afterwards. Median fibrinogen plasma activity levels were at or close to the limit of detection by Day 10 post-infusion. PK findings were similar for fibrinogen activity and antigen. Median Cmax and AUC were 1.3 g/L and 126.8 hours*mg/mL, with a median t1/2 of 77.1 hours for fibrinogen activity. For fibrinogen antigen, median Cmax and AUC were 1.3 g/L and 122.4 hours*mg/mL, with a median t1/2 of 88.0 hours. Whereas no statistically relevant effect of gender was seen on the PK parameters for fibrinogen activity, subjects &lt;16 years old (N=4) had higher median Vss, and Cl values and lower median t1/2, AUC, and MRT values than older subjects (N=10). The median incremental IVR was 1.7 mg/dL increase per mg/kg body weight. for fibrinogen activity and antigen. EFFICACY: The mean change in MCF between pre-infusion and 1 hour post-infusion was (8.9 mm) (p&lt;0.0001). A secondary analysis performed as a sensitivity analysis in the ITT population confirmed this result (mean change of 10.3 mm; p&lt;0.0001). Mean change from pre-infusion to 1 hour post-infusion was similar for subjects &lt;16 years of age (9.9 mm; N=4) and subjects ≥16 to &lt;65 years of age (8.5 mm; N=10) as well as for males (9.0 mm; N=9) and females (8.8 mm; N=5). SAFETY: Four adverse events from two patients were reported. All were mild, non-serious and assessed by the investigators as not related to study medication. CONCLUSION: The PK results for this study of a plasma-derived fibrinogen concentrate showed a sufficient and rapid increase in fibrinogen plasma level and a long half-life. The study demonstrated a significant increase in MCF as a surrogate efficacy parameter and a good safety profile for fibrinogen concentrate in patients with afibrinogenemia.

Prediction Model of Serum Lithium Concentrations

2017 ◽  
Vol 51 (03) ◽  
pp. 82-88 ◽  
Author(s):  
Kazunari Yoshida ◽  
Hiroyuki Uchida ◽  
Takefumi Suzuki ◽  
Masahiro Watanabe ◽  
Nariyasu Yoshino ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Prediction Model ◽  
Predictive Accuracy ◽  
Compartment Model ◽  
Absolute Error ◽  
Oral Dosage ◽  
Therapeutic Drug ◽  
Suitable Model ◽  
Blood Draw ◽  
The Mean

Abstract Introduction Therapeutic drug monitoring is necessary for lithium, but clinical application of several prediction strategies is still limited because of insufficient predictive accuracy. We herein proposed a suitable model, using creatinine clearance (CLcr)-based lithium clearance (Li-CL). Methods Patients receiving lithium provided the following information: serum lithium and creatinine concentrations, time of blood draw, dosing regimen, concomitant medications, and demographics. Li-CL was calculated as a daily dose per trough concentration for each subject, and the mean of Li-CL/CLcr was used to estimate Li-CL for another 30 subjects. Serum lithium concentrations at the time of sampling were estimated by 1-compartment model with Li-CL, fixed distribution volume (0.79 L/kg), and absorption rate (1.5/hour) in the 30 subjects. Results One hundred thirty-one samples from 82 subjects (44 men; mean±standard deviation age: 51.4±16.0 years; body weight: 64.6±13.8 kg; serum creatinine: 0.78±0.20 mg/dL; dose of lithium: 680.2±289.1 mg/day) were used to develop the pharmacokinetic model. The mean±standard deviation (95% confidence interval) of absolute error was 0.13±0.09 (0.10–0.16) mEq/L. Discussion Serum concentrations of lithium can be predicted from oral dosage with high precision, using our prediction model.

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