Early goal-directed therapy reduces mortality in adult patients with severe sepsis and septic shock: Systematic review and meta-analysis

Introduction:

Survival sepsis campaign guidelines have promoted early goal-directed therapy (EGDT) as a means for reduction of mortality. On the other hand, there were conflicting results coming out of recently published meta-analyses on mortality benefits of EGDT in patients with severe sepsis and septic shock. On top of that, the findings of three recently done randomized clinical trials (RCTs) showed no survival benefit by employing EGDT compared to usual care. Therefore, we aimed to do a meta-analysis to evaluate the effect of EGDT on mortality in severe sepsis and septic shock patients.

Methodology:

We included RCTs that compared EGDT with usual care in our meta-analysis. We searched in Hinari, PubMed, EMBASE, and Cochrane central register of controlled trials electronic databases and other articles manually from lists of references of extracted articles. Our primary end point was overall mortality.

Results:

A total of nine trails comprising 4783 patients included in our analysis. We found that EGDT significantly reduced mortality in a random-effect model (RR, 0.86; 95% confidence interval [CI], 0.72–0.94; P = 0.008;   I² =50%). We also did subgroup analysis stratifying the studies by the socioeconomic status of the country where studies were conducted, risk of bias, the number of sites where the trials were conducted, setting of trials, publication year, and sample size. Accordingly, trials carried out in low to middle economic income countries (RR, 0.078; 95% CI, 0.67–0.91; P = 0.002; I² = 34%) significantly reduced mortality compared to those in higher income countries (RR, 0.93; 95% CI, 0.33–1.06; P = 0.28; I² = 29%). On the other hand, patients receiving EGDT had longer length of hospital stay compared to the usual care (mean difference, 0.49; 95% CI, –0.04–1.02; P = 0.07; I² = 0%).

Conclusion:

The result of our study showed that EGDT significantly reduced mortality in patients with severe sepsis and septic shock. Paradoxically, EGDT increased the length of hospital stay compared to usual routine care.     

Drug-induced thrombocytopenia: localization of the binding site of GPIX-specific quinine-dependent antibodies

Immune thrombocytopenia is a common complication of therapy with a large number of drugs. The most widely studied drug-induced immune thrombocytopenia (DIT) is caused by quinine. In most cases of DIT, antibodies bind to the platelet membrane glycoprotein (GP) Ib-IX complex in a drug-dependent fashion and bring about increased platelet clearance by the reticuloendothelial system resulting in thrombocytopenia. Here, we report the characterization of the quinine-dependent antibody activity of sera from 13 patients with quinine-induced thrombocytopenia. In our series of patients, GPIX was the most prevalent target of quinine-dependent antibodies. To identify the structural determinants of GPIX recognized by quinine-dependent antibodies, 4 chimeric mouse/human GPIX constructs and stable Chinese hamster ovary (CHO) cell lines that expressed the chimeras in association with GPIbalpha and GPIbbeta were produced. The analysis of 6 patient sera with the chimeric cell lines provided evidence for localization of the anti-GPIX quinine-dependent antibody binding site to the C-ext region (amino acid [aa] 64-135) of human GPIX. Further characterization of the C-ext region of the GPIX indicated that replacement of the Arg110 and Gln115 of the human GPIX with the corresponding residues from mouse (Gln and Glu, respectively) resulted in a significant reduction in the binding of GPIX antibodies in our series of patients, with Arg110Gln, giving a more pronounced effect than Gln115Glu. Hence, these 2 residues, particularly Arg110, play an important role in the structure of the antigenic site on GPIX recognized by anti-GPIX antibodies.     

Machine learning algorithms for activity recognition in ambulant children and adolescents with cerebral palsy

Background

Cerebral palsy (CP) is the most common physical disability among children (2.5 to 3.6 cases per 1000 live births). Inadequate physical activity (PA) is a major problem effecting the health and well-being of children with CP. Practical, yet accurate measures of PA are needed to evaluate the effectiveness of surgical and therapy-based interventions to increase PA. Accelerometer-based motion sensors have become the standard for objectively measuring PA in children and adolescents; however, current methods for estimating physical activity intensity in children with CP are associated with significant error and may dramatically underestimate HPA in children with more severe mobility limitations. Machine learning (ML) models that first classify the PA type and then predict PA intensity or energy expenditure using activity specific regression equations may be more accurate than standalone regression models. However, the feasibility and validity of ML methods has not been explored in youth with CP. Therefore, the purpose of this study was to develop and test ML models for the automatic identification of PA type in ambulant children with CP.

Methods

Twenty two children and adolescents (mean age: 12.8?±?2.9 y) with CP classified at GMFCS Levels I to III completed 7 activity trials while wearing an ActiGraph GT3X+ accelerometer on the hip and wrist. Trials were categorised as sedentary (SED), standing utilitarian movements (SUM), comfortable walking (CW), and brisk walking (BW). Random forest (RF), support vector machine (SVM), and binary decision tree (BDT) classifiers were trained with features extracted from the vector magnitude (VM) of the raw acceleration signal using 10?s non-overlapping windows. Performance was evaluated using leave-one-subject out cross validation.

Results

SVM (82.0–89.0%) and RF (82.6–88.8%) provided significantly better classification accuracy than BDT (76.1–86.2%). Hip (82.7–85.5%) and wrist (76.1–82.6%) classifiers exhibited comparable prediction accuracy, while the combined hip and wrist (86.2–89.0%) classifiers achieved the best overall performance. For all classifiers, recognition accuracy was excellent for SED (94.1–97.9%), good to excellent for SUM (74.0–96.6%) and brisk walking (71.5–86.0%), and modest for comfortable walking (47.6–70.4%). When comfortable and brisk walking were combined into a single walking class, recognition accuracy ranged from 90.3 to 96.5%.

Conclusions

ML methods provided acceptable classification accuracy for detection of a range of activities commonly performed by ambulatory children with CP. The resultant models can help clinicians more effectively monitor bouts of brisk walking in the community. The results indicate that 2-step models that first classify PA type and then predict energy expenditure using activity specific regression equations are worthy of exploration in this patient group.

     

Relationship Between Proprioception and Endurance Functionality of the Cervical Flexor Muscles in Chronic Neck Pain and Asymptomatic Participants

Objective

The purpose of this study was to compare the relationship between flexion endurance capacity and joint position error in participants with or without chronic neck pain (CNP).

Decarboxylative cross-coupling reactions for P(O)–C bond formation

Phosphorus-containing compounds are one of the most important classes of organic compounds, which have wide applications in organic chemistry, medicinal chemistry, agricultural chemistry, and materials chemistry. In particular, organophosphorus compounds bearing a P(O)–C bond have attracted significant attention in recent decades due to their widespread biological and pharmacological activities. In this review, we will highlight the most important developments in the construction of P(O)–C bonds through decarboxylative C–P cross-coupling reactions. The literature has been surveyed from 2011 to May 2018.

Phosphorus-containing compounds are one of the most important classes of organic compounds, which have wide applications in organic chemistry, medicinal chemistry, agricultural chemistry, and materials chemistry.     

Lesion-Specific and Vessel-Related Determinants of Fractional Flow Reserve Beyond Coronary Artery Stenosis

Objectives

The aims of the present study were: 1) to investigate the contribution of the extent of luminal stenosis and other lesion composition-related factors in predicting invasive fractional flow reserve (FFR); and 2) to explore the distribution of various combinations of morphological characteristics and the severity of stenosis among lesions demonstrating normal and abnormal FFR.

Excessive carotid in-stent neointimal formation predicts late cardiovascular events.

PURPOSE: To examine if excessive in-stent neointimal formation causing a subcritical stenosis may indicate enhanced vascular reactivity in response to injury, thus predicting late cardiovascular events. METHODS: One hundred consecutive patients (64 men; median age 71 years) with high-grade internal carotid artery stenoses (68 asymptomatic, 32 symptomatic) underwent carotid artery stenting (CAS). High-sensitivity C-reactive protein (hs-CRP) was measured before CAS. Patients were monitored with duplex ultrasound for excessive in-stent neointimal formation (flow-compromising lumen diameter reduction >/=50%), critical restenosis (>/=70%), or the occurrence of late major adverse cardiovascular events (MACE) defined as myocardial infarction (MI), stroke, and death occurring later than 30 days poststenting. RESULTS: Over a median 23-month follow-up, excessive neointimal formation was observed in 14 (14%) patients, restenosis in 2 (2%), and 30 late MACE in 25 [25%: 4 MIs, 2 ipsilateral strokes (in the patients with restenosis), 8 contralateral strokes, and 16 cardiovascular deaths]. Cumulative MACE-free survival rates at 6, 12, and 24 months were 92%, 84%, and 77%, respectively. Baseline hs-CRP levels were associated both with neointimal hyperplasia (p=0.024) and MACE (p=0.021). Patients with excessive neointimal formation exhibited a significantly increased adjusted risk for MACE (hazard ratio 3.56, p=0.010). CONCLUSIONS: Excessive in-stent neointimal formation after CAS indicates an increased risk for late MACE, potentially reflecting a state of exaggerated vascular reactivity in response to injury. Inflammation, which is associated both with neointimal hyperplasia and MACE, seems a common characteristic of different vascular pathologies.