Utility of somatosensory evoked potentials in the assessment of response to IVIG in a long-lasting case of chronic immune sensory polyradiculopathy

Chronic immune sensory polyradiculopathy (CISP) identifies a progressive acquired peripheral dysimmune neuropathy recognized as a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) variant. We de...

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Treatment of Gabapentin Toxicity With Peritoneal Dialysis: Assessment of Gabapentin Clearance

Gabapentin is almost exclusively cleared by the kidney and thus presents challenges in patients with kidney failure. Gabapentin is known to be effectively cleared by hemodialysis, but the efficiency of clearance by peritoneal dialysis (PD) has not been previously described. We report a case of gabapentin toxicity in a patient on long-term PD who was treated with continuous automated cycling PD. We find that continuous PD provides significant clearance of gabapentin. With 2-L exchanges every 2 hours, we document an apparent elimination half-life of 41.33 hours, which is substantially shorter than the reported elimination half-life of 132 hours in the absence of kidney function.

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Erratum Regarding “Phosphate-Binding Agents in Adults With CKD: A Network Meta-analysis of Randomized Trials” (Am J Kidney Dis. 2016;68[5]:691-702)

In the Original Investigation entitled "Phosphate-Binding Agents in Adults With CKD: A Network Meta-analysis of Randomized Trials" that appeared in the November 2016 issue of AJKD (Palmer et al, volume 68, issue 5, pages 691-702), there were wording errors in 2 sentences of the Results and 1 sentence of a figure legend. In particular, the second sentence of the "Adverse Effects: Nausea, Constipation, Diarrhea, Abdominal Pain" subsection of "Results" (page 695), which originally read "Lanthanum ranked as the treatment with the highest probability of causing nausea (Fig 3)," should have read "Colestilan ranked as the treatment with the highest probability of causing nausea (Fig 3)." In the same subsection, in the first full sentence on page 696, the second odds ratio should have been 3.04 instead of 3.03, and the upper bound of the 95% confidence interval for the third odds ratio should have been 5.75 instead of 7.53.

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Association between F508 deletion in CFTR and chronic pancreatitis risk

The cystic fibrosis transmembrane conductance regulator (CFTR) has been reported to influence individual susceptibility to chronic pancreatitis (CP), but the results of previous studies are controversial.

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The terminal latency of the phrenic nerve correlates with respiratory symptoms in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that involves limb, axial, bulbar, and respiratory muscles.(Haverkamp et al., 1995) Weakness and fatigue of the respiratory muscles eventually induce respiratory insufficiency, which is the main cause of death in this disease.(Haverkamp et al., 1995) Since respiratory function is an important factor influencing the survival of patients with ALS,(Lechtzin et al., 2001; Lechtzin et al., 2007) its assessment is essential for monitoring disease progression and determining the timing for non-invasive ventilation that is proven to increase the survival and quality of life of patients with ALS.(Bourke et al., 2006; Andersen et al., 2007) Generally, forced vital capacity (FVC) has been suggested to be a prognostic factor for ALS.(Fallat et al., 1979; Czaplinski et al., 2006) In patients with ALS with bulbar symptoms, however, respiratory function tests, such as FVC, are not always reliable in practice; these patients have weak lip seal that impairs the accurate evaluation of their respiratory function.(Pinto et al., 2009) Moreover, assessment of respiratory function depends on cooperation, which is difficult to obtain in patients who are less motivated, depressed, or have behavioral changes as commonly observed in patients with ALS.(Phukan et al., 2007)

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SCOPE-mTL: a non-invasive tool for identifying and lateralizing mesial temporal lobe seizures prior to scalp EEG ictal onset

The first phase in epilepsy presurgical evaluation uses scalp EEG monitoring to record seizures, with the intent of lateralizing and localizing the seizure onset zone. While scalp EEG is non-invasive and cost-effective, several drawbacks frequently hamper interpretation of these recordings. First, scalp EEG recordings are prone to extracerebral artifacts. Myogenic artifacts at the start of a seizure can obscure cerebral activity, making it difficult to lateralize or localize seizure onsets. Second, scalp EEG has poor sensitivity for deep brain structures.

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Effects of Bu Shen Yi sui capsule on NogoA/NgR and its signaling pathways RhoA/ROCK in mice with experimental autoimmune encephalomyelitis

Axon growth inhibitory factors NogoA/Nogo receptor (NgR) and its signaling pathways RhoA/Rho kinase (ROCK) play a critical role in the repair of nerve damage in multiple sclerosis (MS). Bu Shen Yi Sui Capsule ...

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Hospitalization Rates during Potentially Inappropriate Medication Use in a Large Population-Based Cohort of Older Adults

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Co-morbidity and polypharmacy in Parkinson’s disease: insights from a large Scottish primary care database

Parkinson's disease is complicated by comorbidity and polypharmacy, but the extent and patterns of these are unclear. We describe comorbidity and polypharmacy in patients with and without Parkinson's disease a...

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Extraction of Organochlorine Pesticides from Plastic Pellets and Plastic Type Analysis

Microplastics act as vector of potentially toxic organic contaminants with unpredictable effects. This protocol describes an alternative methodology for assessing the levels of organochlorine pesticides adsorbed on plastic pellets and identifying the polymer chemical structure. The focus is on pressurized fluid extraction and attenuated total reflectance Fourier transform infrared spectroscopy.

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Distribution of Vascular Patterns in Different Subtypes of Renal Cell Carcinoma. A Morphometric Study in Two Distinct Types of Blood Vessels

Abstract

To analyze the presence of mature and immature vessels as a prognostic factor in patients with renal cell carcinoma and propose a classification of renal cancer tumor blood vessels according to morphometric parameters. Tissue samples were obtained from 121 renal cell carcinoma patients who underwent radical nephrectomy. Staining with CD31 and CD34 was used to differentiate between immature (CD31+) and mature (CD34+) blood vessels. We quantified the microvascular density, microvascular area and different morphometric parameters: maximum diameter, minimum diameter, major axis, minor axis, perimeter, radius ratio and roundness. We found that the microvascular density was higher in CD31+ than CD34+ vessels, but CD34+ vessels were larger than CD31+ vessels, as well as being strongly correlated with the ISUP tumor grade. We also identified four vascular patterns: pseudoacinar, fascicular, reticular and diffuse. Pseudoacinar and fascicular patterns were more frequent in clear cell renal cell carcinoma (37.62 and 35.64% respectively), followed by reticular pattern (21.78%), while in chromophobe tumors the reticular pattern predominated (90%). The isolated pattern was present in all papillary tumors (100%). In healthy renal tissue, the pseudoacinar and isolated patterns were differentially found in the renal cortex and medulla respectively. We defined four distinct vascular patterns significantly related with the ISUP tumor grade in renal cell carcinomas. Further studies in larger series are needed in order to validate these results. Analysis of both mature and immature vessels (CD34+ and CD31+) provides additional information when evaluating microvascular density.

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Identification of Potential Gene Network Associated with HCV-Related Hepatocellular Carcinoma Using Microarray Analysis

Abstract

In order to identify potential specific gene networks of Hepatitis C virus (HCV) related hepatocellular carcinoma (HCC), weighted gene co-expression network analysis (WGCNA) was performed, which may provide an insight into the potential mechanism of the HCC development. HCV-related HCC and normal sample data were downloaded from GEO, T test of limma package was used to screen different expression genes (DEGs); KEGG pathway was used to analyze related biochemical pathways, and WGCNA was used to construct clustering trees and screen hub genes in the HCC-specific modules. A total of 1151 DEGs were authenticated between the HCC and normal liver tissue samples, including 433 upregulated and 718 downregulated genes. Among these genes, three specific modules of HCC were constructed, including Tan, Yellow and Cyan, but only Yellow module had a significant enrichment score in substance combination module with three hub genes: SLA2547, EFNA4 and MME. Although Tan and Cyan separately had four and three hub genes, but the bio-functions of them did not have significant enrichment scores (score < 2). SLA2547, EFNA4 and MME may play important roles in the substance combination of HCV-related HCC, so studying the function of this gene network may provide us a deeper understanding of HCV-related HCC.

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Greater diversity of soil fungal communities and distinguishable seasonal variation in temperate deciduous forests compared with subtropical evergreen forests of eastern China

Abstract

Whether and how seasonality of environmental variables impacts the spatial variability of soil fungal communities remain poorly understood. We assessed soil fungal diversity and community composition of five Chinese zonal forests along a latitudinal gradient spanning 23°N to 42°N in three seasons to address these questions. We found that soil fungal diversity increased linearly or parabolically with latitude. The seasonal variations in fungal diversity were more distinguishable in three temperate deciduous forests than in two subtropical evergreen forests. Soil fungal diversity was mainly correlated with edaphic factors such as pH and nutrient contents. Both latitude and its interactions with season also imposed significant impacts on soil fungal community composition (FCC), but the effects of latitude were stronger than those of season. Vegetational properties such as plant diversity and forest age were the dominant factors affecting FCC in the subtropical evergreen forests while edaphic properties were the dominant ones in the temperate deciduous forests. Our results indicate that latitudinal variation patterns of soil fungal diversity and FCC may differ among seasons. The stronger effect of latitude relative to that of season suggests a more important influence by the spatial than temporal heterogeneity in shaping soil fungal communities across zonal forests.

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Sequence of inoculation influences the nature of extracellular polymeric substances and biofilm formation in Azotobacter chroococcum and Trichoderma viride

Abstract

Extracellular polymeric substances (EPS) are important structural components of biofilms. In the present study, the EPS in biofilms developed using two agriculturally beneficial organisms—Azotobacter chroococcum (Az) and Trichoderma viride (Tv) were quantified and characterised. Time course experiments were undertaken to optimise the EPS yield of biofilm samples resulting from coculture and staggered inoculation. The EPS produced during biofilm formation was found to differ quantitatively and qualitatively in individual cultures (Az alone, Tv alone), and in treatments differing in the sequence of inoculation of bacterium and fungus (Az + Tv coculture, staggered inoculation of Az followed by Tv i.e. Az – Tv, or Tv followed by Az i.e. Tv – Az). Significant enhancement in terms of growth and biofilm formation, as compared to individual inoculation was recorded, with Tv – Az exhibiting higher values of these attributes. The EPS from biofilms showed significantly higher concentrations of protein, acetyl, and uronic acids, while planktonic EPS recorded higher total carbohydrates. Fourier transform infrared spectroscopy analyses illustrated the significant influence on chemical and structural aspects of EPS (planktonic and biofilm). This represents a first report correlating EPS production, cell aggregation and biofilm formation during bacterial–fungal biofilm development, which can have implications in the colonisation of soil and plants.

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Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility: A Single-Institution Experience

Abstract

Background

Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value.

Objective

We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s).

Patients and Methods

From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36–86) and the median number of previous treatment lines was five (range 2–8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF ^V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%).

Results

One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63–3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0–15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80–5.03] vs. 2.13 months [95% CI 1.77–2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17–9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33–10.80] vs. 7.18 months [95% CI 5.63–9.33], respectively, p = 0.06).

Conclusions

This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment.

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Magnesium-Zinc-Calcium-Vitamin D Co-supplementation Improves Hormonal Profiles, Biomarkers of Inflammation and Oxidative Stress in Women with Polycystic Ovary Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Data on the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress among women with polycystic ovary syndrome (PCOS) are scarce. The objective of this study was to assess the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress in women with PCOS. Sixty PCOS women were randomized into two groups and treated with 100 mg magnesium, 4 mg zinc, 400 mg calcium plus 200 IU vitamin D supplements (n = 30), or placebo (n = 30) twice a day for 12 weeks. Hormonal profiles, biomarkers of inflammation, and oxidative stress were assessed at baseline and at end-of-treatment. After the 12-week intervention, compared with the placebo, magnesium-zinc-calcium-vitamin D co-supplementation resulted in significant reductions in hirsutism (−2.4 ± 1.2 vs. −0.1 ± 0.4, P < 0.001), serum high sensitivity C-reactive protein (−0.7 ± 0.8 vs. +0.2 ± 1.8 mg/L, P < 0.001), and plasma malondialdehyde (−0.4 ± 0.3 vs. +0.2 ± 1.0 μmol/L, P = 0.01), and a significant increase in plasma total antioxidant capacity concentrations (+46.6 ± 66.5 vs. −7.7 ± 130.1 mmol/L, P = 0.04). We failed to find any significant effect of magnesium-zinc-calcium-vitamin D co-supplementation on free androgen index, and other biomarkers of inflammation and oxidative stress. Overall, magnesium-zinc-calcium-vitamin D co-supplementation for 12 weeks among PCOS women had beneficial effects on hormonal profiles, biomarkers of inflammation, and oxidative stress.

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Lower Cranial Nerves Paralysis Following Prone-Position Mechanical Ventilation.

Objective: To communicate a complication of prone-position ventilation. Data Sources: Case history. Study Selection: Case report. Data Extraction and Data Synthesis: Clinical information from medical record. Conclusions: This is a very infrequent cause of dysphagia following prone-position ventilation. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Hydrogen Sulfide Confers Lung Protection During Mechanical Ventilation via Cyclooxygenase 2, 15-deoxy [DELTA]12,14-Prostaglandin J2, and Peroxisome Proliferator-Activated Receptor Gamma.

Objectives: Hydrogen sulfide reduces ventilator-induced lung injury in mice. Here, we have examined the underlying mechanisms of hydrogen sulfide-mediated lung protection and determined the involvement of cyclooxygenase 2, 15-deoxy [DELTA]12,14-prostaglandin J2, and peroxisome proliferator-activated receptor gamma in this response. Design: Randomized, experimental study. Setting: University medical center research laboratory. Subjects: C57BL/6 mice and in vitro cell catheters. Interventions: The effects of hydrogen sulfide were analyzed in a mouse ventilator-induced lung injury model in vivo as well as in a cell stretch model in vitro in the absence or presence of hydrogen sulfide. The physiologic relevance of our findings was confirmed using pharmacologic inhibitors of cyclooxygenase 2 and peroxisome proliferator-activated receptor gamma. Measurements and Main Results: Mechanical ventilation caused significant lung inflammation and injury that was prevented in the presence of hydrogen sulfide. Hydrogen sulfide-mediated protection was associated with induction of cyclooxygenase 2 and increases of its product 15-deoxy [DELTA]12,14-prostaglandin J2 as well as cyclooxygenase 2/15-deoxy [DELTA]12,14-prostaglandin J2-dependent activation of peroxisome proliferator-activated receptor gamma. Hydrogen sulfide-dependent effects were mainly observed in macrophages. Applied mechanical stretch to RAW 264.7 macrophages resulted in increased expression of interleukin receptor 1 messenger RNA and release of macrophage inflammatory protein-2. In contrast, incubation of stretched macrophages with sodium hydrosulfide prevented the inflammatory response dependent on peroxisome proliferator-activated receptor gamma activity. Finally, application of a specific peroxisome proliferator-activated receptor gamma inhibitor abolished hydrogen sulfide-mediated protection in ventilated animals. Conclusions: One hydrogen sulfide-triggered mechanism in the protection against ventilator-induced lung injury involves cyclooxygenase 2/15-deoxy [DELTA]12,14-prostaglandin J2-dependent activation of peroxisome proliferator-activated receptor gamma and macrophage activity. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Efficacy and Safety of Combination Therapy of Shenfu Injection and Postresuscitation Bundle in Patients With Return of Spontaneous Circulation After In-Hospital Cardiac Arrest: A Randomized, Assessor-Blinded, Controlled Trial.

Objectives: Postresuscitation care bundle treatment after return of spontaneous circulation in patients experiencing in-hospital cardiac arrest can improve patients' survival and quality of life. The aim of the study was to evaluate the efficacy and safety of combined therapy of Shenfu injection and postresuscitation care bundle in these patients. Design: Prospective, randomized, controlled clinical study. Setting: Fifty hospitals in China. Patients: Adult patients had experienced in-hospital cardiac arrest between 2012 and 2015. Interventions: Based on the standardized postresuscitation care bundle treatment, patients were randomized to a Shenfu injection group (Shenfu injection + postresuscitation care bundle) or control group (postresuscitation care bundle) for 14 days or until hospital discharge. In the Shenfu injection group, 100 mL Shenfu injection was additionally administered via continuous IV infusion, bid. Measurements and Main Results: The primary outcome was 28-day survival after randomization. The secondary outcomes included 90-day survival as well as the duration of mechanical ventilation and the hospital stay and the total cost of hospitalization. Of 1,022 patients enrolled, a total of 978 patients were allocated to the two groups: the control (n = 486) and Shenfu injection (n = 492) groups. The Shenfu injection group had a significantly greater 28-day survival rate (42.7%) than the control group (30.1%). Also, the Shenfu injection group had a significantly higher survival rate at 90 days (39.6%) than the control group (25.9%). Compared with patients in the control group, patients in the Shenfu injection group had lower risks of 28-day mortality (hazard ratio, 0.61; 95% CI, 0.43-0.89; p = 0.009) and 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79; p = 0.002). In the Shenfu injection group, the duration of mechanical ventilation (8.6 +/- 3.2 vs 12.7 +/- 7.9 d; p

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Preadmission Use of Calcium Channel Blocking Agents Is Associated With Improved Outcomes in Patients With Sepsis: A Population-Based Propensity Score-Matched Cohort Study.

Objectives: Use of calcium channel blockers has been found to improve sepsis outcomes in animal studies and one clinical study. This study determines whether the use of calcium channel blockers is associated with a decreased risk of mortality in patients with sepsis. Design: Population-based matched cohort study. Setting: National Health Insurance Research Database of Taiwan. Patients: Hospitalized severe sepsis patients identified from National Health Insurance Research Database by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Interventions: None. Measurements and Main Results: The association between calcium channel blocker use and sepsis outcome was determined by multivariate-adjusted Cox proportional hazard models and propensity score analysis. To examine the influence of healthy user bias, beta-blocker was used as an active comparator. Our study identified 51,078 patients with sepsis, of which, 19,742 received calcium channel blocker treatments prior to the admission. Use of calcium channel blocker was associated with a reduced 30-day mortality after propensity score adjustment (hazard ratio, 0.94; 95% CI, 0.89-0.99), and the beneficial effect could extend to 90-day mortality (hazard ratio, 0.95; 95% CI, 0.89-1.00). In contrast, use of beta-blocker was not associated with an improved 30-day (hazard ratio, 1.06; 95% CI, 0.97-1.15) or 90-day mortality (hazard ratio, 1.00; 95% CI, 0.90-1.11). On subgroup analysis, calcium channel blockers tend to be more beneficial to patients with male gender, between 40 and 79 years old, with a low comorbidity burden, and to patients with cardiovascular diseases, diabetes, or renal diseases. Conclusions: In this national cohort study, preadmission calcium channel blocker therapy before sepsis development was associated with a 6% reduction in mortality when compared with patients who have never received calcium channel blockers. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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The Impact of Mortality on Total Costs Within the ICU.

Objectives: The high cost of critical care has engendered research into identifying influential factors. However, existing studies have not considered patient vital status at ICU discharge. This study sought to determine the effect of mortality upon the total cost of an ICU stay. Design: Retrospective cohort study. Setting: Twenty-six ICUs at 13 hospitals in the United States. Patients: 58,344 admissions from January 1, 2012, to June 30, 2016, obtained from a commercial ICU database. Interventions: None. Measurements and Main Results: The median observed cost of a unit stay was $9,619 (mean = $16,353). A multivariable regression model was developed on the log of total costs for a unit stay, using severity of illness, unit admitting diagnosis, mortality in the unit, daily unit occupancy (occupying a bed at midnight), and length of mechanical ventilation. This model had an r2 of 0.67 and a median difference between observed and expected costs of $437. The first few days of care and the first day receiving mechanical ventilation had the largest effect on total costs. Patients dying before unit discharge had 12.4% greater costs than survivors (p

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Faster Blood Flow Rate Does Not Improve Circuit Life in Continuous Renal Replacement Therapy: A Randomized Controlled Trial.

Objectives: To determine whether blood flow rate influences circuit life in continuous renal replacement therapy. Design: Prospective randomized controlled trial. Setting: Single center tertiary level ICU. Patients: Critically ill adults requiring continuous renal replacement therapy. Interventions: Patients were randomized to receive one of two blood flow rates: 150 or 250 mL/min. Measurements and Main Results: The primary outcome was circuit life measured in hours. Circuit and patient data were collected until each circuit clotted or was ceased electively for nonclotting reasons. Data for clotted circuits are presented as median (interquartile range) and compared using the Mann-Whitney U test. Survival probability for clotted circuits was compared using log-rank test. Circuit clotting data were analyzed for repeated events using hazards ratio. One hundred patients were randomized with 96 completing the study (150 mL/min, n = 49; 250 mL/min, n = 47) using 462 circuits (245 run at 150 mL/min and 217 run at 250 mL/min). Median circuit life for first circuit (clotted) was similar for both groups (150 mL/min: 9.1 hr [5.5-26 hr] vs 10 hr [4.2-17 hr]; p = 0.37). Continuous renal replacement therapy using blood flow rate set at 250 mL/min was not more likely to cause clotting compared with 150 mL/min (hazards ratio, 1.00 [0.60-1.69]; p = 0.68). Gender, body mass index, weight, vascular access type, length, site, and mode of continuous renal replacement therapy or international normalized ratio had no effect on clotting risk. Continuous renal replacement therapy without anticoagulation was more likely to cause clotting compared with use of heparin strategies (hazards ratio, 1.62; p = 0.003). Longer activated partial thromboplastin time (hazards ratio, 0.98; p = 0.002) and decreased platelet count (hazards ratio, 1.19; p = 0.03) were associated with a reduced likelihood of circuit clotting. Conclusions: There was no difference in circuit life whether using blood flow rates of 250 or 150 mL/min during continuous renal replacement therapy. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Both Positive and Negative Fluid Balance May Be Associated With Reduced Long-Term Survival in the Critically Ill.

Objectives: Among critically ill patients with acute kidney injury, exposure to positive fluid balance, compared with negative fluid balance, has been associated with mortality and impaired renal recovery. However, it is unclear whether positive and negative fluid balances are associated with poor outcome compared to patients with even fluid balance (euvolemia). In this study, we examined the association between exposure to positive or negative fluid balance, compared with even fluid balance, on 1-year mortality and renal recovery. Design: Retrospective cohort study. Setting: Eight medical-surgical ICUs at the University of Pittsburgh Medical Center, Pittsburgh, PA. Patients: Critically ill patients admitted between July 2000 and October 2008. Interventions: None. Measurements and Main Results: Among 18,084 patients, fluid balance was categorized as negative (= 5%). Following propensity matching, positive fluid balance, compared with even or negative fluid balance, was associated with increased mortality (30.3% vs 21.1% vs 22%, respectively; p

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Determinants of Receiving Palliative Care and Ventilator Withdrawal Among Patients With Prolonged Mechanical Ventilation.

Objectives: Increasing numbers of patients with prolonged mechanical ventilation generates a tremendous strain on healthcare systems. Patients with prolonged mechanical ventilation suffer from long-term poor quality of life. However, no study has ever explored the willingness to receive palliative care or terminal withdrawal and the factors influencing willingness. Design: Cross-sectional study. Setting: Five different hospitals of Taipei City Hospital system. Patients: Adult patients with ventilatory support for more than 60 days. Interventions: None. Measurements and Main Results: We identified the family members of 145 consecutive patients with prolonged mechanical ventilation in five hospitals of Taipei City Hospital system and enrolled family members for 106 patients (73.1%). We collected information from patient families' regarding concepts (knowledge, attitude, and experiences) of palliative care, caregiver burden, family function, patient quality of life, and physician-family communications. From the medical record, we obtained duration of hospitalization, consciousness level, disease severity, medical cost, and the presence of do-not-resuscitate orders. The vast majority of family members agreed with the concept of palliative care (90.4%) with 17.3% of the family members agreeing to ventilator withdrawal currently and 67.5% terminally in anticipation of death. Approximately half of the family members regretted having chosen prolonged mechanical ventilation (56.7%). Reduced patient quality of life and increased family understanding of palliative care significantly associated with increased caregiver willingness to endorse palliative care and withdraw life-sustaining agents in anticipation of death. Longer duration of ventilator usage and hospitalization was associated with increased feelings of regret about choosing prolonged mechanical ventilation. Conclusions: During prolonged mechanical ventilation, physicians should thoroughly discuss its benefits and burdens. Families should be given the opportunity to discuss the circumstances under which they might request the implementation of palliative care or withdrawal of mechanical ventilation in order to avoid prolonging the dying process. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Organ Support After Death by Neurologic Criteria in Pediatric Patients.

Objectives: We sought to 1) evaluate how pediatricians approach situations in which families request continuation of organ support after declaration of death by neurologic criteria and 2) explore potential interventions to make these situations less challenging. Design: A survey on management and personal experience with death by neurologic criteria was distributed electronically to pediatric intensivists and neurologists. We compared responses from individuals who practice in states with accommodation exceptions (accommodation states where religious or moral beliefs must be taken into consideration when declaring death: California, Illinois, New Jersey, New York) to those from non-accommodation states. Setting: United States. Subjects: The survey was opened by 254 recipients, with 186 meeting inclusion criteria and providing data about the region in which they practice; of these, 26% were from accommodation states. Interventions: None. Measurements and Main Results: More than half of physicians (61% from both accommodation states and non-accommodation states) reported they cared for a pediatric patient whose family requested continuation of organ support after declaration of death by neurologic criteria (outside of organ donation; range, 1-17 times). Over half of physicians (53%) reported they would not feel comfortable handling a situation in which a pediatric patient's family requested care be continued after declaration of death by neurologic criteria. Nearly every physician (98%) endorsed that something needs to be done to make situations involving families who object to discontinuation of organ support after declaration of death by neurologic criteria easier to handle. Respondents felt that public education, physician education, and uniform state laws about these situations are warranted. Conclusions: It is relatively common for pediatricians who care for critically ill patients to encounter families who object to discontinuation of organ support after death by neurologic criteria. Management of these situations is challenging, and guidance for medical professionals and the public is needed. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Validation of an Administrative Definition of ICU Admission Using Revenue Center Codes.

Objectives: Describe the operating characteristics of a proposed set of revenue center codes to correctly identify ICU stays among hospitalized patients. Design: Retrospective cohort study. We report the operating characteristics of all ICU-related revenue center codes for intensive and coronary care, excluding nursery, intermediate, and incremental care, to identify ICU stays. We use a classification and regression tree model to further refine identification of ICU stays using administrative data. The gold standard for classifying ICU admission was an electronic patient location tracking system. Setting: The University of Pennsylvania Health System in Philadelphia, PA, United States. Patients: All adult inpatient hospital admissions between July 1, 2013, and June 30, 2015. Interventions: None. Measurements and Main Results: Among 127,680 hospital admissions, the proposed combination of revenue center codes had 94.6% sensitivity (95% CI, 94.3-94.9%) and 96.1% specificity (95% CI, 96.0-96.3%) for correctly identifying hospital admissions with an ICU stay. The classification and regression tree algorithm had 92.3% sensitivity (95% CI, 91.6-93.1%) and 97.4% specificity (95% CI, 97.2-97.6%), with an overall improved accuracy ([chi]2 = 398; p

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Transcranial Doppler Microemboli Monitoring for Stroke Risk Stratification in Blunt Cerebrovascular Injury.

Objectives: To assess whether microemboli burden, assessed noninvasively by bedside transcranial Doppler ultrasonography, correlates with risk of subsequent stroke greater than 24 hours after hospital arrival among patients with blunt cerebrovascular injury. The greater than 24-hour time frame provides a window for transcranial Doppler examinations and therapeutic interventions to prevent stroke. Design: Retrospective cohort study. Setting: Level I trauma center. Patients: One thousand one hundred forty-six blunt cerebrovascular injury patients over 10 years. Interventions: None. Measurements and Main Results: We identified 1,146 blunt cerebrovascular injury patients; 54 (4.7%) experienced stroke detected greater than 24 hours after arrival. Among those with isolated internal carotid artery injuries, five of nine with delayed stroke had positive transcranial Dopplers (at least one microembolus detected with transcranial Dopplers) before stroke, compared with 46 of 248 without (risk ratio, 5.05; 95% CI, 1.41-18.13). Stroke risk increased with the number of microemboli (adjusted risk ratio, 1.03/microembolus/hr; 95% CI, 1.01-1.05) and with persistently positive transcranial Dopplers over multiple days (risk ratio, 16.0; 95% CI, 2.00-127.93). Among patients who sustained an internal carotid artery injury with or without additional vessel injuries, positive transcranial Dopplers predicted stroke after adjusting for ipsilateral and contralateral internal carotid artery injury grade (adjusted risk ratio, 2.91; 95% CI, 1.42-5.97). No patients with isolated vertebral artery injuries had positive transcranial Dopplers before stroke, and positive transcranial Dopplers were not associated with delayed stroke among patients who sustained a vertebral artery injury with or without additional vessel injuries (risk ratio, 0.90; 95% CI, 0.21-3.83). Conclusions: Microemboli burden is associated with higher risk of stroke due to internal carotid artery injuries, but monitoring was not useful for vertebral artery injuries. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2t2V2sa

Sequential Analysis of a Panel of Biomarkers and Pathologic Findings in a Resuscitated Rat Model of Sepsis and Recovery.

Objectives: To characterize the temporal pattern of a panel of blood and urinary biomarkers in an animal model of fecal peritonitis and recovery. Design: Prospective observational animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Interventions: A fluid-resuscitated, long-term (3 d) rat model of sepsis (fecal peritonitis) and recovery was used to understand the temporal association of sepsis biomarkers in relation to systemic hemodynamics, inflammation, and renal function. At predefined time points (3, 6, 12, 24, 48, 72 hr), animals (>= 6 per group) underwent echocardiography, blood and urine sampling, and had kidneys taken for histological analysis. Comparison was made against sham-operated controls and naive animals. Measurements and Main Results: The systemic proinflammatory response was maximal at 6 hours, corresponding with the nadir of stroke volume. Serum creatinine peaked late (24 hr), when clinical recovery was imminent. Histological evidence of tubular injury and cell death was minimal. After a recovery period, all biomarkers returned to levels approaching those observed in sham animals. Apart from urine clusterin and interleukin-18, all other urinary biomarkers were elevated at earlier time points compared with serum creatinine. Urine neutrophil gelatinase-associated lipocalin was the most sensitive marker among those studied, rising from 3 hours. While serum creatinine fell at 12 hours, serum cystatin C increased, suggestive of decreased creatinine production. Conclusions: Novel information is reported on the temporal profile of a panel of renal biomarkers in sepsis in the context of systemic and renal inflammation and recovery. Insight into the pathophysiology of acute kidney injury is gleaned from the temporal change markers of renal injury (urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, calbindin), followed by a marker of cell cycle arrest (urine insulin-like growth factor-binding protein 7) and, finally, by functional markers of filtration (serum creatinine and cystatin C). These clinically relevant findings should have significant influence on future clinical testing. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Neurobiologic Correlates of Attention and Memory Deficits Following Critical Illness in Early Life.

Objectives: Survivors of critical illness in early life are at risk of long-term-memory and attention impairments. However, their neurobiologic substrates remain largely unknown. Design: A prospective follow-up study. Setting: Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. Patients: Thirty-eight school-age (8-12 yr) survivors of neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia with an intelligence quotient greater than or equal to 80 and a below average score (z score

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Brain Gray Matter MRI Morphometry for Neuroprognostication After Cardiac Arrest.

Objectives: We hypothesize that the combined use of MRI cortical thickness measurement and subcortical gray matter volumetry could provide an early and accurate in vivo assessment of the structural impact of cardiac arrest and therefore could be used for long-term neuroprognostication in this setting. Design: Prospective cohort study. Setting: Five Intensive Critical Care Units affiliated to the University in Toulouse (France), Paris (France), Clermont-Ferrand (France), Liege (Belgium), and Monza (Italy). Patients: High-resolution anatomical T1-weighted images were acquired in 126 anoxic coma patients ("learning" sample) 16 +/- 8 days after cardiac arrest and 70 matched controls. An additional sample of 18 anoxic coma patients, recruited in Toulouse, was used to test predictive model generalization ("test" sample). All patients were followed up 1 year after cardiac arrest. Interventions: None. Measurements and Main Results: Cortical thickness was computed on the whole cortical ribbon, and deep gray matter volumetry was performed after automatic segmentation. Brain morphometric data were employed to create multivariate predictive models using learning machine techniques. Patients displayed significantly extensive cortical and subcortical brain volumes atrophy compared with controls. The accuracy of a predictive classifier, encompassing cortical and subcortical components, has a significant discriminative power (learning area under the curve = 0.87; test area under the curve = 0.96). The anatomical regions which volume changes were significantly related to patient's outcome were frontal cortex, posterior cingulate cortex, thalamus, putamen, pallidum, caudate, hippocampus, and brain stem. Conclusions: These findings are consistent with the hypothesis of pathologic disruption of a striatopallidal-thalamo-cortical mesocircuit induced by cardiac arrest and pave the way for the use of combined brain quantitative morphometry in this setting. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Identifying Distinct Subgroups of ICU Patients: A Machine Learning Approach.

Objectives: Identifying subgroups of ICU patients with similar clinical needs and trajectories may provide a framework for more efficient ICU care through the design of care platforms tailored around patients' shared needs. However, objective methods for identifying these ICU patient subgroups are lacking. We used a machine learning approach to empirically identify ICU patient subgroups through clustering analysis and evaluate whether these groups might represent appropriate targets for care redesign efforts. Design: We performed clustering analysis using data from patients' hospital stays to retrospectively identify patient subgroups from a large, heterogeneous ICU population. Setting: Kaiser Permanente Northern California, a healthcare delivery system serving 3.9 million members. Patients: ICU patients 18 years old or older with an ICU admission between January 1, 2012, and December 31, 2012, at one of 21 Kaiser Permanente Northern California hospitals. Interventions: None. Measurements and Main Results: We used clustering analysis to identify putative clusters among 5,000 patients randomly selected from 24,884 ICU patients. To assess cluster validity, we evaluated the distribution and frequency of patient characteristics and the need for invasive therapies. We then applied a classifier built from the sample cohort to the remaining 19,884 patients to compare the derivation and validation clusters. Clustering analysis successfully identified six clinically recognizable subgroups that differed significantly in all baseline characteristics and clinical trajectories, despite sharing common diagnoses. In the validation cohort, the proportion of patients assigned to each cluster was similar and demonstrated significant differences across clusters for all variables. Conclusions: A machine learning approach revealed important differences between empirically derived subgroups of ICU patients that are not typically revealed by admitting diagnosis or severity of illness alone. Similar data-driven approaches may provide a framework for future organizational innovations in ICU care tailored around patients' shared needs. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Brain-Dead Donors on Extracorporeal Membrane Oxygenation.

Objectives: To describe donors after brain death with ongoing extracorporeal membrane oxygenation and to analyze the outcome of organs transplanted from these donors. Design: Retrospective analysis of the national information system run by the French Biomedicine Agency (CRISTAL database). Setting: National registry data of all donors after brain death in France and their organ recipients between 2007 and 2013. Patients: Donors after brain death and their organ recipients. Interventions: None. Measurements and Main Results: During the study period, there were 22,270 brain-dead patients diagnosed in France, of whom 161 with extracorporeal membrane oxygenation. Among these patients, 64 donors on extracorporeal membrane oxygenation and 10,805 donors without extracorporeal membrane oxygenation had at least one organ retrieved. Donors on extracorporeal membrane oxygenation were significantly younger and had more severe intensive care medical conditions (hemodynamic, biological, renal, and liver insults) than donors without extracorporeal membrane oxygenation. One hundred nine kidneys, 37 livers, seven hearts, and one lung were successfully transplanted from donors on extracorporeal membrane oxygenation. We found no significant difference in 1-year kidney graft survival (p = 0.24) and function between recipients from donors on extracorporeal membrane oxygenation (92.7% [85.9-96.3%]) and matching recipients from donors without extracorporeal membrane oxygenation (95.4% [93.0-97.0%]). We also found no significant difference in 1-year liver recipient survival (p = 0.91): 86.5% (70.5-94.1) from donors on extracorporeal membrane oxygenation versus 80.7% (79.8-81.6) from donors without extracorporeal membrane oxygenation. Conclusions: Brain-dead patients with ongoing extracorporeal membrane oxygenation have more severe medical conditions than those without extracorporeal membrane oxygenation. However, kidney graft survival and function were no different than usual. Brain-dead patients with ongoing extracorporeal membrane oxygenation are suitable for organ procurement. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Challenging Authority During an Emergency-the Effect of a Teaching Intervention.

Objectives: Previous research has shown that residents were unable to effectively challenge a superior's wrong decision during a crisis situation, a problem that can contribute to preventable mortality. We aimed to assess whether a teaching intervention enabled residents to effectively challenge clearly wrong clinical decisions made by their staff. Subjects and Intervention: Following ethics board approval, second year residents were randomized to a teaching intervention targeting cognitive skills needed to challenge a superior's decision, or a control group receiving general crisis management instruction. Two weeks later, subjects participated in a simulated crisis that presented them with opportunities to challenge clearly wrong decisions in a can't-intubate-can't-ventilate scenario. It was only disclosed that the staff was a confederate during the debriefing. Performances were video recorded and assessed by two raters blinded to group allocation using the modified Advocacy-Inquiry Score. Measurements and Main Results: Fifty residents completed the study. The interrater reliability of the modified Advocacy-Inquiry Scores (intraclass correlation coefficient = 0.87) was excellent. The median (interquartile range) best modified Advocacy-Inquiry Score was significantly better in the intervention group 5.0 (4.50-5.62 [4-6]) than in the control group 3.5 (3.0-4.75 [3-6]) (p

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Preventing Harm in the ICU-Building a Culture of Safety and Engaging Patients and Families.

Objective: Preventing harm remains a persistent challenge in the ICU despite evidence-based practices known to reduce the prevalence of adverse events. This review seeks to describe the critical role of safety culture and patient and family engagement in successful quality improvement initiatives in the ICU. We review the evidence supporting the impact of safety culture and provide practical guidance for those wishing to implement initiatives aimed at improving safety culture and more effectively integrate patients and families in such efforts. Data Sources: Literature review using PubMed including evaluation of key studies assessing large-scale quality improvement efforts in the ICU, impact of safety culture on patient outcomes, methodologies for quality improvement commonly used in healthcare, and patient and family engagement. Print and web-based resources from leading patient safety organizations were also searched. Study Selection: Our group completed a review of original studies, review articles, book chapters, and recommendations from leading patient safety organizations. Data Extraction: Our group determined by consensus which resources would best inform this review. Data Synthesis: A strong safety culture is associated with reduced adverse events, lower mortality rates, and lower costs. Quality improvement efforts have been shown to be more effective and sustainable when paired with a strong safety culture. Different methodologies exist for quality improvement in the ICU; a thoughtful approach to implementation that engages frontline providers and administrative leadership is essential for success. Efforts to substantively include patients and families in the processes of quality improvement work in the ICU should be expanded. Conclusions: Efforts to establish a culture of safety and meaningfully engage patients and families should form the foundation for all safety interventions in the ICU. This review describes an approach that integrates components of several proven quality improvement methodologies to enhance safety culture in the ICU and highlights opportunities to include patients and families. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Repeated Critical Illness and Unplanned Readmissions Within 1 Year to PICUs.

Objectives: To determine the occurrence rate of unplanned readmissions to PICUs within 1 year and examine risk factors associated with repeated readmission. Design: Retrospective cohort analysis. Setting: Seventy-six North American PICUs that participated in the Virtual Pediatric Systems, LLC (VPS, LLC, Los Angeles, CA). Patients: Ninety-three thousand three hundred seventy-nine PICU patients discharged between 2009 and 2010. Interventions: None. Measurements and Main Results: Index admissions and unplanned readmissions were characterized and their outcomes compared. Time-to-event analyses were performed to examine factors associated with readmission within 1 year. Eleven percent (10,233) of patients had 15,625 unplanned readmissions within 1 year to the same PICU; 3.4% had two or more readmissions. Readmissions had significantly higher PICU mortality and longer PICU length of stay, compared with index admissions (4.0% vs 2.5% and 2.5 vs 1.6 d; all p

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Molecular Adsorbent Recirculating System Can Reduce Short-Term Mortality Among Patients With Acute-on-Chronic Liver Failure-A Retrospective Analysis.

Objectives: : Acute-on-chronic liver failure is associated with numerous consecutive organ failures and a high short-term mortality rate. Molecular adsorbent recirculating system therapy has demonstrated beneficial effects on the distinct symptoms, but the associated mortality data remain controversial. Design: Retrospective analysis of acute-on-chronic liver failure patients receiving either standard medical treatment or standard medical treatment and molecular adsorbent recirculating system. Secondary analysis of data from the prospective randomized Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial by applying the recently introduced Chronic Liver Failure-criteria. Setting: Medical Departments of University Hospital Muenster (Germany). Patients: This analysis was conducted in two parts. First, 101 patients with acute-on-chronic liver failure grades 1-3 and Chronic Liver Failure-C-Organ Failure liver subscore equals to 3 but stable pulmonary function were identified and received either standard medical treatment (standard medical treatment, n = 54) or standard medical treatment and molecular adsorbent recirculating system (n = 47) at the University Hospital Muenster. Second, the results of this retrospective analysis were tested against the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial. Interventions: Standard medical treatment and molecular adsorbent recirculating system. Measurements and Main Results: Additionally to improved laboratory variables (bilirubin and creatinine), the short-term mortality (up to day 14) of the molecular adsorbent recirculating system group was significantly reduced compared with standard medical treatment. A reduced 14-day mortality rate was observed in the molecular adsorbent recirculating system group (9.5% vs 50.0% with standard medical treatment; p = 0.004), especially in patients with multiple organ failure (acute-on-chronic liver failure grade 2-3). Concerning the affected organ system, this effect of molecular adsorbent recirculating system on mortality was particularly evident among patients with increased kidney, brain, or coagulation Chronic Liver Failure-C-Organ Failure subscores. Subsequent reanalysis of the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure dataset with adoption of the Chronic Liver Failure-classification resulted in similar findings. Conclusions: Molecular adsorbent recirculating system treatment was associated with an improved short-term survival of patients with acute-on-chronic liver failure and multiple organ failure. Among these high-risk patients, molecular adsorbent recirculating system treatment might bridge to liver recovery or liver transplantation. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Current challenges in the management of follicular lymphoma

International Journal of Hematologic Oncology June 2017, Vol. 6, No. 1, Pages 13-24.


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Survivors at risk: Hodgkin lymphoma survivors at high risk of second cancers

International Journal of Hematologic Oncology June 2017, Vol. 6, No. 1, Pages 5-8.


http://ift.tt/2ssj5Ce

Updated classification and novel treatment prospective for nodal peripheral T-cell lymphomas

International Journal of Hematologic Oncology June 2017, Vol. 6, No. 1, Pages 1-4.


http://ift.tt/2tbUrCF

The bone marrow transplant clinical nurse specialist in hemato-oncology: an interview with Anthony Nolan Nurse Specialist Susan Paskar

International Journal of Hematologic Oncology June 2017, Vol. 6, No. 1, Pages 9-11.


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Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013-08)

Abstract

Background

Studies showed that axillary lymph node dissection can be safely omitted in presence of positive sentinel lymph node(s) in breast cancer patients treated with breast conserving therapy. Since the outcome of the sentinel lymph node biopsy has no clinical consequence, the value of the procedure itself is being questioned. The aim of the BOOG 2013–08 trial is to investigate whether the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients treated with breast conserving therapy.

Methods

The BOOG 2013–08 is a Dutch prospective non-inferiority randomized multicentre trial. Women with pathologically confirmed clinically node negative T1–2 invasive breast cancer undergoing breast conserving therapy will be randomized for sentinel lymph node biopsy versus no sentinel lymph node biopsy. Endpoints include regional recurrence after 5 (primary endpoint) and 10 years of follow-up, distant-disease free and overall survival, quality of life, morbidity and cost-effectiveness. Previous data indicate a 5-year regional recurrence free survival rate of 99% for the control arm and 96% for the study arm. In combination with a non-inferiority limit of 5% and probability of 0.8, this result in a sample size of 1.644 patients including a lost to follow-up rate of 10%. Primary and secondary endpoints will be reported after 5 and 10 years of follow-up.

Discussion

If the sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients undergoing breast conserving therapy, this study will cost-effectively lead to a decreased axillary morbidity rate and thereby improved quality of life with non-inferior regional control, distant-disease free survival and overall survival.

Trial registration

The BOOG 2013–08 study is registered in ClinicalTrials.gov since October 20, 2014, Identifier: NCT02271828. http://ift.tt/2ssLB6G

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Inhibition of HDAC6 activity through interaction with RanBPM and its associated CTLH complex

Abstract

Background

Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase that promotes many cellular processes that lead to cell transformation and tumour development. We previously documented an interaction between Ran-Binding Protein M (RanBPM) and HDAC6 and found that RanBPM expression inhibits HDAC6 activity. RanBPM is part of a putative E3 ubiquitin ligase complex, termed the C-terminal to LisH (CTLH) complex. Here, we investigated the involvement of the CTLH complex on HDAC6 inhibition and assessed the outcome of this regulation on the cellular motility induced by HDAC6.

Methods

Cell lines (Hela, HEK293 and immortalized mouse embryonic fibroblasts) stably or transiently downregulated for several components of the CTLH complex were employed for the assays used in this study. Interactions of HDAC6, RanBPM and muskelin were assessed by co-immunoprecipitations. Quantifications of western blot analyses were employed to evaluate acetylated α-tubulin levels. Confocal microscopy analyses were used to determine microtubule association of HDAC6 and CTLH complex members. Cell migration was evaluated using wound healing assays.

Results

We demonstrate that RanBPM-mediated inhibition of HDAC6 is dependent on its association with HDAC6. We show that, while HDAC6 does not require RanBPM to associate with microtubules, RanBPM association with microtubules requires HDAC6. Additionally, we show that Twa1 (Two-hybrid-associated protein 1 with RanBPM) and MAEA (Macrophage Erythroblast Attacher), two CTLH complex members, also associate with α-tubulin and that muskelin, another component of the CTLH complex, is able to associate with HDAC6. Downregulation of CTLH complex members muskelin and Rmnd5A (Required for meiotic nuclear division homolog A) resulted in decreased acetylation of HDAC6 substrate α-tubulin. Finally, we demonstrate that the increased cell migration resulting from downregulation of RanBPM is due to the relief in inhibition of HDAC6 α-tubulin deacetylase activity.

Conclusions

Our work shows that RanBPM, together with the CTLH complex, associates with HDAC6 and restricts cell migration through inhibition of HDAC6 activity. This study uncovers a novel function for the CTLH complex and suggests that it could have a tumour suppressive role in restricting HDAC6 oncogenic properties.

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Persistent accumulation of gut macrophages with impaired phagocytic function correlates with SIV disease progression in macaques

The contribution of macrophages in the gastrointestinal tract to disease control or progression in HIV infection remains unclear. To address this question, we analyzed CD163⁺ macrophages in ileum and mesenteric lymph nodes (LN) from SIV-infected rhesus macaques with dichotomous expression of controlling MHC class I alleles predicted to be SIV controllers or progressors. Infection induced accumulation of macrophages into gut mucosa in the acute phase that persisted in progressors but was resolved in controllers. In contrast, macrophage recruitment to mesenteric LNs occurred only transiently in acute infection irrespective of disease outcome. Persistent gut macrophage accumulation was associated with CD163 expression on α4β7⁺CD16⁺ blood monocytes and correlated with epithelial damage. Macrophages isolated from intestine of progressors had reduced phagocytic function relative to controllers and uninfected macaques, and the proportion of phagocytic macrophages negatively correlated with mucosal epithelial breach, lamina propria E. coli density, and plasma virus burden. Macrophages in intestine produced low levels of cytokines regardless of disease course, while mesenteric LN macrophages from progressors became increasingly responsive as infection advanced. These data indicate that non-inflammatory CD163⁺ macrophages accumulate in gut mucosa in progressive SIV infection in response to intestinal damage but fail to adequately phagocytose debris, potentially perpetuating their recruitment.

This article is protected by copyright. All rights reserved

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Flt3 ligand-eGFP-reporter expression characterizes functionally distinct subpopulations of CD150+ long-term repopulating murine hematopoietic stem cells

The pool of hematopoietic stem cells (HSCs) in the bone marrow is a mixture of resting, proliferating and differentiating cells. Long-term repopulating HSCs (LT-HSC) are routinely enriched as Lin⁻Sca1⁺c-Kit⁺CD34⁻Flt3⁻CD150⁺CD48⁻ cells. The Flt3 ligand (Flt3L) and its receptor Flt3 are important regulators of HSC maintenance, expansion and differentiation. Using Flt3L-eGFP reporter mice, we show that endogenous Flt3L-eGFP-reporter RNA expression correlates with eGFP-protein expression. This Flt3L-eGFP-reporter expression distinguishes two LT-HSC populations with differences in gene expressions and reconstituting potential. Thus, Flt3L-eGFP-reporter^low cells are identified as predominantly resting HSCs with long-term repopulating capacities. In contrast, Flt3L-eGFP-reporter^high cells are in majority proliferating HSCs with only short-term repopulating capacities. Flt3L-eGFP-reporter^ow cells express hypoxia, autophagy-inducing, and the LT-HSC-associated genes HoxB5 and Fgd5, while Flt3L-eGFP-reporter^high HSCs upregulate genes involved in HSC differentiation. Flt3L-eGFP-reporter^low cells develop to Flt3L-eGFP-reporter^high cells in vitro, although Flt3L-eGFP-reporter^high cells remain Flt3L-eGFP-reporter^high. CD150⁺Flt3L-eGFP-reporter^low cells express either endothelial protein C receptor (EPCR) or CD41, while Flt3L-eGFP-reporter^high cells do express EPCR but not CD41. Thus, FACS-enrichment of Flt3/ Flt3L-eGFP-reporter negative, Lin⁻CD150⁺CD48⁻ EPCR⁺CD41⁺ HSCs allows a further 5-fold enrichment of functional LT-HSCs.

This article is protected by copyright. All rights reserved

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Associations between treatment, scoliosis, pulmonary function, and physical performance in long-term survivors of sarcoma

Abstract

Purpose

Longer survival for children with sarcoma has led to the recognition of chronic health conditions related to prior therapy. We sought to study the association of sarcoma therapy with the development of scoliosis.

Methods

We reviewed patient demographics, treatment exposures, and functional outcomes for patients surviving >10 years after treatment for sarcoma between 1964 and 2002 at our institution. The diagnosis of scoliosis was determined by imaging. Functional performance and standardized questionnaires were completed in a long-term follow-up clinic.

Results

We identified 367 patients, with median age at follow-up of 33.1 years. Scoliosis was identified in 100 (27.2%) patients. Chest radiation (relative risk (RR), 1.88 (95% confidence interval (CI), 1.21–2.92), p < 0.005) and rib resection (RR, 2.64 (CI, 1.79–3.89), p < 0.0001) were associated with an increased incidence of scoliosis; thoracotomy without rib resection was not. Of 21 patients who underwent rib resection, 16 (80.8%) had the apex of scoliosis towards the surgical side. Scoliosis was associated with worse pulmonary function (RR, 1.74 (CI, 1.14–2.66), p < 0.01) and self-reported health outcomes, including functional impairment (RR, 1.60 (CI, 1.07–2.38), p < 0.05) and cancer-related pain (RR, 1.55 (CI, 1.11–2.16), p < 0.01). Interestingly, pulmonary function was not associated with performance on the 6-min walk test in this young population.

Conclusions

Children with sarcoma are at risk of developing scoliosis when treatment regimens include chest radiation or rib resection. Identification of these risk factors may allow for early intervention designed to prevent adverse long-term outcomes.

Implications for cancer survivors

Cancer survivors at risk of developing scoliosis may benefit from monitoring of pulmonary status and early physical therapy.

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Synthesis and evaluation of novel thiazole-based derivatives as selective inhibitors of DNA-binding domain of the androgen receptor

Abstract

A series of thiazole-based inhibitors selectively targeting DNA-binding domain of the androgen receptor (AR) were synthesized, evaluated and the SAR data were summarized. We identified a novel compound SKLB-C2807 that effectively inhibited the human prostate cancer cell line LNCaP/AR with the IC₅₀ value of 0.38 μM without significant antiproliferative effects on other cell lines PC-3 (AR-negative), SW620, MCF-7 (ER-positive) and L-O2 (non-cancerous). This compound also considerably decreased the expression of prostate-specific antigen (PSA). Its binding mode to the AR-DBD was studied. These efforts lay the foundation for developing the next generation of anti-androgens.

This article is protected by copyright. All rights reserved.

1.A series of new thiazole-based derivatives were synthesized and evaluated.

2.SKLB-C2807 effectively inhibits the LNCaP/AR and decreases the expression of prostate-specific antigen.

3.SARs and binding mode to AR-DBD studies were discussed in detail.

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Preparation, characterization and in vitro evaluation of isoniazid and rifampicin-loaded archaeosomes

Abstract

The ability of Archaea to adapt their membrane lipid compositions to extreme environments has brought in archaeosomes into consideration for the development of drug delivery systems overcoming the physical, biological blockades that the body exhibits against drug therapies. In this study, we prepared unilamellar archaeosomes, from the polar lipid fraction extracted from Haloarcula 2TK2 strain, and explored its potential as a drug delivery vehicle. Rifampicin and isoniazid which are conventional drugs in tuberculosis medication were loaded separately and together in the same archaeosome formulation for the benefits of the combined therapy. Particle size and zeta potential of archaeosomes were measured by photon correlation spectroscopy and the morphology was assessed by with an atomic force microscope. Encapsulation efficiency and loading capacities of the drugs were determined and in vitro drug releases were monitored spectrophotometrically. Our study demonstrates that rifampicin and isoniazid could be successfully loaded separately and together in archaeosomes with reasonable drug-loading and desired vesicle specific characters. Both of the drugs had greater affinity for archaeosomes than a conventional liposome formulation. The results imply that archaeosomes prepared from extremely halophilic archaeon were compatible with the liposomes for the development of stable and sustained release of antituberculosis drugs.

This article is protected by copyright. All rights reserved.

Unilamellar archaeosomes were prepared from the polar lipid fraction extracted from Haloarcula 2TK2 strain, and its potential as a drug delivery vehicle was explored using rifampicin and isoniazid. Particle size, zeta potential, morphology, encapsulation efficiency and loading capacities of the archaeosomes were analyzed. The results demonstrated that rifampicin and isoniazid were successfully loaded in archaeosomes prepared from extremely halophilic archaeon and the results were compatible with the liposomes for the development of stable and sustained release of antituberculosis drugs.

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Influence of EGCG on α-synuclein (αS) aggregation and identification of their possible binding mode: a computational study by using molecular dynamics simulation

Abstract

The accumulation of intrinsically disordered α-synuclein (αS) protein that can form β-sheet–rich fibrils is linked to Parkinson diseases (PD). (-)-Epigallocatechin-3-gallate (EGCG) is the most abundant active component in green tea and can inhibit the fibrillation of αS. The elucidation of this molecular mechanism will be helpful to understand the inhibition mechanism of EGCG to the fibrillation of αS and also to find more potential small molecules that can inhibit the aggregation of αS. In this work, in order to study the influence of EGCG on the structure of β-sheet-rich fibrils of α-synuclein (αS) and identification of their possible binding mode, molecular dynamics simulations of pentamer and decamer aggregates of αS in complex with EGCG were performed. The obtained results indicate that EGCG can remodel the αS fibrils and break the initial ordered pattern by reducing the β-sheet content. EGCG can also break the Greek conformation of αS by the disappeared H-bond in the secondary structure of turn. The results from our study can not only reveal the specific interaction between EGCG and β-sheet-rich fibrils of αS, but also provide the useful guidance for the discovery of other potential inhibitors.

This article is protected by copyright. All rights reserved.

Molecular dynamics simulations were performed to study the influence of EGCG on α-synuclein aggregation and identification of their possible binding mode,.

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Production of Chemicals from Microalgae Lipids – Status and Perspectives

Abstract

The engineering of algae strains, cultivation and further processing steps in microalgae production are considered in view of the utilization of microalgae lipids for chemicals. Insights from biofuel production trials on the one hand and existing processes for very high-value pharmaceuticals on the other hand are instructive to this end. A recent example of the production of a surfactant from chemical intermediates gained from algae oil and further opportunities are discussed.

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Lactobacilli survival and adhesion to colonic epithelial cell lines is dependent on long chain fatty acid exposure

Abstract

Lactobacilli and long chain polyunsaturated fatty acids are commonly consumed as functional foods. However, there is very little research into their interactions. The aim of the present study was to investigate the interaction between fatty acids (FA) and lactobacilli by exploring lactobacilli survival following exposure to different FA and their adhesion to epithelial cells pre-treated with different FA.

Three strains of lactobacilli were cultured with 20 μM eicosapentaenoic acid (EPA, n-3), docosahexaenoic acid (DHA, n-3), arachidonic acid (AA, n-6) or oleic acid (OA, n-9) to assess survival. Additionally, adhesion of radioactively labelled bacteria to confluent layers of three colorectal cell lineswas measured following pre-treatment of the epithelial cells with 50 μM EPA, DHA, AA or OA.

Results show that exposure to FA slowed log-phase growth of two human derived strains of lactobacilli, but reduced survival of a chicken derived strain to 20%. Survival was associated with the formation of the FA cyc19:0 in the human derived strains. The chicken derived strain showed greatest adherence to epithelial cells and adhesion was increased following epithelial cell exposure to DHA.

In conclusion, the survival and adhesion of lactobacilli in the intestinal tract is likely to be affected by FA content of the diet.

Practical applications: The fatty acid composition of the diet has the potential to modulate the behaviour of probiotic bacteria in the gut and in probiotic foods. We showed that combining high polyunsaturated fatty acids (PUFA) with certain probiotics may lead to reduced numbers of probiotic bacteria. Despite this, we showed that PUFA could enhance adhesion of some lactobacilli strains and that increasing the PUFA content of epithelial cells via the diet may aid the adherence of some potentially beneficial lactobacilli. We also highlight a potential concern for the chicken industry whereby PUFA inhibited the growth of the lactobacilli isolated from chicken. With the increasing use of PUFA in chicken feed this could lead to a dysbiosis in normal chicken microflora and requires further investigation.

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The effects of 2-hydroxyethyl methacrylate on matrix metalloproteinases 2 and 9 in human pulp cells and odontoblast-like cells in vitro

Abstract

Aim

To assess the effects of 2-hydroxyethyl methacrylate (HEMA) on proliferation and migration of human pulp cells, as well as on matrix metalloproteinase (MMP-2 and MMP-9) expression in human odontoblast-like cells, contributing to the goal of determining the relationship between resin materials and MMP activity in pulp-dentine complexes.

Methodology

Dental pulp cell cultures were established from pulp tissue of human teeth extracted for orthodontic purposes. Pulp cell differentiation was characterized in the presence of dentine sialophosphoprotein, bone sialoprotein, and alkaline phosphatase by reverse-transcription polymerase chain reaction. MMP activity was assessed by gelatin zymography with media containing HEMA. Cell viability was evaluated using methyl thiazolyl tetrazolium assay for 24–72 h. Cell migration was tested using Transwell migration assay. Western blotting was used to visualize MMP expression with the nontoxic HEMA concentrations (0–400 μg/mL) for 48 h.

Results

Pulp cell proliferation decreased with HEMA exposure in a time- and concentration-dependent manner. HEMA concentrations <400 μg/mL did not induce changes in cell viability at 48 h (P < 0.05). Pulp cells were induced to differentiate into odontoblast-like cells in media containing 5 mg/mL ascorbic acid and 10 mmol/L β-sodium glycerophosphate for 3–4 weeks. After incubation with HEMA, dose-dependent inhibition was observed; HEMA had a strong inhibitory effect on MMP activity. Compared with the control group, cell migration and MMP expression were inhibited significantly with increasing HEMA concentration at non-cytotoxic doses (P < 0.05).

Conclusions

Cell viability was not affected at HEMA concentrations < 400 μg/mL. Within this range, HEMA inhibited MMP-2 and MMP-9 expression and activity, which may protect against type I collagen degradation effectively during dentine adhesive procedures.

This article is protected by copyright. All rights reserved.

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MTA-induced Notch activation enhances the proliferation of human dental pulp cells by inhibiting autophagic flux

Abstract

Aim

To determine the roles of autophagy and Notch signalling in mineral trioxide aggregate (MTA)-mediated proliferation and differentiation of human dental pulp cells (hDPCs).

Methodology

hDPCs were separated from human healthy molar teeth using collagenase I/dispase II digestion, and then cultured in α-MEM medium with 15% foetal bovine serum. hDPCs were seeded in 96-well plates, and cell counting kit assays were carried out to test their viability. Real-time quantitative polymerase chain reaction (qPCR) was used to evaluate ALP, Runx2, Notch1, Hes1, and Hey1 mRNA levels. Notch1, hes1, LC3, and p62 protein levels were quantified by western blotting. Co-localisation of LC3 and Notch1 was measured by immunofluorescence. Two-tailed student's t-tests were used for statistical analysis.

Results

Autophagic flux was significantly (p<0.05) inhibited by MTA extracts, causing Notch degradation arrest. This resulted in the promotion of cell proliferation and inhibition of differentiation during the logarithmic phase of cell growth.

Conclusion

MTA extract promoted the proliferation of hDPCs in part by activating Notch signalling through inhibition of autophagic flux during the early stage, and thus, might potentially induce rapid restoration of injured pulps.

This article is protected by copyright. All rights reserved.

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Micro-CT assessment of the shaping ability of four root canal instrumentation systems in oval-shaped canals

Abstract

Aim

To compare the shaping ability of four root canal instrumentation systems in oval-shaped canals using micro-computed tomographic analysis.

Methodology

Forty anatomically matched mandibular incisors were scanned and assigned to four groups (n = 10), according to the canal preparation protocol: BioRace, Reciproc, Self-Adjusting File (SAF) and TRUShape systems. After canal instrumentation, the specimens were re-scanned and the registered pre- and postoperative datasets were examined to evaluate the percentages of accumulated hard-tissue debris, untouched canal areas and dentine removed. Kruskal-Wallis and Mann-Whitney U tests with Bonferroni correction were used to compare the variables in the groups (α = 5%).

Results

The preparation techniques did not affect the percentage of accumulated hard-tissue debris (P = 0.126). The percentage of untouched canal areas was significantly higher for BioRace (32.38%), and Reciproc (18.95%) with the SAF (16.08%) system having the least untouched area results (P < 0.05). The Reciproc system removed significantly more dentine (4.18%) compared to the BioRace (2.21%) and SAF (2.56%) systems (P < 0.05). The TRUShape system had intermediate results for both untouched canal areas (19.20%) and dentine removed (3.77%), with no significant difference compared to BioRace, Reciproc and SAF systems.

Conclusions

The preparation techniques resulted in the same level of accumulated hard-tissue debris. Compared to the other tested systems, BioRace was associated with more untouched canal areas, and Reciproc produced the greatest amount of removed dentine. Although it touched more of the root canal walls, the SAF system removed less dentine, whereas TRUShape had intermediate results for these same parameters. None of the systems tested were able to provide optimal shaping ability in oval-shaped canals.

This article is protected by copyright. All rights reserved.

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The five-year cost-effectiveness of two-level anterior cervical discectomy and fusion or cervical disc replacement: a markov analysis

Publication date: Available online 30 June 2017
Source:The Spine Journal
Author(s): Samuel C. Overley, Steven J. McAnany, Robert L. Brochin, Jun S. Kim, Robert K. Merrill, Sheeraz A. Qureshi
Background ContextAnterior cervical discectomy and fusion (ACDF) and cervical disc replacement (CDR) are both acceptable surgical options for the treatment of cervical myelopathy and/or radiculopathy. To date, there are limited economic analyses assessing the relative cost-effectiveness of two-level ACDF versus CDR.PurposeThe purpose of this study was to determine the five-year cost-effectiveness of two-level ACDF versus CDR.Study DesignSecondary analysis of prospectively collected data.Patient SamplePatients in the Prestige Cervical Disc Investigational Device Exemption study who underwent either 2 level CDR or 2 level ACDF.Outcome MeasuresCost and quality adjusted life years (QALYs).MethodsA Markov-state transition model was used to evaluate data from the two-level Prestige Cervical Disc IDE study. Data from the 36-item Short Form Health Survey were converted into utilities using the SF-6D algorithm. Costs were calculated from the payer perspective. QALYs were used to represent effectiveness. A probabilistic sensitivity analysis was performed using a Monte Carlo simulation.ResultsThe base case analysis, assuming a 40 year-old person who failed appropriate conservative care, generated a five-year cost of $130,417 for CDR and $116,717 for ACDF. CDR and ACDF generated of 3.45 and 3.23 QALY's respectively. The ICER was calculated to be $62,337/QALY for CDR. The Monte Carlo simulation validated the base case scenario. CDR had an average cost of $130,445 (CI: $108,395; $152,761) with an average effectiveness of 3.46 (CI: 3.05; 3.83). ACDF had an average cost of $116,595 (CI: 95,439; $137,937) and an average effectiveness of 3.23 (CI: 2.84; 3.59). The ICER was calculated at $62,133/QALY with respect to CDR. Using a $100,000/QALY WTP, CDR is the more cost-effective strategy and would be selected 61.5% of the time by the simulation.ConclusionsTwo-level CDR and ACDF are both cost-effective strategies at five years. Neither strategy was found to be more cost-effective with an ICER greater than the $50,000/QALY WTP threshold. The assumptions used in the analysis were strongly validated with the results of the probabilistic sensitivity analysis.



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Lumbar spine surgery in patients with rheumatoid arthritis (RA): what affects the outcomes

Publication date: Available online 1 July 2017
Source:The Spine Journal
Author(s): Shoji Seki, Norikazu Hirano, Isao Matsushita, Yoshiharu Kawaguchi, Masato Nakano, Taketoshi Yasuda, Hiraku Motomura, Kayo Suzuki, Yasuhito Yahara, Kenta Watanabe, Hiroto Makino, Tomoatsu Kimura
Background ContextWhile the cervical spine is only occasionally involved in rheumatoid arthritis (RA), involvement of the lumbar spine is even less common. A few reports on lumbar spinal stenosis in patients with RA have appeared. Although disc space narrowing occurs in aging, postoperative ASD in RA patients has not been subject to much analysis.PurposeTo investigate differences in adjacent segment disease (ASD) and clinical outcomes between lumbar spinal decompression with and without fusion in patients with rheumatoid arthritis (RA).Study Design/SettingRetrospective comparative study.Patient SampleA total of 52 RA patients who underwent surgery for lumbar spinal disorders were included. Twenty-seven patients underwent decompression surgery with fusion and 25 underwent decompression surgery alone.Outcome MeasuresIntervertebral disc space narrowing and spondylolisthesis of the segment immediately cranial to the surgical site were measured using three-dimensional volume rendering software. Pre- and post-operative evaluation of RA activity and Japanese Orthopaedic Association (JOA) scores were conducted.MethodsAll patients had preoperative and annual postoperative lumbar radiographs and were followed for a mean of 5.1 years (range 3.5-10.9 years). Pre- and postoperative (2 years after surgery) JOA scores were recorded and any postoperative complications were investigated. Degrees of intervertebral disc narrowing and spondylolisthesis at the adjacent levels were evaluated on radiographs and compared between the two groups. Analysis was performed to look for any correlation between ASD and RA disease activity.ResultsPostoperative JOA scores were significantly improved in both groups. The rate of revision surgery was significantly higher in the fusion group than in the non-fusion group. The rate of ASD was significantly greater in the fusion group than in the non-fusion group at the final follow-up examination. Both matrix metalloproteinases 3 (MMP-3) and the 28-joint disease activity score incorporating C-reactive protein levels (DAS28CRP) were significantly associated with the incidence and severity of ASD.ConclusionsASD and the need for revision surgery were significantly higher in the fusion group than in the non-fusion group. A preoperative high MMP-3 and DAS28CRP are likely to be associated with postoperative ASD.



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Risk factors for laryngeal penetration-aspiration in patients with acute traumatic cervical spinal cord injury

Publication date: Available online 30 June 2017
Source:The Spine Journal
Author(s): Tiina Ihalainen, Irina Rinta-Kiikka, Teemu M. Luoto, Tuomo Thesleff, Mika Helminen, Anna-Maija Korpijaakko-Huuhka, Antti Ronkainen
Background ContextLaryngeal penetration-aspiration, entry of material into the airways, is considered the most severe subtype of dysphagia and common among patients with acute cervical spinal cord injury.PurposeThe aim of this study was to investigate risk factors for penetration-aspiration in patients with acute traumatic cervical spinal cord injury (TCSCI).Study designA prospective cohort study.Patient sampleThirty-seven patients with TCSCI.Outcome measuresThe highest Rosenbek's penetration-aspiration scale (PAS; range 1-8) score of each patient was the primary outcome measure. The risk factors consisted of patient characteristics, demographics and clinical signs observed during a clinical swallowing trial.MethodsA clinical swallowing trial and videofluoroscopic swallowing study (VFSS) was performed to all patients within 28 days post-injury. For group comparisons, the patients were divided into two groups: (i) penetrator/aspirators (PAS score ≥3) and (ii) non-penetrator/aspirators (PAS score ≤2). This study was self-funded with no conflict of interest.ResultsOf the 37 patients, 83.8% were male. The mean age at the time of the injury was 61.2 years. Most patients had an incomplete TCSCI (78.4%) due to a fall (75.7%). In the VFSS, 51.4% of the patients were penetrator/aspirators, and 71.4% had silent aspiration. The risk factors for predicting penetration-aspiration were: (i) necessity of bronchoscopies, (ii) lower level of anterior cervical operation, (iii) coughing, throat clearing, choking related to swallowing, and (iv) changes in voice quality related to swallowing. Binary logistic regression identified coughing, throat clearing, choking and changes in voice quality related to swallowing as independent risk factors for penetration-aspiration.ConclusionsThe necessity of bronchoscopies, post-injury lower cervical spine anterior surgery, coughing, throat clearing, choking and changes in voice quality related to swallowing were marked risk factors for aspiration and penetration following a cervical spinal cord injury. These factors and signs should be used to suspect injury-related pharyngeal dysfunction and initiate preventive measures to avoid complications. The clinical swallowing evaluation is a relevant adjunct in the management of these patients and can improve the detection of penetration and aspiration.



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Motion preservation following total lumbar disc replacement at the lumbosacral junction: a prospective long-term clinical and radiographic investigation

Publication date: Available online 30 June 2017
Source:The Spine Journal
Author(s): Christoph Wuertinger, Raphael Dàgostino Annes, Wolfgang Hitzl, Christoph J. Siepe
Background ContextTotal lumbar disc replacement (TDR) intends to avoid fusion related negative side effects by means of motion preservation. Despite of their widespread use, the adequate quality and quantity of motion as well as the correlation between radiographic data with the patient's clinical symptomatology remains to be established. Long-term data are lacking in particular.PurposeTo perform a clinical and radiographic long-term investigation following TDR with special emphasis on motion preservation assessment and to establish any potential correlation with patient reported outcome parameters.Study Design/SettingProspective, single-center, clinical and radiological investigation following TDR with ProDisc II (Synthes, Paoli, PA, USA).Patient SamplePatients with a minimum 5-year FU after TDR performed for the treatment of intractable and predominant (≥80%) axial LBP resulting from single-level DDD without instabilities or deformities at the lumbosacral junction (L5/S1).Outcome MeasuresVisual analogue scale (VAS), Oswestry Disability Index (ODI) and patient satisfaction rates (three-scale outcome rating); range of motion (ROM) at the index- and cranially adjacent level as well as segmental and global lumbar lordosis.MethodsAll data were acquired within the framework of an ongoing prospective clinical trial. Patients were examined preoperatively, 3, 6, and 12 months postoperatively, annually thereafter. X-rays were performed in ap- and lateral views as well as functional flexion / extension images. Radiological examinations included range of motion (ROM) at the index- and cranially adjacent level as well as segmental and global lumbar lordosis. X-Ray measurements were correlated with the clinical outcome parameters. A longitudinal analysis was performed between baseline data with those from the early (3-6 months), mid- (12-24 months) and late FU stages (≥ 5 years).ResultsResults from 51 patients with a mean FU of 7.8 years (range 5.0-13.3 years) were available for the final analysis. X-ray measurements revealed a maintained mobility with a trend towards gradually declining ROM values. Whilst no statistically significant difference in ROM was detected between the preoperative and early FU (6.8° vs. 5.8°, p=0.1), a further reduction in ROM became statistically significant at the mid- and final FU with mean ROM of 5.2° and 4.4°, respectively (p <0.001).Global lumbar lordosis increased from 48.8° to 54.4° (p<0.0001) which was attributed to a lordotic shift from 18.2° to 28.0° at the index segment (p<0.00001) and which was positively correlated with the applied implant lordosis (p<0.05). A compensatory reduction of lordosis was observed at the cranially adjacent segment (p <0.0001). The mobility of the cranially adjacent level remained unchanged (p>0.05).The clinical outcome scores (VAS, ODI) revealed a significant improvement from baseline levels (p<0.05). The reduction in ROM was not negatively correlated with the patient's clinical symptomatology (p>0.05).ConclusionThe present data reveal an increased global lumbar lordosis resulting from a lordotic shift of the index segment, which was strongly correlated with the applied implant lordosis. This lordotic shift was accompanied by a compensatory reduction of lordosis at the cranially adjacent segment.A gradual and statistically significant decline of the device mobility was noted over time which, however, did not negatively impact the patient's clinical symptomatology.Whilst the present long-term investigation provides additional insight into longitudinal radiographic changes and their influence on the patient's clinical symptomatology following TDR, the adequate quality and quantity of motion with artificial motion preserving implants remains to be established which will aid in defining more refined treatment concepts for both fusion and motion preserving techniques alike.



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The impact of spine stability on cervical spinal cord injury with respect to demographics, management and outcome: a prospective cohort from a national SCI registry

Publication date: Available online 1 July 2017
Source:The Spine Journal
Author(s): Jérôme Paquet, Carly S. Rivers, Dilinuer Kuerban, Joel Finkelstein, Jin W. Tee, Vanessa K. Noonan, Brian K. Kwon, R. John Hurlbert, Sean Christie, Eve C. Tsai, Henry Ahn, Brian Drew, Christopher S. Bailey, Daryl R. Fourney, Najmedden Attabib, Michael G. Johnson, Michael G. Fehlings, Stefan Parent, Marcel F. Dvorak
Background contextEmergent surgery for patients with a traumatic spinal cord injury (SCI) is seen as the gold standard in acute management. However, optimal treatment for those with the clinical diagnosis of central cord syndrome (CCS) is less clear and classic definitions of CCS do not identify a unique population of patients.PurposeTo test the authors' hypothesis that spine stability can identify a unique group of patients with regards to demographics, management, and outcomes, which classic CCS definitions do not.Study design/settingProspective observational study.Patient sampleParticipants with cervical SCI included in a prospective Canadian registry.Outcome measuresInitial hospitalization length of stay, change in total motor score from admission to discharge, and in-hospital mortality.MethodsPatients with cervical SCI from a prospective Canadian SCI registry were grouped into stable and unstable spine cohorts. Bivariate analyses were used to identify differences in demographic, injury, management, and outcomes. Multivariate analysis was used to better understand the impact of spine stability on motor score improvement. No conflicts of interest were identified.ResultsCompared to those with an unstable spine, patients with cervical SCI and a stable spine were older (58.8 vs 44.1 years, p<0.0001), more likely male (86.4% vs. 76.1%, p=0.0059), and have more medical comorbidities. Patients with stable spine cervical SCI were more likely to have sustained their injury by a fall (67.4% vs. 34.9%, p<0.0001), have high cervical (C1-C4; 58.5% vs. 43.3%, p=0.0009) and less severe neurological injuries (AIS C or D; 81.3% vs. 47.5%, p<0.0001). Those with stable spine injuries were less likely to have surgery (67.6% vs. 92.6%, p<0.0001), had shorter in-hospital lengths of stay (median 84.0 vs. 100.5 days, p=0.0062), and higher total motor score change (20.7 vs. 19.4 points, p=0.0014). Multivariate modelling revealed that neurological severity of injury and spine stability were significantly related to motor score improvement; patients with stable spine injuries had more motor score improvement.ConclusionsWe propose that classification of stable cervical SCI is more clinically relevant than classic CCS classification as this group was found to be unique with regards to demographics, neurological injury, management, and outcome whereas classic CCS classifications do not . This classification can be used to assess optimal management in patients where it is less clear if and when surgery should be performed.



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Gender trends in authorship of spine-related academic literature – a 39-year perspective

Publication date: Available online 1 July 2017
Source:The Spine Journal
Author(s): David C Sing, Deeptee Jain, David Ouyang
Background ContextDespite recent advances in gender equity in medicine, the representation of women in orthopaedic and neurosurgery remains particularly low. Furthermore compared to their male colleagues female faculty members are less likely to publish research, limiting opportunities in the academic promotion process. Understanding disparities in research productivity provides insight into the "gender gap" in the spine surgeon workforce.PurposeTo determine the representation and longevity of female physician-investigators among the authors of five spine-related research journals from 1978 to 2016.Study DesignRetrospective bibliometric reviewMethodsAuthors of original research articles from five prominent spine-related journals (European Spine Journal, the Spine Journal, Spine, Journal of Spinal Disorders and Techniques and Journal of Neurosurgery: Spine) were extracted from PubMed. For authors with a complete first name listed, gender was determined by matching first name using an online database containing 216,286 distinct names across 79 countries and 89 languages. The proportion of female first and senior authors was determined during the time periods 1978-1994, 1995-1999, 2000-2004, 2005-2009, and 2010-2016. Authors who had their first paper published between 2000-2009 were included in additional analyses for publication count and longevity (whether additional articles were published 5 years after first publication). Student's t-test, chi-squared analysis, and Cochran-Armitage trend test were used to determine significance between groups.ResultsFrom 1978-2016, 28,882 original research articles were published in the five spine-related journals. 24,334 abstracts (90.9%) had first names listed, identifying 120,723 authors in total of which 100,286 were successfully matched to a gender. 33,480 unique authors were identified (female: 31.8%). Female representation increased for first and senior authors from 6.5% and 4.7% (1978-1994) to 18.5% and 13.6% (2010-2016, p<0.001). Growth in female senior author representation declined after 2000 (12.3% vs. 12.9% vs. 13.5% between 2000-2004, 2005 – 2009, and 2010-2016). Compared to men authors, on average women authors published fewer articles (mean: 2.1 vs 3.3, p<0.001). Of 15,304 authors who first published during 2000-2009, 3,478 authors (22.7%) continued to publish 5 years after their first publication. Women were less likely to continue publishing after their first article (15.3% of female authors vs. 24.8%, p <0.001).ConclusionsFemale representation in academic spine research has doubled over the past 4 decades, although the growth of female representation as senior author has plateaued. Female physician-investigators are half as likely to continue participating in spine-related research longer than 5 years and on average publish half as many articles as senior author. In addition to recruiting more women into research, efforts should be made to identify and address barriers in research advancement and promotion for female physician-investigators.



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Incorporating ligament laxity in a finite element model for the upper cervical spine

Publication date: Available online 30 June 2017
Source:The Spine Journal
Author(s): Timothy L Lasswell, Duane S Cronin, John B Medley, Parham Rasoulinejad
Background ContextPredicting physiological range of motion (ROM) using a finite element (FE) model of the upper cervical spine requires the incorporation of ligament laxity. The effect of ligament laxity can only be observed on a macro level of joint motion and is lost once ligaments have been dissected and preconditioned for experimental testing. As a result, although ligament laxity values are recognized to exist, specific values are not directly available in the literature for use in FE models.PurposeThe purpose of the current study is to propose an optimization process that can be used to determine a set of ligament laxity values for upper cervical spine FE models. Furthermore, an FE model that includes ligament laxity is applied and the resulting ROM values are compared with experimental data for physiological ROM as well as experimental data for the increase in ROM when a type II odontoid fracture is introduced.Study Design/SettingThe upper cervical spine FE model was adapted from a fiftieth percentile male full body model developed with the Global Human Body Models Consortium (GHBMC). FE modeling was performed in LS-DYNA (Livermore Software Technology Group, Livermore CA) and LS-OPT (Livermore Software Technology Group, Livermore CA) was used for ligament laxity optimization.MethodsOrdinate-based curve matching was used to minimize the mean squared error (MSE) between computed load-rotation curves and experimental load-rotation curves under flexion, extension and axial rotation with pure moment loads from 0-3.5Nm. Lateral bending was excluded from the optimization since the upper cervical spine was considered to be primarily responsible for flexion, extension and axial rotation. Based on recommendations from the literature, four varying inputs representing laxity in select ligaments were optimized in order to minimize the MSE. Funding was provided by the Natural Sciences and Engineering Research Council of Canada as well as GHMBC. The present study was funded by the Natural Sciences and Engineering Research Council of Canada to support the work of one graduate student. There are no conflicts of interest to be reported.ResultsThe MSE was reduced to 0.28 in the FE model with optimized ligament laxity compared to an MSE 0f 4.16 in the FE model without laxity. In all load cases, incorporating ligament laxity improved the agreement between the ROM of the FE model and the ROM of the experimental data. The ROM for axial rotation and extension was within one standard deviation of the experimental data. The ROM for flexion and lateral bending was outside one standard deviation of the experimental data but a compromise was required in order to use one set of ligament laxity values to achieve a best fit to all load cases. Atlanto-occiptial motion was compared as a ratio to overall ROM and only in extension did the inclusion of ligament laxity not improve the agreement. After a type II odontoid fracture was incorporated into the model, the increase in ROM was consistent with experimental data from the literature.ConclusionsThe optimization approach used in this study provided values for ligament laxities that, when incorporated into the FE model, generally improved the ROM response when compared with experimental data. Successfully modeling a type II odontoid fracture showcased the robustness of the FE model which can now be used in future biomechanics studies.



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