Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often ...modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H‐MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (P < 0.01) and hepatic triglyceride concentration by 21% (P < 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (P < 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, 1H‐MRS–measured hepatic lipid saturation, or HOMA‐IR (homeostasis model assessment of insulin resistance; P > 0.05). Conclusion: These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss. (HEPATOLOGY 2009.)
Retrospective review of a multicenter database.
To determine the complication rates associated with surgical treatment of pediatric scoliosis and to assess variables associated with increased ...complication rates.
Wide variability is reported for complications associated with the operative treatment of pediatric scoliosis. Limited number of patients, surgeons, and diagnoses occur in most reports. The Scoliosis Research Society Morbidity and Mortality (M&M) database aggregates deidentified data, permitting determination of complication rates from large numbers of patients and surgeons.
Cases of pediatric scoliosis (age ≤18 years), entered into the Scoliosis Research Society M&M database between 2004 and 2007, were analyzed. Age, scoliosis type, type of instrumentation used, and complications were assessed.
A total of 19,360 cases fulfilled inclusion criteria. Of these, complications occurred in 1971 (10.2%) cases. Overall complication rates differed significantly among idiopathic, congenital, and neuromuscular cases (P < 0.001). Neuromuscular scoliosis had the highest rate of complications (17.9%), followed by congenital scoliosis (10.6%) and idiopathic scoliosis (6.3%). Rates of neurologic deficit also differed significantly based on the etiology of scoliosis (P < 0.001), with the highest rate among congenital cases (2.0%), followed by neuromuscular types (1.1%) and idiopathic scoliosis (0.8%). Neur-omuscular scoliosis and congenital scoliosis had the highest rates of mortality (0.3% each), followed by idiopathic scoliosis (0.02%). Higher rates of new neurologic deficits were associated with revision procedures (P < 0.001) and with the use of corrective osteotomies (P < 0.001). The rates of new neurologic deficit were significantly higher for procedures using anterior screw-only constructs (2.0%) or wire-only constructs (1.7%), compared with pedicle screw-only constructs (0.7%) (P < 0.001).
In this review of a large multicenter database of surgically treated pediatric scoliosis, neuromuscular scoliosis had the highest morbidity, but relatively high complication rates occurred in all groups. These data may be useful for preoperative counseling and surgical decision-making in the treatment of pediatric scoliosis.
Recent research highlights that founders' early decisions and the environmental conditions at founding each imprint upon a new venture in ways that affect growth and survival. However, we know much ...less about how the entrepreneur is imprinted and how the outcome of this imprinting process influences the entrepreneur and the venture. Through semi-structured interviews and content analysis, our study examines entrepreneurs' formative experiences during sensitive periods of transition, which we refer to as sources of imprint. We illustrate how these sources of imprint impact entrepreneurial decision making and explain how they guide entrepreneurs' decisions as they progress through their entrepreneurial careers. In doing so, we improve our understanding of how entrepreneurs navigate the entrepreneurial process.
•We examine how foundational experiences ‘imprint’ entrepreneurs' decision-making.•We illustrate how different entrepreneurs draw from different spheres of influence.•We demonstrate how spheres of influence impact entrepreneurial identity.•The enduring influence of different spheres alters venture development trajectories.•Imprinting explains how entrepreneurs make decisions both now and in the future.
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We describe the development of a method for the extraction and analysis of 62 sterols, oxysterols, and secosteroids from human plasma using a combination of HPLC-MS and GC-MS. Deuterated standards ...are added to 200 μl of human plasma. Bulk lipids are extracted with methanol:dichloromethane, the sample is hydrolyzed using a novel procedure, and sterols and secosteroids are isolated using solid-phase extraction (SPE). Compounds are resolved on C18 core-shell HPLC columns and by GC. Sterols and oxysterols are measured using triple quadrupole mass spectrometers, and lathosterol is measured using GC-MS. Detection for each compound measured by HPLC-MS was ∪ 1 ng/ml of plasma. Extraction efficiency was between 85 and 110%; day-to-day variability showed a relative standard error of <10%. Numerous oxysterols were detected, including the side chain oxysterols 22-, 24-, 25-, and 27-hydroxycholesterol, as well as ring-structure oxysterols 7α- and 4β-hydroxycholesterol. Intermediates from the cholesterol biosynthetic pathway were also detected, including zymosterol, desmosterol, and lanosterol. This method also allowed the quantification of six secosteroids, including the 25-hydroxylated species of vitamins D2 and D3. Application of this method to plasma samples revealed that at least 50 samples could be extracted in a routine day.
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles ...outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required.
Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals.
Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families.
Retrospective review of a prospectively collected database.
Our objective was to assess the rates of postoperative wound infection associated with spine surgery.
Although wound infection after spine ...surgery remains a common source of morbidity, estimates of its rates of occurrence remain relatively limited. The Scoliosis Research Society prospectively collects morbidity and mortality data from its members, including the occurrence of wound infection.
The Scoliosis Research Society morbidity and mortality database was queried for all reported spine surgery cases from 2004 to 2007. Cases were stratified based on factors including diagnosis, adult (≥ 21 years) versus pediatric (<21 years), primary versus revision, use of implants, and whether a minimally invasive approach was used. Superficial, deep, and total infection rates were calculated. RESULTS.: In total, 108,419 cases were identified, with an overall total infection rate of 2.1% (superficial = 0.8%, deep = 1.3%). Based on primary diagnosis, total postoperative wound infection rate for adults ranged from 1.4% for degenerative disease to 4.2% for kyphosis. Postoperative wound infection rates for pediatric patients ranged from 0.9% for degenerative disease to 5.4% for kyphosis. Rate of infection was further stratified based on subtype of degenerative disease, type of scoliosis, and type of kyphosis for both adult and pediatric patients. Factors associated with increased rate of infection included revision surgery (P < 0.001), performance of spinal fusion (P < 0.001), and use of implants (P < 0.001). Compared with a traditional open approach, use of a minimally invasive approach was associated with a lower rate of infection for lumbar discectomy (0.4% vs. 1.1%; P < 0.001) and for transforaminal lumbar interbody fusion (1.3% vs. 2.9%; P = 0.005).
Our data suggest that postsurgical infection, even among skilled spine surgeons, is an inherent potential complication. These data provide general benchmarks of infection rates as a basis for ongoing efforts to improve safety of care.
Background
Calcitonin gene-related peptide plays an important role in migraine pathophysiology. We evaluated eptinezumab, an intravenous (IV) anti-calcitonin gene-related peptide monoclonal antibody, ...for the prevention of chronic migraine.
Objective
To determine the safety, tolerability, and effectiveness of four dose levels of eptinezumab and to inform the phase 3 development program.
Methods
This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial. Men and women (N = 616) aged 18–55 years were included if they had a diagnosis of chronic migraine, with onset at age ≤35 years and history of chronic migraine ≥1 year. During the 28-day screening period, patients must have had ≥15 headache days, including ≥8 migraine days, with ≥5 migraine attacks as recorded in the electronic diary. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a ≥75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period.
Results
The ≥75% migraine responder rates over weeks 1–12 for eptinezumab 300, 100, 30, and 10 mg were 33.3%, 31.4%, 28.2%, and 26.8%, respectively, versus 20.7% for placebo (p = 0.033, 0.072, 0.201, 0.294 vs. placebo). Secondary efficacy endpoints (e.g. ≥50% responder rate, change from baseline in frequency of migraine/headache days, and percentage of severe migraines) had results favoring the three higher eptinezumab doses versus placebo. Eptinezumab was well tolerated and adverse event rates were similar to placebo.
Conclusions
The results of this trial demonstrate that eptinezumab appears effective and well-tolerated for the preventive treatment of chronic migraine and justifies the conduct of pivotal phase 3 trials for migraine prevention.
Trial Registration
ClinicalTrials.gov identifier: NCT02275117.
ObjectiveWe aimed to assess risk factors for the development of severe infection in patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) receiving rituximab.Methods192 patients ...with AAV were identified. Univariate and multivariate analyses were performed to identify risk factors for severe infection following rituximab. Severe infections were classified as grade ≥3 as proposed by the Common Terminology Criteria for Adverse Events V.4.0.Results95 severe infections were recorded in 49 (25.52%) patients, corresponding to an event rate of 26.06 per 100 person-years. The prophylactic use of trimethoprim–sulfamethoxazole was associated with a lower frequency of severe infections (HR 0.30, 95% CI 0.13 to 0.69), while older age (HR 1.03, 95% CI 1.01 to 1.05), endobronchial involvement (HR 2.21, 95% CI 1.14 to 4.26), presence of chronic obstructive pulmonary disease (HR 6.30, 95% CI 1.08 to 36.75) and previous alemtuzumab use (HR 3.97, 95% CI 1.50 to 10.54) increased the risk. When analysis was restricted to respiratory tract infections (66.3% of all infections), endobronchial involvement (HR 4.27, 95% CI 1.81 to 10.06), severe bronchiectasis (HR 6.14, 95% CI 1.18 to 31.91), higher neutrophil count (HR 1.19, 95% CI 1.06 to 1.33) and major relapse (HR 3.07, 95% CI 1.30 to 7.23) as indication for rituximab use conferred a higher risk, while refractory disease (HR 0.25, 95% CI 0.07 to 0.90) as indication had a lower frequency of severe infections.ConclusionsWe found severe infections in one quarter of patients with AAV receiving rituximab. Trimethoprim–sulfamethoxazole prophylaxis reduced the risk, while especially bronchiectasis and endobronchial involvement are risk factors for severe respiratory infections.
We demonstrate the use of a scanning transmission electron microscope (STEM) equipped with a monochromator and an electron energy loss (EEL) spectrometer as a powerful tool to study localized surface ...plasmons in metallic nanoparticles. We find that plasmon modes can be influenced by changes in nanostructure geometry and electron beam damage and show that it is possible to delineate the two effects through optimization of specimen preparation techniques and acquisition parameters. The results from the experimental mapping of bright and dark plasmon energies are in excellent agreement with the results from theoretical modeling.
Summary Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare ...gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio HR 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 16% of 224 patients on gefitinib vs six 3% of 225 on placebo) and skin toxicity (46 21% vs two 1%), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 11% vs 13 6% patients) and diarrhoea (13 6% vs two 1%). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. Funding Cancer Research UK.
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