Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib

Background: Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib

Hip fracture evaluation with alternatives of total hip arthroplasty versus hemiarthroplasty (HEALTH): protocol for a multicentre randomised trial

Introduction: Hip fractures are a leading cause of mortality and disability worldwide, and the number of hip fractures is expected to rise to over 6 million per year by 2050. The optimal approach for the surgical management of displaced femoral neck fractures remains unknown. Current evidence suggests the use of arthroplasty; however, there is lack of evidence regarding whether patients with displaced femoral neck fractures experience better outcomes with total hip arthroplasty (THA) or hemiarthroplasty (HA). The HEALTH trial compares outcomes following THA versus HA in patients 50 years of age or older with displaced femoral neck fractures. Methods and analysis: HEALTH is a multicentre, randomised controlled trial where 1434 patients, 50 years of age or older, with displaced femoral neck fractures from international sites are randomised to receive either THA or HA. Exclusion criteria include associated major injuries of the lower extremity, hip infection(s) and a history of frank dementia. The primary outcome is unplanned secondary procedures and the secondary outcomes include functional outcomes, patient quality of life, mortality and hiprelated complications—both within 2 years of the initial surgery. We are using minimisation to ensure balance between intervention groups for the following factors: age, prefracture living, prefracture functional status, American Society for Anesthesiologists (ASA) Class and centre number. Data analysts and the HEALTH Steering Committee are blinded to the surgical allocation throughout the trial. Outcome analysis will be performed using a χ2 test (or Fisher’s exact test) and Cox proportional hazards modelling estimate. All results will be presented with 95% CIs. Ethics and dissemination: The HEALTH trial has received local and McMaster University Research Ethics Board (REB) approval (REB#: 06-151). Results: Outcomes from the primary manuscript will be disseminated through publications in academic journals and presentations at relevant orthopaedic conferences. We will communicate trial results to all participating sites. Participating sites will communicate results with patients who have indicated an interest in knowing the results. Trial registration number: The HEALTH trial is registered with clinicaltrials.gov (NCT00556842)

Resveratrol inhibits nonalcoholic fatty liver disease in rats

<p>Abstract</p> <p>Background</p> <p>The prevalence of nonalcoholic fatty liver disease (NAFLD) is high. NAFLD is linked to obesity, diabetes mellitus, and hypertriglyceridemia. Approximately 20% of patients with NAFLD will eventually develop cirrhosis. Our purpose was to investigate whether resveratrol decreased hepatic steatosis in an animal model of steatosis, and whether this therapeutic approach resulted in a decrease in tumor necrosis factor α (TNF-α) production, lipid peroxidation and oxidative stress.</p> <p>Methods</p> <p>Male Wistar CRL: Wi (Han) (225 g) rats were randomized into three groups. A control group (n = 12) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 12) and resveratrol (n = 12) groups were given free access to feed (a high carbohydrate-fat free modified diet) and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. Rats in the resveratrol group were given resveratrol 10 mg daily by the oral route. All rats were killed at 4 weeks and assessed for fatty infiltration and bacterial translocation. Levels of TNF-α in serum, hepatic malondialdehyde (MDA), oxidative stress (superoxide dismutase, glutathione peroxidase, catalase and nitric oxide synthase) and biochemical parameters were measured.</p> <p>Results</p> <p>Fat deposition was decreased in the resveratrol group as compared to the steatosis group (Grade 1 vs Grade 3, P < 0.05). TNF-α and MDA levels were significantly increased in the steatosis group (TNF-α; 33.4 ± 5.2 vs 26.24 ± 3.47 pg/ml and MDA; 9.08 ± 0.8 vs 3.17 ± 1.45 μM respectively, <it>P </it>< 0.05). This was accompanied by increased superoxide dismutase, glutathione peroxidase and catalase and decreased nitric oxide synthase in the liver of resveratrol group significantly (<it>P </it>< 0.05 vs steatosis group). Bacterial translocation was not found in any of the groups. Glucose levels were decreased in the group of rats given resveratrol (<it>P </it>< 0.05).</p> <p>Conclusion</p> <p>Resveratrol decreased NAFLD severity in rats. This effect was mediated, at least in part, by TNF-α inhibition and antioxidant activities.</p

Probing Chemical Space with Alkaloid-Inspired Libraries

Screening of small molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries, due to their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin, and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant

Effectiveness of electronic guideline-based implementation systems in ambulatory care settings - a systematic review

<p>Abstract</p> <p>Background</p> <p>Electronic guideline-based decision support systems have been suggested to successfully deliver the knowledge embedded in clinical practice guidelines. A number of studies have already shown positive findings for decision support systems such as drug-dosing systems and computer-generated reminder systems for preventive care services.</p> <p>Methods</p> <p>A systematic literature search (1990 to December 2008) of the English literature indexed in the Medline database, Embase, the Cochrane Central Register of Controlled Trials, and CRD (DARE, HTA and NHS EED databases) was conducted to identify evaluation studies of electronic multi-step guideline implementation systems in ambulatory care settings. Important inclusion criterions were the multidimensionality of the guideline (the guideline needed to consist of several aspects or steps) and real-time interaction with the system during consultation. Clinical decision support systems such as one-time reminders for preventive care for which positive findings were shown in earlier reviews were excluded. Two comparisons were considered: electronic multidimensional guidelines versus usual care (comparison one) and electronic multidimensional guidelines versus other guideline implementation methods (comparison two).</p> <p>Results</p> <p>Twenty-seven publications were selected for analysis in this systematic review. Most designs were cluster randomized controlled trials investigating process outcomes more than patient outcomes. With success defined as at least 50% of the outcome variables being significant, none of the studies were successful in improving patient outcomes. Only seven of seventeen studies that investigated process outcomes showed improvements in process of care variables compared with the usual care group (comparison one). No incremental effect of the electronic implementation over the distribution of paper versions of the guideline was found, neither for the patient outcomes nor for the process outcomes (comparison two).</p> <p>Conclusions</p> <p>There is little evidence at the moment for the effectiveness of an increasingly used and commercialised instrument such as electronic multidimensional guidelines. After more than a decade of development of numerous electronic systems, research on the most effective implementation strategy for this kind of guideline-based decision support systems is still lacking. This conclusion implies a considerable risk towards inappropriate investments in ineffective implementation interventions and in suboptimal care.</p

A prospective study of the importance of enteric fever as a cause of non-malarial febrile illness in patients admitted to Chittagong Medical College Hospital, Bangladesh

BACKGROUND: Fever is a common cause of hospital admission in Bangladesh but causative agents, other than malaria, are not routinely investigated. Enteric fever is thought to be common. METHODS: Adults and children admitted to Chittagong Medical College Hospital with a temperature of ≥38.0 °C were investigated using a blood smear for malaria, a blood culture, real-time PCR to detect Salmonella Typhi, S. Paratyphi A and other pathogens in blood and CSF and an NS1 antigen dengue ELISA. RESULTS: We enrolled 300 febrile patients with a negative malaria smear between January and June 2012: 156 children (aged ≤15 years) and 144 adults with a median (interquartile range) age of 13 (5-31) years and median (IQR) illness duration before admission of five (2-8) days. Clinical enteric fever was diagnosed in 52 patients (17.3 %), lower respiratory tract infection in 48 (16.0 %), non-specific febrile illness in 48 (16.0 %), a CNS infection in 37 patients (12.3 %), urinary sepsis in 23 patients (7.7 %), an upper respiratory tract infection in 21 patients (7.0 %), and diarrhea or dysentery in 21 patients (7.0 %). Malaria was still suspected in seven patients despite a negative microscopy test. S. Typhi was detected in blood by culture or PCR in 34 (11.3 %) of patients. Of note Rickettsia typhi and Orientia tsutsugamushi were detected by PCR in two and one patient respectively. Twenty-nine (9 %) patients died during their hospital admission (15/160 (9.4 %) of children and 14/144 (9.7 %) adults). Two of 52 (3.8 %) patients with enteric fever, 5/48 (10.4 %) patients with lower respiratory tract infections, and 12/37 (32.4 %) patients with CNS infection died. CONCLUSION: Enteric fever was confirmed in 11.3 % of patients admitted to this hospital in Bangladesh with non-malaria fever. Lower respiratory tract and CNS infections were also common. CNS infections in this location merit more detailed study due to the high mortality

Variation of Maximum Tree Height and Annual Shoot Growth of Smith Fir at Various Elevations in the Sygera Mountains, Southeastern Tibetan Plateau

Little is known about tree height and height growth (as annual shoot elongation of the apical part of vertical stems) of coniferous trees growing at various altitudes on the Tibetan Plateau, which provides a high-elevation natural platform for assessing tree growth performance in relation to future climate change. We here investigated the variation of maximum tree height and annual height increment of Smith fir (Abies georgei var. smithii) in seven forest plots (30 m×40 m) along two altitudinal transects between 3,800 m and 4,200/4,390 m above sea level (a.s.l.) in the Sygera Mountains, southeastern Tibetan Plateau. Four plots were located on north-facing slopes and three plots on southeast-facing slopes. At each site, annual shoot growth was obtained by measuring the distance between successive terminal bud scars along the main stem of 25 trees that were between 2 and 4 m high. Maximum/mean tree height and mean annual height increment of Smith fir decreased with increasing altitude up to the tree line, indicative of a stress gradient (the dominant temperature gradient) along the altitudinal transect. Above-average mean minimum summer (particularly July) temperatures affected height increment positively, whereas precipitation had no significant effect on shoot growth. The time series of annual height increments of Smith fir can be used for the reconstruction of past climate on the southeastern Tibetan Plateau. In addition, it can be expected that the rising summer temperatures observed in the recent past and anticipated for the future will enhance Smith fir's growth throughout its altitudinal distribution range