Search

Background: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Materials and methods: Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m² weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m² via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m² weekly for 3 weeks in a 4-week cycle (GEM). Results: A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation. [ABSTRACT FROM AUTHOR]

An experimental investigation of an above-ferromagnetic resonant self-biased hexagonal ferrite circulator is detailed in this paper. The concept of the "region of opportunity" is invoked to establish a relationship between the ferrite's geometry and its M H large-signal data for self-biased operation. This concept is used to design a working three-port nonreciprocal device that will serve as a basis for experimentally ascertaining best case insertion losses (ILs), return losses (RLs), and/or isolations (ISs) for circulator applications. Furthermore, we show that this nonreciprocal device when externally tuned as a circulator exhibits RLs and ISs of better than 15 dB across a narrow band; the ILs are on the order of 1.5 dB within this same band. This IL is correlated to the best case IL. Results confirm the conclusion that a ferrite with = 4.0 kOe, 4 π Ms = 4.375 kG, and ΔH = 1.862 kOe is suitable for self-biased circulator applications. [ABSTRACT FROM AUTHOR]

Purpose Femoral lengthening using a circular or mono-lateral frame is a commonly used technique. Fracture at the site of the regenerate bone is a major concern especially following removal of the external fixator. This aim of this study was to assess the rate of fracture of the regenerate bone in this single surgeon series of paediatric patients and determine potential risk factors. Methods Retrospective review of all the femoral lengthening performed by the senior author was performed. The medical and physiotherapy notes were reviewed. The gender, age at time of surgery, disease aetiology, total days in the external fixator and length of the new regenerate bone were recorded. Patients who sustained a regenerate fracture were identified. Results A total of 176 femoral lengthening procedures were performed on 108 patients. Eight regenerate fractures occurred in seven patients (4.5%). The mechanism of injury was a fall in five cases and during physiotherapy in three cases. The regenerate fracture occurred a median number of nine days following removal of frame. There was no significant difference between gender, age at time of surgery, total time in external fixator between those who sustained a regenerate fracture and those patients who did not. A significant difference was noted between the amount of lengthening between the ‘regenerate fracture group’ and the ‘no fracture group’ (50 mm vs 38 mm, respectively; p = 0.029). There was no association between disease aetiology and risk of regenerate fracture. Conclusions Femoral lengthening of more than 50 mm increases the risk of a fracture at the regenerate site regardless of the disease aetiology. We recommend avoidance of aggressive physiotherapy for the initial four weeks following external fixator removal. [ABSTRACT FROM AUTHOR]

Objective: To evaluate brief communication skills training for healthcare professionals (HCPs) in offering antenatal sickle cell and thalassaemia (SCT) screening in primary care.Design: Descriptive study within a cluster randomised controlled trial in 17 inner city practices.Methods: 126 HCPs were invited to attend a training session. Outcome measures were: attendance; perceived usefulness of training; comfort and confidence in offering screening; offering screening at pregnancy confirmation consultations; gestational age at test uptake.Results: 62% (78/126) HCPs attended training and 61 completed both pre- and post-training questionnaires. There were 49 new joiners and locums not in post at the start of the trial. After training, HCPs reported greater comfort [4.8 vs 5.4, p = 0.05] and confidence [4.6 vs 5.6, p<0.001] in offering screening. Pregnant women consulting trained HCPs were offered screening more frequently and at an earlier gestational age than those consulting untrained HCPs (75% vs 44%, χ(2) = 122, p<0.001; 91.5 days (attending training) vs 98.5 days (did not attend training) vs 101.8 days (new joiners and locums), F = 8.49, df 1069,2 p = 0.001).Conclusion: Brief communication skills training for HCPs in offering antenatal SCT screening in primary care is feasible and can be effective.Practice Implications: Ways of maximising HCP attendance in training sessions requires consideration. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the demographic and clinical features, hospital complications, and predictors of 90-day mortality in neurologic patients with acute severe hypertension. DESIGN: Studying the Treatment of Acute hyperTension (STAT) was a multicenter (n=25) observational registry of adult critical care patients with severe hypertension treated with intravenous therapy. SETTING: Emergency department or intensive care unit. PATIENTS: A qualifying blood pressure measurement>180 mm Hg systolic or >110 mm Hg diastolic (>140/90 mm Hg for subarachnoid hemorrhage) was required for inclusion in the STAT registry. Patients with a primary neurologic admission diagnosis were included in the present analysis. INTERVENTIONS: All patients were treated with at least one parenteral (bolus or continuous infusion) antihypertensive agent. MEASUREMENTS AND MAIN RESULTS: Of 1,566 patients included in the STAT registry, 432 (28%) had a primary neurologic diagnosis. The most common diagnoses were subarachnoid hemorrhage (38%), intracerebral hemorrhage (31%), and acute ischemic stroke (18%). The most common initial drug was labetalol (48%), followed by nicardipine (15%), hydralazine (15%), and sodium nitroprusside (13%). Mortality at 90 days was substantially higher in neurologic than in non-neurologic patients (24% vs. 6%, p<.0001). Median initial blood pressure was 183/95 mm Hg and did not differ between survivors and nonsurvivors. In a multivariable analysis, neurologic patients who died experienced lower minimal blood pressure values (median 103/45 vs. 118/55 mm Hg, p<.0001) and were less likely to experience recurrent hypertension requiring intravenous treatment (29% vs. 51%, p=.0001) than those who survived. Mortality was also associated with an increased frequency of neurologic deterioration (32% vs. 10%, p<.0001). CONCLUSION: Neurologic emergencies account for approximately 30% of hospitalized patients with severe acute hypertension, and the majority of those who die. Mortality in hypertensive neurologic patients is associated with lower minimum blood pressure values, less rebound hypertension, and a higher frequency of neurologic deterioration. Excessive blood pressure reduction may contribute to poor outcome after severe brain injury. [ABSTRACT FROM AUTHOR]

PURPOSE: The present investigation examined single-fiber MHC alterations in response to high-intensity, short-duration, sprint cycle training. METHODS: Ten untrained college-age male subjects participated in 8 wk of a progressive sprint cycle training program. Training involved 15-s maximal sprints separated by 5 min of rest beginning with four sprints x 2 d in week 1 and increasing to six sprints x 3 d at week 8. Muscle samples from the vastus lateralis were obtained before and after training. A 30-s sprint cycle test was used to evaluate performance before and after training. RESULTS: For the 30-s sprint, mean power and total work increased from pre to post. Single-fiber analyses revealed a reduction in the MHC IIx isoform (2.0 +/- 1.0 to 0.2 +/- 0.1%, pre to post, P < 0.05) and an increase in MHC IIa (P = 0.08), whereas there was no change in hybrid fiber composition (total hybrids = 24%). Generally, MHC IIa content increased and MHC IIx decreased (P < 0.05) as demonstrated by homogenate analyses of tissue samples. CONCLUSIONS: We report that as little as 32 min of high-intensity sprint cycle training over 8 wk is sufficient to improve sprinting performance. This training response is accompanied by an increase in MHC IIa and reduction in MHC IIx content of the vastus lateralis. However, short-duration, high-intensity, sprint cycle training does not cause a reduction in hybrid muscle fiber content. [ABSTRACT FROM AUTHOR]

Context: A previous study suggested that the combination of a normal D-dimer assay and normal alveolar dead-space fraction is a highly sensitive screening test for pulmonary embolism (PE).Objective: To determine if the combination of a normal alveolar dead-space fraction (volume of alveolar dead space/tidal volume Design: Prospective, noninterventional study conducted in 1998-1999. Study data were obtained prior to standard testing for PE, consisting of radionuclide lung scanning or contrast-enhanced computed tomography and 6-month follow-up plus selective use of venous ultrasonography and pulmonary angiography. Imaging studies were interpreted by blinded observers.Setting: Six urban teaching hospitals in the United States.Patients: A total of 380 hemodynamically stable ED patients aged 18 years or older with suspected acute PE.Main Outcome Measures: Sensitivity and specificity for PE with a positive test defined as having either alveolar dead-space fraction or D-dimer assay results abnormal. Alveolar dead-space fraction was determined by subtracting airway dead space from physiological dead space (determined using the modified Bohr equation) and D-dimer assay, assayed at bedside using 20 microL of arterial blood.Results: Pulmonary embolism was diagnosed in 64 patients (16.8%), of those 20 had an abnormal D-dimer assay result, 3 had an abnormal alveolar dead-space fraction, 40 had abnormal results in both, and 1 had normal results for both tests. The sensitivity for diagnosis of PE was 98.4% (95% confidence interval [CI], 91.6%-100.0%). Among the 316 patients without PE, both D-dimer and dead-space results were normal in 163, for a specificity of 51.6% (95% CI, 46.1%-57.1%). Posterior probability of PE with normal results on both tests was 0.75% (95% CI, 0%-3.4%).Conclusion: In this multicenter study of ED patients, a normal D-dimer assay result plus a normal alveolar dead-space fraction was associated with a low prevalence of PE. [ABSTRACT FROM AUTHOR]