Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed ...to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis.
This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s FEV1 ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205.
Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% 95% CI -0.8 to 6.3; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 95% CI 0.57-1.05; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% -4.0 to 2.1 vs -6.4% -9.8 to -3.7; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events 0.9-1.9 vs 2.18 events 1.6-2.7; rate ratio 0.60 0.42-0.86; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group.
Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin.
PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.
Background Long-term results and complication rates in shoulder arthroplasty are related to implant positioning. Current literature reports increased precision in glenoid component positioning using ...3-dimensional (3D) computed tomography (CT) planning tools. This study evaluated the accuracy of glenoid version and inclination measurements using 2D CT scans compared with a validated 3D software program and its influence on decision making on implant selection. Methods Preoperative CT scans were obtained from 50 patients undergoing total shoulder arthroplasty. Glenoid version and inclination measurements were performed in random order by 3 independent qualified orthopedic surgeons on reformatted 2D CT scans. Indication for anatomic or reverse shoulder arthroplasty was based on glenoid deformity and on rotator cuff conditions. Results were compared with those from a validated 3D computer software program, and the final decision was made according to the 3D planning. Results Mean preoperative glenoid retroversion on reformatted 2D CT scans was 11.9° ± 9.6° and mean superior inclination was 10.7° ± 8.6°. When the 3D software was used, glenoid retroversion averaged 15.1° ± 10.6° and superior inclination averaged 8.9° ± 9.9°. The 2D CT demonstrated good interobserver and intraobserver reliability for glenoid version and inclination. Decision on the choice of implant was adjusted in 7 patients after the 3D planning. Conclusions: Our findings show that measurements of glenoid version and inclination on reformatted 2D CT scans are less accurate compared with 3D measurements. A preoperative 3D planning software allows for improvement of virtual glenoid positioning and influences the decision making process.
While macroreentrant atrial tachycardias (ATs) have been reasonably well described, little is known about small reentrant circuits.
To compare characteristics of large and small reentrant circuits ...after ablation of persistent atrial fibrillation.
Seventy-seven patients (age 61±10 years; left atrium 46±6 mm; ejection fraction 0.52±0.13) underwent a procedure for postablation AT. The p-wave duration, circuit size, electrogram characteristics, and conduction velocity were determined.
AT was due to macroreentry in 62 (80%) patients, a small reentrant circuit in 13 (17%), and a focal mechanism in 2 (3%). The p-wave duration during small reentrant ATs was shorter than that during macroreentry (174±12 ms vs 226±22 ms; P<.0001). The duration of fractionated electrograms at the critical site was longer in small vs large circuits (167±43 ms vs 98±38 ms, respectively; P<.0001) and accounted for a greater percentage of the tachycardia cycle length (59%±18% vs 38%±14%, respectively; P<.0001). The mean diameters of macroreentrant and small reentrant circuits were 44±7 and 26±11 mm, respectively (P<.0001). The mean conduction velocity along the small circuits was lower (0.5±0.2 m/s vs 1.2±0.3 m/s; P<.0001). Catheter ablation eliminated the AT in all 77 patients.
AT due to a small reentrant circuit after ablation of atrial fibrillation may be distinguished from macroreentry by a shorter p-wave duration and the presence of long-duration electrograms at the critical site owing to extremely slow conduction. These features may aid the clinician in the mapping of postablation ATs.
During the course of cancer treatment, patients whose disease progresses despite therapy are offered alternative options. Similarly, patients with hepatocellular carcinoma (HCC) whose disease ...progresses following arterial locoregional therapies (LRTs) cross over to undergo systemic therapies or participate in clinical trials. Per current guidelines, patients must meet inclusion criteria (most importantly Child-Pugh class A status) to qualify for systemic options. The present study analyzed the candidacy for systemic agents or clinical trials of patients whose disease progresses despite LRTs.
A total of 245 patients with HCC were treated with LRTs (chemoembolization, n = 123; yttrium-90 (90)Y radioembolization, n = 122) as part of a previously published comparative effectiveness study; 96 patients exhibiting disease progression were followed prospectively. Modes of progression (cancer stage, Child-Pugh class) were analyzed to determine candidacy for systemic therapy or clinical trials, as well as assess ultimate treatment(s) received.
Among the 96 patients with disease progression, 52% and 48% had Child-Pugh class A and class B/C disease, respectively, thereby substantially limiting the latter group's eligibility for systemic therapy and/or clinical trials. Of those whose disease progressed who had advanced-stage HCC, 63% had Child-Pugh class B/C disease. By size and necrosis criteria, the local disease progression rate was higher with chemoembolization than with (90)Y radioembolization (P = .006 and P = .016, respectively). Of the 96 patients with disease progression, only 13 (13%) ultimately received systemic agents or entered clinical trials.
Most patients with advanced HCC that progresses following LRTs were not candidates for clinical trials or systemic agents. There is a need for future research efforts directed at treatment options or novel trial designs that will permit inclusion of patients with progressive liver disease and suboptimal liver function.
Background The anticoagulant treatment of acute deep venous thrombosis (DVT) has been historically directed toward the prevention of recurrent venous thromboembolism. However, such treatment ...imperfectly protects against late manifestations of the postthrombotic syndrome. By restoring venous patency and preserving valvular function, early thrombus removal strategies can potentially decrease postthrombotic morbidity. Objective A committee of experts in venous disease was charged by the Society for Vascular Surgery and the American Venous Forum to develop evidence-based practice guidelines for early thrombus removal strategies, including catheter-directed pharmacologic thrombolysis, pharmacomechanical thrombolysis, and surgical thrombectomy. Methods Evidence-based recommendations are based on a systematic review and meta-analysis of the relevant literature, supplemented when necessary by less rigorous data. Recommendations are made according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, incorporating the strength of the recommendation (strong: 1; weak: 2) and an evaluation of the level of the evidence (A to C). Results On the basis of the best evidence currently available, we recommend against routine use of the term “proximal venous thrombosis” in favor of more precise characterization of thrombi as involving the iliofemoral or femoropopliteal venous segments (Grade 1A). We further suggest the use of early thrombus removal strategies in ambulatory patients with good functional capacity and a first episode of iliofemoral DVT of <14 days in duration (Grade 2C) and strongly recommend their use in patients with limb-threatening ischemia due to iliofemoral venous outflow obstruction (Grade 1A). We suggest pharmacomechanical strategies over catheter-directed pharmacologic thrombolysis alone if resources are available and that surgical thrombectomy be considered if thrombolytic therapy is contraindicated (Grade 2C). Conclusions Most data regarding early thrombus removal strategies are of low quality but do suggest patient-important benefits with respect to reducing postthrombotic morbidity. We anticipate revision of these guidelines as additional evidence becomes available.
Study objective The Universal Termination of Resuscitation Rule (TOR Rule) was developed to identify out-of-hospital cardiac arrests eligible for field termination of resuscitation, avoiding futile ...transportation to the hospital. The validity of the rule in emergency medical services (EMS) systems that do not routinely transport out-of-hospital cardiac arrest patients to the hospital is unknown. We seek to validate the TOR Rule in British Columbia. Methods This study included consecutive, nontraumatic, adult, out-of-hospital cardiac arrests treated by EMS in British Columbia from April 2011 to September 2015. We excluded patients with active do-not-resuscitate orders and those with missing data. Following consensus guidelines, we examined the validity of the TOR Rule after 6 minutes of resuscitation (to approximate three 2-minute cycles of resuscitation). To ascertain rule performance at the different time junctures, we recalculated TOR Rule classification accuracy at subsequent 1-minute resuscitation increments. Results Of 6,994 consecutive, adult, EMS-treated, out-of-hospital cardiac arrests, overall survival was 15%. At 6 minutes of resuscitation, rule performance was sensitivity 0.72, specificity 0.91, positive predictive value 0.98, and negative predictive value 0.36. The TOR Rule recommended care termination for 4,367 patients (62%); of these, 92 survived to hospital discharge (false-positive rate 2.1%; 95% confidence interval 1.7% to 2.5%); however, this proportion steadily decreased with later application. The TOR Rule recommended continuation of resuscitation in 2,627 patients (38%); of these, 1,674 died (false-negative rate 64%; 95% confidence interval 62% to 66%). Compared with 6-minute application, test characteristics at 30 minutes demonstrated nearly perfect positive predictive value (1.0) and specificity (1.0) but a lower sensitivity (0.46) and negative predictive value (0.25). Conclusion In this cohort of adult out-of-hospital cardiac arrest patients, the TOR Rule applied at 6 minutes falsely recommended care termination for 2.1% of patients; however, this decreased with later application. Systems using the TOR Rule to cease resuscitation in the field should consider rule application at points later than 6 minutes.
Background Peripheral arterial disease (PAD) is one of the most underestimated diseases because of its high prevalence and unfavorable prognosis. Many PAD patients without suitable autologous veins ...or options for endovascular treatment receive prosthetic above-knee femoropopliteal bypass (PAKB). Until now predictors of prosthetic bypass failure and of increased amputation risk remain indistinct. This study aimed to identify predictive factors associated with better bypass patency and limb salvage to achieve a more favorable outcome after PAKB reconstruction. Methods Pre-, intra-, and postoperative data of 244 PAKB procedures performed at a German university medical center were collected and analyzed using univariate and multivariate methods. To our knowledge this 12-year experience is the largest retrospective study to identify predictors for patency and limb salvage after PAKB reconstruction. Results Of the PAD patients 94% (229/244) were followed for an average of 34.9 months. Patient cohorts characteristics were: mean age, 66.1 years, 181 men (74%), claudication (64%), rest pain (16%), ischemic lesions (20%), arterial hypertension (92%), smoking (79%), hyperlipidemia (65%) and type 2 diabetes (43%). Cumulative primary 1- and 3-year graft patency rates were 60.8% and 50.7%, respectively, and cumulative 1- and 3-year limb salvage rates were 89.3% and 86.1%, respectively. One hundred seven bypasses (43.9%) failed, 26 patients (10.7%) required a major and seven patients (2.9%) required a minor amputation. Overall survival rates of PAD patients after 1- and 3-years were 94.4% and 82.9%, respectively. Subjective symptom improvement was found to be the most important prognostic follow-up factor for graft patency and limb salvage. Patients with recurrent symptoms in the follow-up had an increased risk of emerging bypass failure compared with patients with subjective symptom improvement (patency at 1 year: 40.8% vs 100% and at 3 years: 26% vs 100%; P < .001). No patient with subjective improvement in symptoms during follow-up underwent an amputation (limb salvage at 1 year: 100% vs 79% and at 3 years: 100% vs 72.8%; P < .001). Therefore, subjective symptom improvement should be the decisive criterion to determine follow-up intervals of PAD patients. In univariate analysis further significant factors associated with better graft patency and limb salvage rates were: claudication compared with critical ischemia, larger graft diameter (>6 mm), pre- and postoperative antiplatelet therapy, statin therapy independent from lipid values after PAKB revascularization, and an experienced vascular surgeon. Conclusions In our study, we determined the subjective improvement in symptoms as the most important prognostic factor for bypass function and limb salvage after PAKB. Furthermore, disease stage of critical ischemia, graft diameter, preoperative aspirin use, and postoperative statin medication were independent predictive factors. Therefore, PAD patients should be treated with aspirin pre- and postoperatively as well as with a statin postoperatively. In case of PAKB reconstruction only prostheses with a large diameter ( > 6 mm) should be used and the procedure should be performed by an experienced surgeon. Considering these results with regard to the predictive factors for better graft patency and limb salvage rates a significant more favorable outcome during the follow-up and an increased 5-year patency rate for PAKB reconstructions can be expected.
Background The GI Mentor is a virtual reality simulator that uses force feedback technology to create a realistic training experience. Objective To define the benefit of training on the GI Mentor on ...competency acquisition in colonoscopy. Design Randomized, controlled, blinded, multicenter trial. Setting Academic medical centers with accredited gastroenterology training programs. Subjects First-year GI fellows. Interventions Subjects were randomized to receive 10 hours of unsupervised training on the GI Mentor or no simulator experience during the first 8 weeks of fellowship. After this period, both groups began performing real colonoscopies. The first 200 colonoscopies performed by each fellow were graded by proctors to measure technical and cognitive success, and patient comfort level during the procedure. Main Outcome Measurements A mixed-effects model comparison between the 2 groups of objective and subjective competency scores and patient discomfort in the performance of real colonoscopies over time. Results Forty-five fellows were randomized from 16 hospitals over 2 years. Fellows in the simulator group had significantly higher objective competency rates during the first 100 cases. A mixed-effects model demonstrated a higher objective competence overall in the simulator group ( P < .0001), with the difference between groups being significantly greater during the first 80 cases performed. The median number of cases needed to reach 90% competency was 160 in both groups. The patient comfort level was similar. Conclusions Fellows who underwent GI Mentor training performed significantly better during the early phase of real colonoscopy training.
Abstract Background Context Adult spinal deformity (ASD) patients may gain minimal clinically important difference (MCID) in one or more of the health-related quality-of-life instruments without ...surgical intervention. The present study identifies the baseline characteristics of this subset of nonoperative patients and proposes predictors of those most likely to benefit. Purpose The study aims to determine the factors that affect likelihood of nonoperative patients to reach MCID. Study Design/Setting This is a retrospective review of a prospective, multicenter database. Patient Sample The study includes nonoperative ASD patients. Outcome Measures Health-related quality-of-life measures, including the Scoliosis Research Society (SRS)-22 questionnaire, were used. Methods The study used a multicenter database of 215 nonoperative patients with ASD and with minimum 2-year follow-up. Using a multivariate analysis, two groups were compared to identify possible predictors: those who reached MCID in the SRS pain or activity (N=86) at 2 years and those who did not reach MCID (N=129). A subgroup multivariate analysis of patients with a deficit (potential improvement) in both SRS pain and activity (N=84) was performed. Data collection was supported by a grant from DePuy for the International Spine Study Group Foundation. Results At baseline, the nonoperative patients who reached MCID had a significantly lower SRS pain score (3.0 vs. 3.6), smaller thoracolumbar Cobb (TL Cobb) angle (29.6° vs. 36.5°; 87 patients with SRS-Schwab classification of lumbar or double), lower sacral slope (33.1° vs. 36.4°), and less lumbar lordosis (46.5° vs. 52.8°) (all p<.05). The SRS pain and TL Cobb were significant predictors for reaching MCID. The pelvic incidence minus lumbar lordosis (PI−LL) was significant on univariate analysis but not on multivariate analysis (7.5° vs. 2.6°; p=.14). In the subset of severely disabled patients, worse vertebral obliquity was a predictor for not achieving MCID (p<.05). Conclusions Nonoperative ASD patients who achieved MCID in SRS activity or pain had a lower baseline SRS pain score and less coronal deformity in the TL region. Greater baseline pain offers significant room for potential improvement, which may be important in identifying ASD patients who have the potential to reach MCID nonoperatively. Coronal deformities in the TL region and associated vertebral obliquity may negatively impact potential for improvement in nonoperative care.
Background The use of stent grafts and mortality of stent graft repair of type B thoracic aortic dissection (TB AD) is not well defined. We sought to determine national estimates for the use and ...mortality of thoracic endovascular aortic repair (TEVAR) for TB AD in the United States. Methods Records of the Nationwide Inpatient Sample (NIS) database between 2005 and 2007 were examined. International Classification of Diseases , 9th edition (ICD-9) diagnosis codes were used to select patients who underwent open or TEVAR with a stent graft for a diagnosis of thoracic aortic dissection or thoracoabdominal aortic dissection. We excluded patients with a diagnosis code for aortic aneurysm and those with procedure codes for cardioplegia or for operations on heart vessels or valves, which were considered type A dissections (TA AD). The remaining patients were considered as TB AD. We compared demographics and comorbidities, as well as adjusted complications and mortality rates, between patients undergoing TEVAR vs open repair. Results We identified an estimated 10,466 repairs for dissection of the thoracic or thoracoabdominal aorta (open, 8659; TEVAR, 1818). Of these, 464 had a diagnosis of aortic aneurysm, and 5002 patients were considered TA AD. Of nonaneurysmal dissections, 5000 repairs were considered TB AD (open, 3619; TEVAR, 1381). The endovascular patients were older and had greater comorbidities, although only cardiac disease, renal failure, hypertension, and peripheral vascular disease were statistically significant. In-hospital mortality was 19% for open repair vs 10.6% for TEVAR (odds ratio OR, 2.24; 95% confidence interval CI, 1.36-3.67; P < .01). In-hospital mortality was significantly higher with open repairs coded as emergent admissions (20.1% vs 13.1%; P = .03), but did not reach statistical significance for elective admissions (12.3% vs 4.8%; P = .09). Cardiac complications (12.4% vs 4.9%, P < .01), respiratory complications (7.7% vs 4.3%, P = .02), genitourinary complications (9.0% vs 2.5%, P < .01), hemorrhage (14.0% vs 2.8%, P < .01), and acute renal failure (32.1% vs 17.2%, P < .01) were more frequent in the open repair group. Median length of stay was greater in the open repair group (10.7 vs 8.3 days, P < .01). Conclusion For patients with a diagnosis of TB AD who undergo repair, the endovascular approach is being used for older patients with greater comorbidities, yet has reduced morbidity and in-hospital mortality. The use of endovascular stent graft repair for type B thoracic aortic dissection merits further longitudinal analysis.
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