Hazard ratios are ubiquitously used in time to event analysis to quantify treatment effects. Although hazard ratios are invaluable for hypothesis testing, other measures of association, both relative ...and absolute, may be used to fully elucidate study results. Restricted mean survival time (RMST) differences between groups have been advocated as useful measures of association. Recent work focused on model-free estimates of the difference in restricted mean survival through follow-up times, instead of focusing on a single time horizon. The resulting curve can be used to quantify the association in time units with a simultaneous confidence band. In this work a model-based estimate of the curve is proposed using pseudo-values allowing for possible covariate adjustment. The method is easily implementable with available software and makes possible to compute a simultaneous confidence region for the curve. The pseudo-values regression using multiple restriction times is in good agreement with the estimates obtained by standard direct regression models fixing a single restriction time. Moreover, the proposed method is flexible enough to reproduce the results of the non-parametric approach when no covariates are considered. Examples where it is important to adjust for baseline covariates will be used to illustrate the different methods together with some simulations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Autologous microfragmented lipoaspirate tissue has been recently introduced in orthopaedics as an easily available source of nonexpanded adipose-derived mesenchymal stem cells. Autologous ...microfragmented lipoaspirate tissue is expected to create a suitable microenvironment for tendon repair and regeneration. Rotator cuff tears show a high incidence of rerupture and represent an ideal target for nonexpanded mesenchymal stem cells.
Purpose:
To evaluate the safety and efficacy of autologous lipoaspirate tissue in arthroscopic rotator cuff repair.
Study Design:
Randomized controlled trial; Level of evidence, 2.
Methods:
Consecutive patients referring to the investigation center for surgical treatment of magnetic resonance imaging–confirmed degenerative posterosuperior rotator cuff tears were assessed for eligibility. Those who were included were randomized to receive a single-row arthroscopic rotator cuff repair, followed by intraoperative injection of autologous microfragmented adipose tissue processed with an enzyme-free technology (treatment group) or not (control group). Clinical follow-up was conducted at 3, 6, 12, 18, and 24 months; at 18 months after surgery, magnetic resonance imaging of the operated shoulder was obtained to assess tendon integrity and rerupture rate.
Results:
An overall 177 patients were screened, and 44 (22 per group) completed the 24-month follow-up. A statistically significant difference in favor of the treatment group in terms of Constant-Murley score emerged at the primary endpoint at 6-month follow-up (mean ± SD; control group, 76.66 ± 10.77 points; treatment group, 82.78 ± 7.00 points; P = .0050). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of rerupture rate, complication rate, and number of adverse events.
Conclusion:
This prospective randomized controlled trial demonstrated that the intraoperative injection of autologous microfragmented adipose tissue is safe and effective in improving short-term clinical and functional results after single-row arthroscopic rotator cuff repair.
Registration:
NCT02783352 (ClinicalTrials.gov identifier).
To determine whether a goal-directed perfusion (GDP) strategy aimed at maintaining oxygen delivery (DO2) at ≥280 mL·min−1·m−2 reduces the incidence of acute kidney injury (AKI).
This multicenter ...randomized trial enrolled a total of 350 patients undergoing cardiac surgery in 9 institutions. Patients were randomized to receive either GDP or conventional perfusion. A total of 326 patients completed the study and were analyzed. Patients in the treatment arm were treated with a GDP strategy during cardiopulmonary bypass (CPB) aimed to maintain DO2 at ≥280 mL·min−1·m−2. The perfusion strategy for patients in the control arm was factored on body surface area and temperature. The primary endpoint was the rate of AKI. Secondary endpoints were intensive care unit length of stay, major morbidity, red blood cell transfusions, and operative mortality.
Acute Kidney Injury Network (AKIN) stage 1 was reduced in patients treated with GDP (relative risk RR, 0.45; 95% confidence interval CI, 0.25-0.83; P = .01). AKIN stage 2-3 did not differ between the 2 study arms (RR, 1.66; 95% CI, 0.46-6.0; P = .528). There were no significant differences in secondary outcomes. In a prespecified analysis of patients with a CPB time between 1 and 3 hours, the differences in favor of the treatment arm were more pronounced, with an RR for AKI of 0.49 (95% CI, 0.27-0.89; P = .017).
A GDP strategy is effective in reducing AKIN stage 1 AKI. Further studies are needed to define perfusion interventions that may reduce more severe levels of renal injury (AKIN stage 2 or 3).
Aim: Cholesterol is an essential component of cell membranes and serves as a precursor for several bioactive molecules, including steroid hormones and isoprenoids. Generally supplied by the ...bloodstream, the de novo cholesterol biosynthesis is activated in response to an increased cell requirement due to normal tissue remodeling or tumor proliferation. In estrogen receptor (ER)-positive breast cancers, cholesterol biosynthesis may promote and sustain tumor growth and concur with the failure of the treatment with aromatase inhibitors. Methods: In this study, the comparison of gene compared the expression involved in cholesterol biosynthesis was conducted in ER-positive tumors that were responsive and nonresponsive to letrozole; besides, an exploration of their association with genes implicated in estrogen production, the Hippo pathway, and cell cycle control was performed. Results: In responsive tumors, letrozole significantly decreased the expression of five genes acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), farnesyl diphosphate synthase (FDPS), and squalene epoxidase (SQLE) crucial for the biosynthetic process. Conversely, in nonresponsive tumors, these genes were unaffected by letrozole but associated with several genes involved in estrogens production cytochrome P450 family 19 subfamily A member 1 (CYP19A1), hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2), and sulfotransferase family 1A member 1 (SULT1A1), cell cycle control cyclin dependent kinase 4 (CDK4) and CDK6, and Hippo pathway Yes1 associated transcriptional regulator (YAP1) and baculoviral inhibitor of apoptosis (IAP) repeat containing 5 (BIRC5). Conclusions: The findings corroborated the notion that the dysregulation of the mevalonate pathway may contribute to the resistance to letrozole and supported the use of statins to contrast this metabolic dysfunction.
BACKGROUND—The purpose of this study was to provide an updated worldwide report on the methods, efficacy, and safety of catheter ablation of atrial fibrillation (AF).
METHODS AND RESULTS—A ...questionnaire with 46 questions was sent to 521 centers from 24 countries in 4 continents. Complete interviews were collected from 182 centers, of which 85 reported to have performed 20 825 catheter ablation procedures on 16 309 patients with AF between 2003 and 2006. The median number of procedures per center was 245 (range, 2 to 2715). All centers included paroxysmal AF, 85.9% also included persistent and 47.1% also included long-lasting AF. Carto-guided left atrial circumferential ablation (48.2% of patients) and Lasso-guided ostial electric disconnection (27.4%) were the most commonly used techniques. Efficacy data were analyzed with centers representing the unit of analysis. Of 16 309 patients with full disclosure of outcome data, 10 488 (median, 70.0%; interquartile range, 57.7% to 75.4%) became asymptomatic without antiarrhythmic drugs and another 2047 (10.0%; 0.5% to 17.1%) became asymptomatic in the presence of previously ineffective antiarrhythmic drugs over 18 (range, 3 to 24) months of follow-up. Success rates free of antiarrhythmic drugs and overall success rates were significantly larger in 9590 patients with paroxysmal AF (74.9% and 83.2%) than in 2800 patients with persistent AF (64.8% and 75.0%) and 1108 patients with long-lasting AF (63.1% and 72.3%) (P<0.0001). Major complications were reported in 741 patients (4.5%).
CONCLUSIONS—When analyzed in a large number of electrophysiology laboratories worldwide, catheter ablation of AF shows to be effective in ≈80% of patients after 1.3 procedures per patient, with ≈70% of them not requiring further antiarrhythmic drugs during intermediate follow-up.
Surgery for low-grade gliomas (LGGs) aims to achieve maximal tumor removal and maintenance of patients' functional integrity. Because extent of resection is one of the factors affecting the natural ...history of LGGs, surgery could be extended further than total resection toward a supratotal resection, beyond tumor borders detectable on FLAIR imaging. Supratotal resection is highly debated, mainly due to a lack of evidence of its feasibility and safety. The authors explored the intraoperative feasibility of supratotal resection and its short- and long-term impact on functional integrity in a large cohort of patients. The role of some putative factors in the achievement of supratotal resection was also studied.
Four hundred forty-nine patients with a presumptive radiological diagnosis of LGG consecutively admitted to the neurosurgical oncology service at the University of Milan over a 5-year period were enrolled. In all patients, a policy was adopted to perform surgery according to functional boundaries, aimed at achieving a supratotal resection whenever possible, without any patient or tumor a priori selection. Feasibility, general safety, and tumor or patient putative factors possibly affecting the achievement of a supratotal resection were analyzed. Postsurgical patient functional performance was evaluated in five cognitive domains (memory, language, praxis, executive functions, and fluid intelligence) using a detailed neuropsychological evaluation and quality of life (QOL) examination.
Total resection was feasible in 40.8% of patients, and supratotal resection in 32.3%. The achievement of a supratotal versus total resection was independent of age, sex, education, tumor volume, deep extension, location, handedness, appearance of tumor border, vicinity to eloquent sites, surgical mapping time, or surgical tools applied. Supratotal resection was associated with a long clinical history and histological grade II, suggesting that reshaping of brain networks occurred. Although a consistent amount of apparently MRI-normal brain was removed with this approach, the procedure was safe and did not carry additional risk to the patient, as demonstrated by detailed neuropsychological evaluation and QOL examination. This approach also improved seizure control.
Supratotal resection is feasible and safe in routine clinical practice. These results show that a long clinical history may be the main factor associated with its achievement.
Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of ...the optimal first-line TKI for newly diagnosed Philadelphia chromosome–positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk RR, 4.28; 95% confidence interval CI, 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.
Background:
Arthroscopic techniques are now considered the gold standard for treatment of most rotator cuff (RC) tears; however, no consensus exists on the maintenance of results over time, and ...long-term follow-up data have been reported for few cohorts of patients.
Purpose:
To present the long-term results associated with the arthroscopic treatment of RC tears and to evaluate associations between preoperative factors and RC integrity at final follow-up.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
A total of 169 patients were contacted at least 10 years after arthroscopic RC surgery and were invited to a clinical evaluation. Information on preoperative conditions, tear size, subjective satisfaction, and functional scores was collected; isometric strength and range of motion were also measured; and each patient underwent an ultrasound examination to evaluate supraspinatus integrity and a shoulder radiograph to evaluate osteoarthritis.
Results:
A total of 149 patients (88.2% of the eligible patients) were available for a complete telephonic interview, and 102 patients were available for the final evaluation. Ultrasound revealed an intact supraspinatus in 54 patients (53.47%). By adding the 10 patients who underwent revision surgery to the nonintact group, this percentage would drop to 48.65%. Tear size was associated with supraspinatus integrity in univariate analysis (hazard ratio, 3.04; 95% CI, 1.63-5.69; P = .001) and multivariable analysis (hazard ratio, 2.18; 95% CI, 1.03-4.62; P = .04). However, no significant differences were encountered in the subjective and functional scores collected, with the exception of the Constant-Murley Score, which was significantly higher in patients with smaller tears at the index procedure. Strength testing also revealed significantly superior abduction and flexion strength in this group, and radiographs showed a significantly higher acromion-humeral distance and lower grades of osteoarthritis. Patients with an intact supraspinatus at final follow-up showed superior results in all functional scores, greater satisfaction, superior abduction and flexion strength, higher acromion-humeral distance, and lower grades of osteoarthritis.
Conclusion:
RC tear size at the time of surgery significantly affects supraspinatus integrity at a minimum follow-up of 10 years. However, a larger tear is not associated with an inferior subjective result, although it negatively influences abduction and flexion strength, range of motion, and osteoarthritis progression. Intraoperative efforts to obtain a durable RC repair are encouraged, since supraspinatus integrity at final follow-up influences clinical and functional outcomes, patient satisfaction, and osteoarthritis progression.
We investigate to which extent the SUSY search results published by ATLAS and CMS in the context of simplified models actually cover the more realistic scenarios of a full model. Concretely, we work ...within the phenomenological MSSM (pMSSM) with 19 free parameters and compare the constraints obtained from
SModelS
v1.1.1 with those from the ATLAS pMSSM study in
arXiv:1508.06608
. We find that about 40–45% of the points excluded by ATLAS escape the currently available simplified model constraints. For these points we identify the most relevant topologies which are not tested by the current simplified model results. In particular, we find that topologies with asymmetric branches, including 3-jet signatures from gluino–squark associated production, could be important for improving the current constraining power of simplified models results. Furthermore, for a better coverage of light stops and sbottoms, constraints for decays via heavier neutralinos and charginos, which subsequently decay visibly to the lightest neutralino are also needed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Trop-2 is a calcium signal transducer that drives tumor growth. Anti-Trop-2 antibodies with selective reactivity versus Trop-2 maturation stages allowed to identify two different pools of Trop-2, one ...localized in the cell membrane and one in the cytoplasm. Of note, membrane-localized/functional Trop-2 was found to be differentially associated with determinants of tumor aggressiveness and distinct breast cancer subgroups. These findings candidated Trop-2 states to having an impact on cancer progression. We tested this model in breast cancer. A large, consecutive human breast cancer case series (702 cases; 8 years median follow-up) was analyzed by immunohistochemistry with anti-Trop-2 antibodies with selective reactivity for cytoplasmic-retained versus functional, membrane-associated Trop-2. We show that membrane localization of Trop-2 is an unfavorable prognostic factor for overall survival (1+ versus 0 for all deaths: hazard ratio, 1.63; P = 0.04), whereas intracellular Trop-2 has a favorable impact on prognosis, with an adjusted hazard ratio for all deaths of 0.48 (high versus low; P = 0.003). A corresponding impact of intracellular Trop-2 was found on disease relapse (high versus low: hazard ratio, 0.51; P = 0.004). Altogether, we demonstrate that the Trop-2 activation states are critical determinants of tumor progression and are powerful indicators of breast cancer patients survival.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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