The incidence of all-cause, cardiovascular and respiratory disease admission among 20,252 users of lisinopril vs. perindopril: a cohort study

Background: Major international guidelines do not offer explicit recommendations on any specific angiotensin-converting enzyme inhibitor (ACEI) agent over another within the same drug group. This study compared the effectiveness of lisinopril vs. perindopril in reducing the incidence of hospital admission due to all-cause, cardiovascular disease and respiratory disease. Methods: Adult patients who received new prescriptions of lisinopril or perindopril from 2001 to 2005 in all public hospitals and clinics in Hong Kong were included, and followed up for ≥2 years. The incidence of admissions due to all-cause, cardiovascular disease and respiratory disease were evaluated, respectively, by using Cox proportional hazard regression models. The regression models were constructed with propensity score matching to minimize indication biases. Results: A total of 20,252 eligible patients with an average age of 64.5 years (standard deviation 15.0) were included. The admission rate at 24 months within the date of index prescription due to any cause, cardiovascular disease and respiratory disease among lisinopril vs. perindopril users was 24.8% vs. 24.8%, 13.7% vs. 14.0% and 6.9% vs. 6.3%, respectively. Lisinopril users were significantly more likely to be admitted due to respiratory diseases (adjusted hazard ratios [AHR] = 1.25, 95% CI 1.08 to 1.43, p = 0.002 at 12 months; AHR = 1.17, 95% CI 1.04 to 1.31, p = 0.009 at 24 months) and all causes (AHR = 1.12, 95% CI 1.05 to 1.19, p < 0.001 at 24 months) than perindopril users. Conclusions: These findings support intra-class differences in the effectiveness of ACEIs, which could be considered by clinical guidelines when the preferred first-line antihypertensive drugs are recommended

Updated Safety And Efficacy Data In The Phase 1 Trial Of Patients With Mantle Cell Lymphoma (Mcl) Treated With Bruton Tyrosine Kinase (Btk) Inhibitor Zanubrutinib (Bgb‐3111)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149513/1/hon55_2630.pd

Final analysis from RESONATE: Up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma

Ibrutinib, a once‐daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single‐agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high‐risk features. Here we report the final analysis from RESONATE with median follow‐up on study of 65.3 months (range, 0.3‐71.6) in the ibrutinib arm. Median progression‐free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113‐0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high‐risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080‐0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418‐0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all‐grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long‐term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high‐risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707)

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Measurement of the top pair production cross section in 8 TeV proton-proton collisions using kinematic information in the lepton plus jets final state with ATLAS

A measurement is presented of the $t\bar{t}$ inclusive production cross-section in $pp$ collisions at a center-of-mass energy of $\sqrt{s}=8$ TeV using data collected by the ATLAS detector at the CERN Large Hadron Collider. The measurement was performed in the lepton+jets final state using a data set corresponding to an integrated luminosity of 20.3 fb$^{-1}$. The cross-section was obtained using a likelihood discriminant fit and $b$-jet identification was used to improve the signal-to-background ratio. The inclusive $t\bar{t}$ production cross-section was measured to be $260\pm 1{\textrm{(stat.)}} ^{+22}_{-23} {\textrm{(syst.)}}\pm 8{\textrm{(lumi.)}}\pm 4{\mathrm{(beam)}}$ pb assuming a top-quark mass of 172.5 GeV, in good agreement with the theoretical prediction of $253^{+13}_{-15}$ pb. The $t\bar{t}\to (e,\mu)+{\mathrm{jets}}$ production cross-section in the fiducial region determined by the detector acceptance is also reported.Comment: Published version, 19 pages plus author list (35 pages total), 3 figures, 2 tables, all figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/TOPQ-2013-06

Chronic lymphocytic leukaemia Australasian consensus practice statement

Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in Australia and New Zealand (ANZ). Considerable changes to diagnostic and management algorithms have occurred within the last decade. The availability of next-generation sequencing and measurable residual disease assessment by flow cytometry allow for advanced prognostication and response assessments. Novel therapies, including inhibitors of Bruton's tyrosine kinase (BTKi) and B-cell lymphoma 2 (BCL2) inhibitors, have transformed the treatment landscape for both treatment-naïve and relapsed/refractory disease, particularly for patients with high-risk genetic aberrations. Recommendations regarding appropriate supportive management continue to evolve, and special considerations are required for patients with CLL with respect to the global SARS-CoV-2 pandemic. The unique funding and treatment environments in Australasia highlight the need for specific local guidance with respect to the investigation and management of CLL. This consensus practice statement was developed by a broadly representative group of ANZ experts in CLL with endorsement by peak haematology bodies, with a view to providing this standardised guidance

Combining Optimization and Randomization Approaches for the Design of Clinical Trials

t Intentional sampling methods are non-randomized procedures that select a group of individuals for a sample with the purpose of meeting specific prescribed criteria. In this paper we extend previous works related to intentional sampling, and address the problem of sequential allocation for clinical trials with few patients. Roughly speaking, patients are enrolled sequentially, according to the order in which they start the treatment at the clinic or hospital. The allocation problem consists in assigning each new patient to one, and only one, of the alternative treatment arms. The main requisite is that the profiles in the alternative arms remain similar with respect to some relevant patients’ attributes (age, gender, disease, symptom severity and others). We perform numerical experiments based on a real case study and discuss how to conveniently set up perturbation parameters, in order to yield a suitable balance between optimality – the similarity among the relative frequencies of patients in the several categories for both arms, and decoupling – the absence of a tendency to allocate each pair of patients consistently to the same arm

Test beam performance measurements for the Phase I upgrade of the CMS pixel detector

A new pixel detector for the CMS experiment was built in order to cope with the instantaneous luminosities anticipated for the Phase I Upgrade of the LHC. The new CMS pixel detector provides four-hit tracking with a reduced material budget as well as new cooling and powering schemes. A new front-end readout chip mitigates buffering and bandwidth limitations, and allows operation at low comparator thresholds. In this paper, comprehensive test beam studies are presented, which have been conducted to verify the design and to quantify the performance of the new detector assemblies in terms of tracking efficiency and spatial resolution. Under optimal conditions, the tracking efficiency is (99.95 ± 0.05) %, while the intrinsic spatial resolutions are (4.80 ± 0.25) μm and (7.99 ± 0.21) μm along the 100 μm and 150 μm pixel pitch, respectively. The findings are compared to a detailed Monte Carlo simulation of the pixel detector and good agreement is found.Peer reviewe

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction