Wright argues convincingly that professionalization inadvertently led to a popular inverse: the amateur historian, whose work is often more widely received and appreciated by the general public.
Donald Creighton Wright, Donald A
Donald Creighton,
2015, 20150908, 2015, 2015-09-08, 2015-09-15
eBook
Through his virtuoso research into Creighton's own voluminous papers,Donald Creightoncaptures the twentieth-century transformation of English Canada through the life and times of one of its leading ...intellectuals.
Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from ...chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer.
In this randomised, open-label, multicentre, phase 2 study, adult patients (aged ≥18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m2 and intravenous carboplatin (area under the concentration-time curve 2 μg × h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m2 on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual.
Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8·4 months (IQR 3·8–13·6) for group 1, 12·7 months (5·5–17·4) for group 2, and 12·9 months (6·7–16·8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0·8 day (SD 2·4) in group 1, 1·5 days (3·5) in group 2, and 1·0 day (2·6) in group 3 (group 3 vs group 1 one-sided adjusted p=0·70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0·70). Overall survival was 12·6 months (IQR 5·8–15·6) in group 1, 20·1 months (9·4–not reached) in group 2, and 17·8 months (8·8–not reached) in group 3 (group 3 vs group 1 two-sided p=0·0023). The most common treatment-emergent adverse events were anaemia (22 73% of 34), neutropenia (21 70%), and thrombocytopenia (18 60%) in group 1; neutropenia (27 82% of 33), thrombocytopenia (18 55%) and anaemia (17 52%) in group 2; and neutropenia (23 66% of 35), thrombocytopenia (22 63%), and nausea (17 49%) in group 3. There were no treatment-related deaths.
No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted.
G1 Therapeutics.
Abstract
Perceptual learning is an enhancement in discriminability of similar stimuli following experience with those stimuli. Here, we examined the efficacy of adding additional active training ...following a standard training session, compared with additional stimulus exposure in the absence of associated task performance. Mice were trained daily in an odor-discrimination task, and then, several hours later each day, received 1 of 3 different manipulations: 1) a second active-training session, 2) non-task-related odor exposure in the home cage, or 3) no second session. For home-cage exposure, odorants were presented in small tubes that mice could sniff and investigate for a similar period of time as in the active discrimination task each day. The results demonstrate that daily home-cage exposure was equivalent to active odor training in supporting improved odor discrimination. Daily home-cage exposure to odorants that did not match those used in the active task did not improve learning, yielding outcomes similar to those obtained with no second session. Piriform cortical local field potential recordings revealed that both sampling in the active learning task and investigation in the home cage evoked similar beta band oscillatory activity. Together the results suggest that odor-discrimination learning can be significantly enhanced by addition of odor exposure outside of the active training task, potentially because of the robust activity evoked in the olfactory system by both exposure paradigms. They further suggest that odorant exposure alone could enhance or maintain odor-discrimination abilities in conditions associated with olfactory impairment, such as aging or dementia.
The development of a prognostic mortality risk model for hospitalized COVID-19 patients may facilitate patient treatment planning, comparisons of therapeutic strategies, and public health ...preparations. We retrospectively reviewed the electronic health records of patients hospitalized within a 13-hospital New Jersey USA network between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2, with follow-up through May 29, 2020. With death or hospital discharge by day 40 as the primary endpoint, we used univariate followed by stepwise multivariate proportional hazard models to develop a risk score on one-half the data set, validated on the remainder, and converted the risk score into a patient-level predictive probability of 40-day mortality based on the combined dataset. The study population consisted of 3123 hospitalized COVID-19 patients; median age 63 years; 60% were men; 42% had >3 coexisting conditions. 713 (23%) patients died within 40 days of hospitalization for COVID-19. From 22 potential candidate factors 6 were found to be independent predictors of mortality and were included in the risk score model: age, respiratory rate greater than or equal to25/minute upon hospital presentation, oxygenation <94% on hospital presentation, and pre-hospital comorbidities of hypertension, coronary artery disease, or chronic renal disease. The risk score was highly prognostic of mortality in a training set and confirmatory set yielding in the combined dataset a hazard ratio of 1.80 (95% CI, 1.72, 1.87) for one unit increases. Using observed mortality within 20 equally sized bins of risk scores, a predictive model for an individual's 40-day risk of mortality was generated as -14.258 + 13.460*RS + 1.585*(RS-2.524)^2-0.403*(RS-2.524)^3. An online calculator of this 40-day COVID-19 mortality risk score is available at www.HackensackMeridianHealth.org/CovidRS. A risk score using six variables is able to prognosticate mortality within 40-days of hospitalization for COVID-19.
Interspinous process devices (IPDs) were developed as minimally invasive alternatives to open decompression surgery for spinal stenosis. However, given high treatment failure and reoperation rates, ...there has been minimal adoption by spine surgeons. This study leveraged a national claims database to characterize national IPD usage patterns and postoperative outcomes after IPD implantation.
Using the PearlDiver database, we identified all patients who underwent 1- or 2-level IPD implantation between 2010 and 2018. Univariate and multivariable logistic regression was performed to identify predictors of the number of IPD levels implanted and reoperation up to 3 years after the index surgery. Right-censored Kaplan-Meier curves were plotted for duration of reoperation-free survival and compared with log-rank tests.
Patients (n = 4865) received 1-level (n = 3246) or 2-level (n = 1619) IPDs. Patients who were older (adjusted odds ratio aOR 1.02, 95% confidence interval CI 1.01-1.03, P < .001), male (aOR 1.31, 95% CI 116-1.50, P < .001), and obese (aOR 1.19, 95% CI 1.05-1.36, P < .01) were significantly more likely to receive a 2-level IPD than to receive a 1-level IPD. The 3-year reoperation rate was 9.3% of patients when mortality was accounted for during the follow-up period. Older age decreased (aOR 0.97, 95% CI 0.97-0.99, P = .0039) likelihood of reoperation, whereas 1-level IPD (aOR 1.37, 95% CI 1.01-1.89, P = .048), Charlson Comorbidity Index (aOR 1.07, 95% CI 1.01-1.14, P = .018), and performing concomitant open decompression increased the likelihood of reoperation (aOR 1.68, 95% CI 1.35-2.09, P = .0014).
Compared with 1-level IPDs, 2-level IPDs were implanted more frequently in older, male, and obese patients. The 3-year reoperation rate was 9.3%. Concomitant open decompression with IPD placement was identified as a significant risk factor for subsequent reoperation and warrants future investigation.
We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to gemcitabine plus carboplatin ...(GCb) in patients with metastatic triple-negative breast cancer (NCT02978716).
Patients were randomized (1:1:1) to group 1 GCb (days 1, 8); n = 34, group 2 trilaciclib prior to GCb (days 1, 8); n = 33, or group 3 trilaciclib (days 1, 8) and trilaciclib prior to GCb (days 2, 9); n = 35. Subgroup analyses were performed according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment.
Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; P = 0.0016), 17.8 months in group 3 (HR = 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1-positive population. T-cell activation was enhanced in patients receiving trilaciclib.
Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.
The purpose of this study is to examine the utilization of kyphoplasty/vertebroplasty procedures in the management of compression fractures. With the growing elderly population and the associated ...increase in rates of osteoporosis, vertebral compression fractures have become a daily encounter for spine surgeons. However, there remains a lack of consensus on the optimal management of this patient population.
A retrospective analysis of 91 million longitudinally followed patients from 2016 to 2019 was performed using the PearlDiver Patient Claims Database. Patients with compression fractures were identified using International Classification of Disease, 10th Revision codes, and a subset of patients who received kyphoplasty/vertebroplasty were identified using Common Procedural Terminology codes. Baseline demographic and clinical data between groups were acquired. Multivariable regression analysis was performed to determine predictors of receiving kyphoplasty/vertebroplasty.
A total of 348,457 patients with compression fractures were identified with 9.2% of patients receiving kyphoplasty/vertebroplasty as their initial treatment. Of these patients, 43.5% underwent additional kyphoplasty/vertebroplasty 30 days after initial intervention. Patients receiving kyphoplasty/vertebroplasty were significantly older (72.2 vs. 67.9, p < 0.05), female, obese, had active smoking status and had higher Elixhauser Comorbidity Index scores. Multivariable analysis demonstrated that female sex, smoking status, and obesity were the 3 strongest predictors of receiving kyphoplasty/vertebroplasty (odds ratio, 1.27, 1.24, and 1.14, respectively). The annual rate of kyphoplasty/vertebroplasty did not change significantly (range, 8%-11%).
The majority of vertebral compression fractures are managed nonoperatively. However, certain patient factors such as smoking status, obesity, female sex, older age, osteoporosis, and greater comorbidities are predictors of undergoing kyphoplasty/vertebroplasty.
John A. Macdonald Creighton, Donald
John A. Macdonald,
2018., 2018, 2018-05-16, 2018-06-11
eBook
"The Dictionary of Canadian Biography calls this work 'probably the greatest Canadian biography yet published in English.' Donald Creighton's two-volume study of Canada's first Prime Minister was ...originally published in the 1950s, and each of the volumes won a Governor General's Literary Award. Sir John A. Macdonald's flamboyant personality dominated Canadian public life from the years preceding Confederation to the end of the nineteenth century. The political structures and national policies which developed under his leadership continue to shape public issues today. Creighton brought a rare combination of rigorous scholarship, magnificent literary style, and romantic and heroic vision to his biography of Macdonald. These qualities give his writing extraordinary power, and explain the work's appeal for both students of history and general readers. P.B. Waite's introduction to this new one-volume republication provides an illuminating account of the impact that Creighton and his biography of Macdonald had on a whole generation of historians and readers."--
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