One of the major challenges in the parameter-free approach to computational shape optimization is the avoidance of oscillating (i.e. non-smooth) boundaries in the optimal design trials. In order to ...achieve this, we investigate a method for regularization that corresponds to the discrete variant of the so-called traction method. In this approach, the design updates are generated in terms of a displacement field, which is obtained as the solution to an auxiliary boundary value problem that is defined on the actual design domain. The main idea herein is to apply fictitious nodal forces corresponding to the discrete sensitivity of the objective function. We propose an algorithm in which constraint functions will be taken into account by using an augmented Lagrangian formulation and a step-length control ensures a sufficient decrease condition in terms of the objective function within each iteration. We examine the benefits of the proposed regularization method on the basis of some numerical examples in comparison to an unregularized steepest-descent algorithm.
We introduce a novel method to handle geometrical and manufacturing constraints in parameter–free shape optimization. Therefore the design node coordinates are split in two sets where one set is ...declared as new design variables and the other set is coupled to the new design variables such that the geometrical constraint is fulfilled. Thereby no additional equations are appended to the optimization problem. In contrast the implementation of a demolding constraint is presented by formulating inequality constraints which indeed have to be attached to the optimization problem. In the context of a sensitivity–based shape optimization approach all manufacturing constraints have to be formulated in terms of the finite element node coordinates such that first order gradients with respect to the design node coordinates can be derived.
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Background: Adherence to oral chemotherapy (OC) is a critical factor in achieving optimal oncologic outcomes. Correct dosing, education, and symptom management are essential to ...maximizing adherence. As part of the 2020 Quality Oncology Practice Initiative Certification Program Fox Chase Cancer Center (FCCC), a NCCN Comprehensive Cancer Center, learned that only 33% of patients on OC had a documented OC plan, 7% were assessed for adherence, and 0% had documentation reflecting efforts to address non-adherence. Methods: Our goal was to create and implement an electronic medical record (EMR) tool (Oral Chemo Smart Form) to address the variance and deficiencies in monitoring adherence to OC. The Smart Form (SF) was designed to include fields to document the OC plan (drug, indication, dose, schedule, duration of cycle, initial start/end date) as well as provide a standard for documentation of education, management of toxicity and non-adherence. We integrated the SF into nursing, pharmacy, and physician workflows to capitalize on shared EMR tools. A series of Plan-Do-Study-Act cycles were conducted over 8 weeks within pilot clinics. Weekly review of the SF and feedback forms generated real-time progress reports which were serially appraised and shared with stakeholders. Results: Two oncologists (piloted in Genitourinary and Breast Cancer clinics), two pharmacists, and several nurses used the SF March 15, 2021 to May 7, 2021. Over these 8 weeks, 223 patients on OC were seen in clinic. If the OC was dispensed from FCCC, pharmacists were to complete the SF at the time of initial OC prescription, 7 days after dispensing, and with each refill. Pharmacists also identified patients receiving OC through a specialty pharmacy and routed a message to clinic nurses via an EMR message pool. The message became the trigger for nurses to call patients within two weeks to troubleshoot dispensing issues and/or complete the SF. Oncologists were to complete the SF with each clinic visit for a patient on OC. Feedback from the clinical and pharmacy teams motivated changes in the content fields of the SF and workflow. Ultimately, 45% of patients on OC had the SF completed. An OC plan was documented in 41% of patients, compared to 33% at baseline; 87% had an administration schedule compared to 81%. There was an increase in the number of patients contacted following start of OC, 35% from 4%. Medication adherence was assessed in 35% of patients, up from 7%. Documented discussions addressing medication adherence increased to 78%, from 0%. Conclusions: Introduction of the Oral Chemo SF in pilot clinics improved documented OC plans and administration schedules. Its use introduced a standard process for monitoring safety, assessing and addressing non-adherence, while troubleshooting specialty pharmacy dispensing issues. The SF will be implemented throughout FCCC and further evaluated with efforts focused on adopting and streamlining this as standard work.
Intradialytic cycling is often performed during the first half of hemodialysis because of concerns regarding increased frequency of intradialytic hypotension (IDH) late in hemodialysis. This ...increases exercise program resource needs and limits utility of intradialytic cycling to treat dialysis-related symptoms.
This multicenter, randomized, crossover trial compared IDH rate when cycling during the first half versus the second half of hemodialysis in 98 adults on maintenance hemodialysis. Group A cycled during the first half of hemodialysis for 2 weeks and subsequently during the second half for 2 weeks. In group B, the cycling schedule was reversed. Blood pressure (BP) was measured every 15 minutes throughout hemodialysis. Primary outcome was IDH rate (systolic BP SBP decrease of >20 mm Hg or SBP <90 mm Hg). Secondary outcomes included symptomatic IDH rate and time to recover post hemodialysis. Data were analyzed using negative binomial and gamma distribution mixed regression.
Mean age 64.7 (SD 12.0) and 64.7 (SD 14.2) years in group A (n = 52) and group B (n = 46), respectively. Proportions of females were 33% in group A and 43% in group B. Median time on hemodialysis was 4.1 (interquartile range IQR 2.5, 6.1) years in group A and 3.9 years (IQR 2.5, 6.7) in group B. IDH rate per 100 hemodialysis hours (95% confidence interval CI) was 34.2 (26.4, 42.0) and 36.0 (28.9, 43.1) during early and late intradialytic cycling, respectively (P = 0.53). Timing of intradialytic cycling was not associated with symptomatic IDH (relative risk RR: 1.07 0.75–1.53) or time to recover post hemodialysis (odds ratio: 0.99 0.79–1.23).
We found no association between the rate of overall or symptomatic IDH and the timing of intradialytic cycling in patients enrolled in an intradialytic cycling program. Increased use of cycling late in hemodialysis may optimize intradialytic cycling program resource use and should be studied as a possible treatment for symptoms common in late hemodialysis.
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Quaternary geographic range dynamics of savannah tree species are still not fully understood. The forest refuge hypothesis postulates that climatic and vegetational upheavals during the Pleistocene ...fragmented the previously continuous ranges of many species into isolated refuges that would have acted as shelters for rainforest taxa and allowed their survival through the Pleistocene cold stages. This hypothesis has recently been applied to studies of taxa in the African savannahs. We here test this hypothesis using the savannah tree species Senegalia senegal (L.) Britton., which is widely distributed across sub-Saharan Africa. Specifically, we ask the following questions: (i) Do we find evidence for savannah refugia during the last 130,000 before-present in sub-Saharan Africa? (ii) Would the climate in West Africa already have been suitable for S. senegal prior to the Last Glacial Maximum (LGM)? Using 1,132 occurrence records,we modeled the geographic distribution of S. senegal and projected the model into the past using climatic conditions from four time slices spanning the last 130,000 years bp. Our analyses show that the projected geographic extent of S. senegal was broader during the Last Interglacial, with a dramatic decline during the LGM and the subsequent recovery through the mid-Holocene to the present day. Our results indicate a range expansion at least from the mid-Holocene to the present and further show that S. senegal had similarly continuous distribution during the LGM as found today in sub-Saharan Africa. We also assessed the regional variation of environmental niche occupancy using a principal components analysis (PCA). The PCA reveals variation in the occupancy of environmental space across sub-Saharan Africa, a key indication of a wide ecological amplitude exhibited by the species. This study provides insights into the ancestral distribution and the temporal dynamics of a key savannah species that have shaped its current areas of occupancy.
Tissue-based assessment of actionable mutations in pts with NSCLC is limited by invasive biopsies and adequacy of biopsied tumour material. Blood-based testing may overcome such limitations, allowing ...multiplex profiling in a single test. BFAST (NCT03178552) is an ongoing multicentre, open-label, multi-cohort study evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations in cell-free DNA, and the activity of targeted therapies and immunotherapy in pts with treatment-naïve advanced NSCLC. We present first results from the ALK+ cohort.
Pts ≥18 years with stage IIIB/IV ALK+ NSCLC (detected by blood-based NGS) received oral alectinib 600mg twice daily. Asymptomatic/treated central nervous system (CNS) metastases were permitted. All pts (with/without CNS disease) had 8-weekly restaging and brain scans. Primary endpoint: confirmed investigator (INV)-assessed objective response rate (ORR; RECIST v1.1). Key secondary endpoints: independent review facility (IRF)-assessed ORR; INV- and IRF-assessed duration of response (DoR), progression-free survival (PFS), overall survival; and safety.
Of 2,219 pts screened, blood-based NGS yielded results in 2,188 pts. Overall, 119 pts (5.4%) had ALK+ disease; 87 pts were enrolled and received alectinib. EML4 was the fusion partner in 73 (84%) pts, with TP53 mutations detected in 38 (44%) pts. Median blood-based tumour mutational burden was 2 (range, 0–21). Median follow-up: 12.6 months (range, 2.6–18.7). Confirmed ORR: 87.4% (95% CI 78.5–93.5) by INV and 92.0% (95% CI 84.1–96.7) by IRF. The 12-month INV-confirmed DoR was 75.9% (95% CI 63.6–88.2). In 35 (40%) pts with asymptomatic baseline CNS disease, ORR by INV was 91.4% (95% CI 76.9–98.2). Median PFS: not reached; 12-month PFS by INV was 78.4% (95% CI 69.1–87.7). Safety data were consistent with the known safety profile of alectinib.
Blood-based detection of ALK fusions results in high ORR and clinical benefit in pts receiving alectinib. These data validate the clinical utility of blood-based NGS as an additional method to inform clinical decision-making in ALK+ NSCLC.
NCT03178552.
Medical Writing support was provided by Nicola Griffin of Gardiner-Caldwell Communications and funded by F. Hoffmann-La Roche.
F. Hoffmann-La Roche Ltd.
F. Hoffman-La Roche Ltd.
S.M. Gadgeel: Honoraria (self), Advisory / Consultancy: Ariad, AstraZeneca, Bristol-Myers Squibb, Pfizer and F. Hoffmann-La Roche Ltd/Genentech. T.S.K. Mok: Leadership role: Sanonics Ltd; Honoraria (self), Advisory / Consultancy: ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chimed, Cirina, Fishawack Facilitate, Ignyta, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, SFJ Pharm; Research grant / Funding (self): AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, SFJ Pharmaceutical and XCovery. S. Peters: Honoraria (self), Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche Ltd, Janssen, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Regeneron and Takeda; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme, Novartis and Pfizer. J.A.A. Alexander: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim Bristol-Myers Squibb, Pfizer and F. Hoffmann-La Roche Ltd/Genentech, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Takeda. N.B. Leighl: Research grant / Funding (self): F. Hoffmann-La Roche, Array, Guardant and AstraZeneca; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, F. Hoffmann-Lar Roche, Pfizer ; Advisory / Consultancy: Excovery. V. Sriuranpong: Honoraria (self), Advisory / Consultancy: AstraZeneca, Novartis, F. Hoffmann-La Roche Ltd, Pfizer, Sanofi, Eisai, Boehringer, Taiho, Merck Sharp & Dohme, Bristol-Myers Squibb ; Research grant / Funding (institution): AstraZeneca, Novartis, F. Hoffmann-La Roche Ltd, Pfizer, Boehringer, Eisai, Taiho, Lilly and Merck Sharp & Dohme. M. Perol: Honoraria (self): F. Hoffmann-La Roche Ltd, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Takeda, Chugai, Boehringer Ingelheim, Eli Lilly, Amgen and AbbVie. G. De Castro Jr.: Advisory / Consultancy: AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Novartis, Boehringer Ingelheim, Pfizer, Bayer; Speaker Bureau / Expert testimony: Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, AstraZeneca, Pfizer, F. Hoffmann-La Roche Ltd, Bayer, TEVA ; Travel / Accommodation / Expenses: Merck Sharp & Dohme, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Bayer, Novartis, Boehringer Ingelheim, AstraZeneca, Pfizer and Bayer.. E. Nadal: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche Ltd, Janssen, Merck Sharp & Dohme, Pfizer and Takeda. F. De Marinis: Honoraria (self): F. Hoffmann La Roche Ltd, Bristol-Myers Squibb, AstraZeneca and Merck. J. Han: Honoraria (self): Roche, AstraZeneca, BMS, MSD, Takeda; Advisory / Consultancy: AstraZeneca, BMS, MSD, Lilly, Novartis, Pfizer, Takeda; Research grant / Funding (self): Roche, Pfizer, ONO . M. Yan: Full / Part-time employment: F. Hoffmann-La Roche Ltd.. T. Riehl: Full / Part-time employment: Genentech, Inc. E. Schleifman: Full / Part-time employment: Genentech, Inc. S.M. Paul: Full / Part-time employment: Genentech, Inc. S. Mocci: Full / Part-time employment: Genentech, Inc. D. Shames: Full / Part-time employment: Genentech, Inc. M.S. Mathisen: Full / Part-time employment: Genentech, Inc. R. Dziadziuszko: Honoraria (self), Advisory / Consultancy: F. Hoffmann-La Roche Ltd, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca and Tesaro..
High-data-rate wireless technologies such as HSUPA and LTE are power-hungry because of the fundamental correlation between data rate and transmit power. Furthermore, the high peak-to-average power ...ratio (PAPR) of the modulated signals causes a degradation in PA efficiency, since the supply voltage of the PA must be high enough to provide the peak output voltage without loss of linearity. Envelope tracking modulators have been proposed to improve the efficiency and linearity of transmitters. Modulators using multiple input voltages have been shown to improve efficiency, but generating multiple supplies imposes substantial overhead. Several recent works have demonstrated a hybrid modulator, combining the output current of a buck output stage with that of a linear amplifier. The hybrid modulator has the notable advantage that the low-frequency power (which constitutes the majority of power, even in high-PAPR scenarios) can be provided through the efficient buck stage. The inherently less efficient linear amplifier stage needs only to supply the high-frequency power. The efficiency of hybrid modulators degrades at moderate power levels, when the ac amplitude is much less than the supply voltage of the linear amplifier. At low power levels, the power savings afforded by the modulator do not offset its own quiescent current, resulting in a lower efficiency than can be achieved using a fixed-drain, average-power-tracking (FD-APT) supply.
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