bluuebunny/crossref_metadata_2025 huggingface dataset:
Theoretical Understanding of the Linear Relationship between Convective Updrafts and Cloud-Base Height for Shallow Cumulus Clouds. Part II: Continental Conditions
Authors: Zheng Youtong , Sakradzija Mirjana , Lee Seoung-Soo , Li Zhanqing
Published: February 2020

Abstracts

This is the Part II of a two-part study that seeks a theoretical understanding of an empirical relationship for shallow cumulus clouds: subcloud updraft velocity covaries linearly with the cloud-base height. This work focuses on continental cumulus clouds that are more strongly forced by surface fluxes and more deviated from equilibrium than those over oceans (Part I). We use a simple analytical model for shallow cumulus that is well tested against a high-resolution (25 m in the horizontal) large-eddy simulation model. Consistent with a conventional idea, we find that surface Bowen ratio is the key variable that regulates the covariability of both parameters: under the same solar insolation, a drier surface allows for stronger buoyancy flux, triggering stronger convection that deepens the subcloud layer. We find that the slope of the Bowen-ratio-regulated relationship between the two parameters (defined as λ) is dependent on both the local time and the stability of the lower free atmosphere. The value of λ decreases with time exponentially from sunrise to early afternoon and linearly from early afternoon to sunset. The value of λ is larger in a more stable atmosphere. In addition, continental λ in the early afternoon more than doubles the oceanic λ. Validation of the theoretical results against ground observations over the Southern Great Plains shows a reasonable agreement. Physical mechanisms underlying the findings are explained from the perspective of different time scales at which updrafts and cloud-base height respond to a surface flux forcing.
High‐Frequency Conductive Hearing following Total Drum Replacement Tympanoplasty
Authors: Polanik Marc D. , Trakimas Danielle R. , Black Nicole L. , Cheng Jeffrey T. , Kozin Elliott D. , Remenschneider Aaron K.
Published: February 2020

Objectives

Conventional reporting of posttympanoplasty hearing outcomes use a pure‐tone averaged air‐bone gap (ABG) largely representing a low‐frequency sound conduction. Few studies report high‐frequency conductive hearing outcomes. Herein, we evaluate high‐frequency ABG in patients following temporalis fascia total drum replacement.

Study Design

Case series with chart review.

Setting

Tertiary care center.

Subjects and Methods

All patients who underwent type 1 tympanoplasty using a lateral graft total drum replacement technique between August 2016 and February 2019 were identified. Patients with pre‐ and postoperative audiograms were included. Low‐frequency ABG was calculated as the mean ABG at 250, 500, and 1000 Hz. High‐frequency ABG was calculated at 4 KHz. Pre‐ and postoperative ABGs were compared.

Results

Twenty‐three patients were included, and the mean age at surgery was 44 years (range, 9‐68 years). Perforation etiology was from trauma (n = 14) or chronic otitis media (n = 9). Preoperative mean low‐frequency ABG was 27.8 ± 12.6 dB and mean high‐frequency ABG was 21.5 ± 15.1 dB (P =. 044). Postoperatively, the mean low‐frequency ABG was significantly reduced by 15.5 ± 13.3 dB (P <. 001) while the mean high‐frequency ABG insignificantly changed (reduced by 2.6 ± 16.2 dB, P =. 450).

Conclusion

In a series of patients undergoing temporalis fascia total drum replacement, low‐frequency ABG improved; however, high‐frequency conductive hearing loss persists. Conventional methods of reporting ABG may not identify persistent high‐frequency ABG. These results merit further study across a range of tympanoplasty graft materials and surgical techniques.
Optimal design for a novel inerter-based clutching tuned mass damper system
Authors: Liang Qigang , Li Luyu
Published: February 2020

In this article, a clutching inerter damper is introduced into the conventional tuned mass damper to replace the typical damping element. Regarding the limitation of the typical damping element, the reformed clutching tuned mass damper system is more flexible in parameter design than the optimal tuned mass damper, which may be constrained by the manufacturing process to realize the too small or too large damping coefficient. To investigate the effectiveness of the clutching tuned mass damper, some fundamental analyses are first conducted on the clutching tuned mass damper, and results show that the clutching tuned mass damper system can achieve a similar control effect to the optimal tuned mass damper design. Considering the inherent nonlinearity of the clutching tuned mass damper, the equivalent linearization is performed based on the equivalent linearization parameters drawn from the single-degree-of-freedom system with clutching inerter damper. The equivalent linear system of the clutching tuned mass damper system has been proved to be quite accurate to approximate the nonlinear clutching tuned mass damper system. Based on the equivalent linear system, the performance evaluation and optimal design of the clutching tuned mass damper system are carried out by numerical analysis and analytical solution. Results have shown that there is an optimum inertance for the clutching tuned mass damper to achieve the optimal performance, and the optimum inertance is related to the structural damping ratio and the tuned mass ratio. Finally, the effectiveness of the clutching tuned mass damper system and its equivalent linear system in a multi-degree-of-freedom structure is verified by a numerical study.
A practical approach to evaluating postoperative thrombocytopenia
Authors: Skeith Leslie , Baumann Kreuziger Lisa , Crowther Mark A. , Warkentin Theodore E.
Published: February 2020

Identifying the cause(s) of postoperative thrombocytopenia is challenging. The postoperative period includes numerous interventions, including fluid administration and transfusion of blood products, medication use (including heparin), and increased risk of organ dysfunction and infection. Understanding normal thrombopoietin physiology and the associated expected postoperative platelet count changes is the crucial first step in evaluation. Timing of thrombocytopenia is the most important feature when differentiating causes of postoperative thrombocytopenia. Thrombocytopenia within 4 days of surgery is commonly caused by hemodilution and increased perioperative platelet consumption prior to thrombopoietin-induced platelet count recovery and transient platelet count overshoot. A much broader list of possible conditions that can cause late-onset thrombocytopenia (postoperative day 5 [POD5] or later) is generally divided into consumptive and destructive causes. The former includes common (eg, infection-associated disseminated intravascular coagulation) and rare (eg, postoperative thrombotic thrombocytopenic purpura) conditions, whereas the latter includes such entities as drug-induced immune thrombocytopenia or posttransfusion purpura. Heparin-induced thrombocytopenia is a unique entity associated with thrombosis that is typically related to intraoperative/perioperative heparin exposure, although it can develop following knee replacement surgery even in the absence of heparin exposure. Very late onset (POD10 or later) of thrombocytopenia can indicate bacterial or fungal infection. Lastly, thrombocytopenia after mechanical device implantation requires unique considerations. Understanding the timing and severity of postoperative thrombocytopenia provides a practical approach to a common and challenging consultation.
Accuracy of transition zone in contrast enema to predict intraoperative aganglionosis level in patients with Hirschsprung disease
Authors: Haikal Zikrul , Dwihantoro Andi , Gunarti Hesti , Gunadi
Published: February 2020

Objective

While frozen section methods have been widely conducted to determine aganglionosis segment during transanal endorectal pull-through (TEPT) for Hirschsprung disease (HSCR) patients in most institutions, some hospitals still rely on contrast enema to predict aganglionosis segments due to unavailability of frozen section facilities. We determined the accuracy of transition zone in contrast enema to predict aganglionosis segments during TEPT. We retrospectively reviewed all contrast enema and frozen sections for HSCR patients under 2 years of age who underwent TEPT at our institution.

Results

We recruited 36 HSCR patients: twenty-six patients (72.2%) had radiographic transition zones limited to rectum, while ten subjects (27.8%) were limited to rectosigmoid. The rectum subgroup of patients showed a concordance of 30.8%, whereas the rectosigmoid subgroup had a concordance of 100%. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of contrast enema compared with intraoperative histopathological findings for aganglionosis level were 100% (95% CI 0.60–1.0), 35.7% (95% CI 0.19–0.56), 30.8% (95% CI 0.15–0.52), 100% (95% CI 0.66–1.0), and 50% (95% CI 0.33–0.67), respectively. In conclusions, contrast enema has low accuracy to predict intraoperative aganglionosis segments in HSCR patients, indicating that it might not be utilized to determine aganglionosis level during TEPT.
Microlaryngeal surgery, difficult airway and a missing throat pack: C Mac D-blade to the rescue!
Authors: Shah Shagun B. , Bhardwaj M. , Bhargava Ajay K. , Bhageria Vani
Published: February 2020

Skilful use of the C Mac D-blade videolaryngoscope, with preservation of spontaneous respiration, can avert preoperative tracheostomy and guide microlaryngeal surgery (MLS) tube insertion in patients with large growths obliterating glottic view. The long narrow stylet accompanying double-lumen tubes can be used for D-Blade guided MLS tube orotracheal intubation. A definite protocol for safe insertion and removal of throat packs has been described here. Throat packs may go missing despite following protocols. Our algorithm includes visual and documentary precautions and means of exploration of missing throat packs. D-blade is invaluable in scanning the oropharynx in event of a lost throat pack.
Peer-led team learning for introductory biology: relationships between peer-leader relatability, perceived role model status, and the potential influences of these variables on student learning gains
Authors: Winterton Christina I. , Dunk Ryan D. P. , Wiles Jason R.
Published: February 2020

Student-instructor interactions have an influence on student achievement and perceptions of learning. In college and university settings, large introductory STEM courses are increasingly including Peer-Led Team Learning (PLTL), an evidence-based technique associated with improved student achievement, recruitment, and retention in STEM fields, especially for underserved populations. Within this technique, peer leaders hold a unique position in a student’s education. Peer leaders have relevant experience in that they have had recent success in the courses in which they facilitate student learning, yet, compared to student-faculty or student-teaching assistant relationships, there is minimal imbalance of authority or power. Students might find their peer leaders to be more relatable than faculty or graduate teaching assistants, and may even consider them to be role models. We explored students’ perceptions of peer leader relatability and role model status in relation to students’ achievement and their perceived learning gains in the context of an introductory biology course with an associated PLTL program. The final course grades and self-assessed learning gains of PLTL students who felt they related to their peer leader were compared to those who did not. We also compared final course grades and self-assessed learning gains between PLTL students who viewed their peer leader as a role model versus those who did not. Self-reported learning gains were significantly higher for students who relate to their peer leader, as well as for students who viewed their peer leaders as a role model. There is some support that this trend is stronger for STEM majors versus those who are not enrolled in a STEM program, though the interaction is not significant. Significant differences in overall course grade were only observed between students who reported that they related to their peer leader versus those who did not relate to their peer leader.
From novice to expert: a qualitative study of implementation facilitation skills
Authors: Ritchie Mona J. , Parker Louise E. , Kirchner JoAnn E.
Published: February 2020

Background

It is widely reported that facilitation can aid implementation of evidence-based practices. Although scholars agree that facilitators need a diverse range of skills, only a few retrospective studies have identified some of these. During the test of a facilitation strategy within the context of a VA initiative to implement evidence-based care delivery models, we documented the skills an expert external facilitator transferred to two initially novice internal regional facilitators. Ours is the first study to explore facilitation skills as they are being applied and transferred.

Methods

Facilitators applied the strategy at eight primary care clinics that lacked implementation capacity in two VA networks. We conducted monthly debriefing interviews over a 30-month period and documented these in detailed notes. External facilitator interviews focused specifically on training and mentoring internal facilitators and the skills that she transferred. We also conducted, recorded, and transcribed two qualitative interviews with each facilitator and queried them about training content and process. We conducted a content analysis of the data, using deductive and inductive methods, to identify skills the external facilitator helped internal facilitators learn. We also explored the complexity of facilitation skills and grouped them into overarching skillsets.

Results

The external facilitator helped internal facilitators learn 22 complex skills; with few exceptions, these skills were not unique but overlapped with one another. We clustered 21 of these into 5 groups of overarching skillsets: (1) building relationships and creating a supportive environment, (2) changing the system of care and the structure and processes that support it, (3) transferring knowledge and skills and creating infrastructure support for ongoing learning, (4) planning and leading change efforts, and (5) assessing people, processes, and outcomes and creating infrastructure for program monitoring.

Conclusions

This study documented a broad range of implementation facilitation skills that are complex and overlapping. Findings suggest that studies and initiatives planning or applying facilitation as an implementation strategy should ensure that facilitators have or have the opportunity to learn the skills they need. Because facilitation skills are complex, the use of didactic methods alone may not be sufficient for transferring skills; future work should explore other methods and techniques.
A behavioral economic intervention to increase psychiatrist adherence to tobacco treatment guidelines: a provider-randomized study protocol
Authors: Rogers Erin S. , Wysota Christina , Prochaska Judith J. , Tenner Craig , Dognin Joanna , Wang Binhuan , Sherman Scott E.
Published: February 2020

Background

People with a psychiatric diagnosis smoke at high rates, yet are rarely treated for tobacco use. Health care systems often use a “no treatment” default for tobacco, such that providers must actively choose (opt-in) to treat their patients who express interest in quitting. Default bias theory suggests that opt-in systems may reinforce the status quo to not treat tobacco use in psychiatry. We aim to conduct a pilot study testing an opt-out system for implementing a 3As (ask, advise, assist) tobacco treatment model in outpatient psychiatry.

Methods

We will use a mixed-methods, cluster-randomized study design. We will implement a tobacco use clinical reminder for outpatient psychiatrists at the VA New York Harbor Healthcare System. Psychiatrists (N = 20) will be randomized 1:1 to one of the two groups: (1) opt-in treatment approach—psychiatrists will receive a reminder that encourages them to offer cessation medications and referral to cessation counseling; (2) opt-out treatment approach—psychiatrists will receive a clinical reminder that includes a standing cessation medication order and a referral to cessation counseling that will automatically generate unless the provider cancels. Prior to implementation of the reminders, we will hold a 1-h training on tobacco treatment for psychiatrists in both arms. We will use VA administrative data to calculate the study’s primary outcomes: (1) the percent of smokers prescribed a cessation medication and (2) the percent of smokers referred to counseling. During the intervention period, we will also conduct post-visit surveys with a cluster sample of 400 patients (20 per psychiatrist) to assess psychiatrist fidelity to the 3As approach and patient perceptions of the opt-out system. At 6 months, we will survey the clustered patient sample again to evaluate the study’s secondary outcomes: (1) patient use of cessation treatment in the prior 6 months and (2) self-reported 7-day abstinence at 6 months. At the end of the intervention period, we will conduct semi-structured interviews with 12–14 psychiatrists asking about their perceptions of the opt-out approach.

Discussion

This study will produce important data on the potential of opt-out systems to overcome the barriers in implementing tobacco use treatment in outpatient psychiatry.

Trial registration

Clinicaltrials.gov NCT04071795 (registered on August 28, 2019)
Development, implementation, and evaluation of a novel guideline engine for pediatric patients with severe traumatic brain injury: a study protocol
Authors: Pilar Meagan R. , Proctor Enola K. , Pineda Jose A.
Published: February 2020

Background

Severe traumatic brain injury (TBI) is a leading cause of death and disability for children. The Brain Trauma Foundation released evidence-based guidelines, a series of recommendations regarding care for pediatric patients with severe TBI. Clinical evidence suggests that adoption of guideline-based care improves outcomes in patients with severe TBI. However, guideline implementation has not been systematic or consistent in clinical practice. There is also a lack of information about implementation strategies that are effective given the nature of severe TBI care and the complex environment in the intensive care unit (ICU). Novel technology-based strategies may be uniquely suited to the fast-paced, transdisciplinary care delivered in the ICU, but such strategies must be carefully developed and evaluated to prevent unintended consequences within the system of care. This challenge presents a unique opportunity for intervention to more appropriately implement guideline-based care for pediatric patients with severe TBI.

Methods

This mixed-method study will develop a novel technology-based bedside guideline engine (the implementation strategy) to facilitate uptake of evidence-based guidelines (the intervention) for management of severe TBI. Group model building and systems dynamics will inform the guideline engine design, and bedside functionality will be initially assessed through patient simulation. Using the Promoting Action on Research Implementation in Health Services (PARIHS) framework, we will determine the feasibility of incorporating the guideline engine in the ICU. Study participants will include pediatric patients with severe TBI and providers at three trauma centers. Quantitative data will include measures of guideline engine acceptance and organizational readiness for change. Qualitative data will include semi-structured interviews from clinicians. We will test the feasibility of incorporating the guideline engine in “real life practice” in preparation for a future clinical trial that will assess clinical and implementation outcomes, including feasibility, acceptability, and adoption of the guideline engine.

Discussion

This study will lead to the development and feasibility testing of an adaptable strategy for implementing guideline-based care for severe TBI, a strategy that meets the needs of individual critical care environments and patients. A future study will test the adaptability and impact of the bedside guideline engine in a randomized clinical trial.
Bayesian Framework for Detecting Gene Expression Outliers in Individual Samples
Authors: Vivian John , Eizenga Jordan M. , Beale Holly C. , Vaske Olena M. , Paten Benedict
Published: February 2020

PURPOSE

Many antineoplastics are designed to target upregulated genes, but quantifying upregulation in a single patient sample requires an appropriate set of samples for comparison. In cancer, the most natural comparison set is unaffected samples from the matching tissue, but there are often too few available unaffected samples to overcome high intersample variance. Moreover, some cancer samples have misidentified tissues of origin or even composite-tissue phenotypes. Even if an appropriate comparison set can be identified, most differential expression tools are not designed to accommodate comparisons to a single patient sample.

METHODS

We propose a Bayesian statistical framework for gene expression outlier detection in single samples. Our method uses all available data to produce a consensus background distribution for each gene of interest without requiring the researcher to manually select a comparison set. The consensus distribution can then be used to quantify over- and underexpression.

RESULTS

We demonstrate this method on both simulated and real gene expression data. We show that it can robustly quantify overexpression, even when the set of comparison samples lacks ideally matched tissue samples. Furthermore, our results show that the method can identify appropriate comparison sets from samples of mixed lineage and rediscover numerous known gene-cancer expression patterns.

CONCLUSION

This exploratory method is suitable for identifying expression outliers from comparative RNA sequencing (RNA-seq) analysis for individual samples, and Treehouse, a pediatric precision medicine group that leverages RNA-seq to identify potential therapeutic leads for patients, plans to explore this method for processing its pediatric cohort.
Phase Ib/II Clinical Trial of Pembrolizumab With Bevacizumab for Metastatic Renal Cell Carcinoma: BTCRC-GU14-003
Authors: Dudek Arkadiusz Z. , Liu Li C. , Gupta Shilpa , Logan Theodore F. , Singer Eric A. , Joshi Monika , Zakharia Yousef N. , Lang Joshua M. , Schwarz James K. , Al-Janadi Anas , Alva Ajjai S.
Published: February 2020

PURPOSE

We hypothesized that bevacizumab will potentiate activity of pembrolizumab. We conducted a phase Ib/II, single-arm, multisite clinical trial of the combination in metastatic renal cell carcinoma (RCC).

PATIENTS AND METHODS

Patients with metastatic clear cell RCC who experienced progression after at least one systemic therapy (phase Ib) or were treatment naïve (phase II) were enrolled. In phase Ib, pembrolizumab (200 mg) and bevacizumab (10 or 15 mg/kg) were given intravenously every 3 weeks. The primary end point for phase II was overall response rate (ORR). With an 80% statistical power and a type I error probability of 0.1, 48 patients were to be accrued to detect an ORR of 42%.

RESULTS

Thirteen patients (ages 33-68 years; median, 55 years) were enrolled in the phase Ib study. No dose-limiting toxicities were reported. Pembrolizumab 200 mg and bevacizumab 15 mg/kg were chosen for phase II. Forty-eight patients (ages 42-84 years; median age, 61 years; 33 males) were accrued for the phase II study. The primary end point was met, with the ORR reaching 60.9% (95% CI, 45.4% to 74.9%), consisting of 1 complete response (CR), 2 CRs in target lesions, 25 partial responses, 18 responses of stable disease, 2 unevaluable responses. Median progression-free survival was 20.7 months (95% CI, 11.3 to 27.4 months). Median overall survival was not reached at the median follow-up of 28.3 months. The most common treatment-related grade 3 toxicities were hypertension and proteinuria. There were two grade 4 toxicities: duodenal ulcer and hyponatremia. Presence of tumor-infiltrating T cells, but not programmed death-ligand 1 expression, in tumor tissue correlated with response.

CONCLUSION

The combination of 200 mg of pembrolizumab and a 15 mg/kg dose of bevacizumab given every 3 weeks is safe and active in metastatic RCC.
Safety and efficacy of tazemetostat, a first-in-class EZH2 inhibitor, in patients (pts) with epithelioid sarcoma (ES) (NCT02601950).
Authors: Stacchiotti Silvia , Schoffski Patrick , Jones Robin , Agulnik Mark , Villalobos Victor Manuel , Jahan Thierry Marie , Chen Tom Wei-Wu , Italiano Antoine , Demetri George D. , Cote Gregory Michael , Chugh Rashmi , Attia Steven , Gupta Abha A. , Loggers Elizabeth T. , Van Tine Brian , Sierra Laura , Yang Jay , Rajarethinam Anand , Gounder Mrinal M.
Published: February 2020

11003

Background: ES is a rare soft tissue sarcoma that metastasizes in approximately 30% to 50% of cases. More than 90% of ES tumors lack expression of INI1, an important component of epigenetic regulation. Loss of INI1 function allows another epigenetic modifier, EZH2, to become an oncogenic driver in tumor cells. Tazemetostat, a first-in-class, selective, oral inhibitor of EZH2, has demonstrated tumor regression and favorable safety in phase 1/2 trials. Methods: Data from a phase 2 open-label, multicenter trial of pts with locally advanced or metastatic ES are reported. Efficacy was assessed with primary and secondary endpoints including objective response rate (ORR) by RECIST 1.1, disease control rate (DCR; objective confirmed response of any duration or stable disease [SD] lasting ≥32 weeks), duration of response (DOR), progression-free survival (PFS), overall survival (OS); safety and tolerability were also evaluated. Results: As of September 17, 2018, 62 INI1-negative ES pts were enrolled and treated with tazemetostat 800 mg BID. The median number of prior lines of therapy was 1 (range: 0-9). There were 9/62 (15%) confirmed partial responses (PRs) with an ORR of 15% and DCR of 26%. The DOR ranged from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median OS of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 pts. Tazemetostat was generally well tolerated. Treatment-emergent adverse events (TEAEs) were generally mild to moderate with the most commonly reported adverse events (AEs; ≥10% incidence) regardless of attribution being fatigue (24/62; 39%), nausea (22/62; 35%), and cancer pain (20/62; 32%). Any treatment-related TEAEs of grade ≥3 were reported in 10/62 (16%) pts. TEAEs grade ≥3 reported in ≥2 pts included anemia (6%) and decreased weight (3%). There were no drug-related deaths and a low discontinuation rate (1.7%). Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat achieved disease control in 26% of pts with advanced ES who entered this study. Durable clinical response of the drug was documented. Tazemetostat demonstrated favorable safety with few pts with treatment-related AEs grade ≥3. Clinical trial information: NCT02601950.
ABI-009 (nab-sirolimus) in advanced malignant perivascular epithelioid cell tumors (PEComa): Preliminary efficacy, safety, and mutational status from AMPECT, an open label phase II registration trial.
Authors: Wagner Andrew J. , Ravi Vinod , Ganjoo Kristen N. , Van Tine Brian Andrew , Riedel Richard F. , Chugh Rashmi , Cranmer Lee D. , Gordon Erlinda Maria , Hornick Jason L. , Kwiatkowski David J. , Du Heng , Grigorian Berta , Schmid Anita N. , Hou Shihe , Harris Katherine , Desai Neil , Dickson Mark Andrew
Published: February 2020

11005

Background: Malignant PEComa is a rare, aggressive sarcoma, with no approved treatment or prior clinical trials. Case reports suggest mTOR activation through mutations or deletions of TSC1 or TSC2 and activity of mTOR inhibitors in this disease. ABI-009 is an albumin-bound mTOR inhibitor with increased tumor uptake. The AMPECT trial is the first prospective study in malignant PEComa. Methods: Eligible patients (pts) with centrally confirmed PEComa receive ABI-009 (100 mg/m2 IV, wkly, 2/3 wks) until progression or unacceptable toxicity. Primary endpoint: ORR by independent review (IR), assessed every 6 wks (RECIST v1.1). Secondary endpoints: duration of response (DOR), PFS6, PFS, and safety. Exploratory endpoints (EE): investigator-assessed (IA) outcomes and mutational status. Sample size: 30 efficacy-evaluable pts based on target ORR of 30% (primary analysis planned when all pts treated ≥6 mo). Results: EE and safety are reported (IR pending). As of Feb 12, 2019, enrollment is complete; 34 pts treated, 31 evaluable for efficacy, 42% (13/31) pts ongoing Rx. IA ORR is 42% PR (13/31, 95% CI: 24.5, 60.9), 35% SD (11/31), and 23% PD (7/31); 69% of PRs were reached at 1st restaging (wk 6); 69% PRs are ongoing, with 5 pts >1yr and 2 pt >2 yrs on Rx (all ongoing). Other IA outcomes: median DOR is not reached; PFS6 is 66%; median PFS is 8.9 mo (95% CI: 5.5, -). The most common (>30%) nonhematologic treatment-related AEs (TRAEs) of any grade: mucositis (65%), fatigue (53%), nausea/weight loss (35% each), diarrhea (32%); the most common (>15%) hematologic TRAEs: anemia (44%) and thrombocytopenia (18%). Pneumonitis (15%) was G1/G2. The most common (>10%) G3 TRAEs: mucositis (18%), anemia (12%); No grade ≥4 TRAEs. TSC1 or TSC2 mutations occurred in 5 and 9 (no overlap) of 25 pts with known mutational status, respectively. PR was seen in 100% (9/9) pts with TSC2 mutation, 20% (1/5) pts with TSC1 mutation, and 9% (1/11) pts without mutation in TSC1 or TSC2, P < 0.0001 (2x3 Fisher exact test). PR was significantly higher in pts with TSC2 mutations vs pts without mutation in TSC1 or TSC2, P = 0.0001 (Fisher exact test). Disease control (PR+SD) was seen in 93% (13/14) pts with TSC1 or TSC2 mutations vs 55% (6/11) pts without mutation in TSC1 or TSC2, P = NS. Conclusions: Preliminary IA outcomes showed that ABI-009 treatment of PEComa resulted in substantial and durable responses with manageable toxicities. TSC2 mutations were associated with IA response. Clinical trial information: NCT02494570.
Does distress screening lead to mental health care in older adult surgical patients?
Authors: Trevino Kelly Marie , Nelson Christian J. , Saracino Rebecca , Korc-Grodzicki Beatriz , Sarraf Saman , Shahrokni Armin
Published: February 2020

11543

Background: Surgery is a notable stressor for older adults with cancer who are often medically complex and frail. The American College of Surgeons Commission on Cancer requires distress screening in accredited cancer care settings. The degree to which distress screening leads to mental health use is unclear. This study examined rates and predictors of post-surgical mental health care in older adults referred for a preoperative evaluation. Methods: Patients aged 75 years or older (n = 1,008) referred to the Geriatrics Service at a comprehensive cancer center were enrolled. Patients underwent elective surgery with a length of stay of 3 days or longer and were followed for at least 30 days after surgery. A comprehensive geriatric assessment (CGA) was administered as part of routine care. Surgical characteristics and post-surgical encounters with social work, psychology, and psychiatry were abstracted from the electronic medical record. Bivariate relationships between demographic and surgical characteristics and the CGA and post-operative receipt of mental health services were examined. Characteristics with significant (p < .01) bivariate relationships were entered into a multivariable regression predicting post-operative mental health service use. Results: One-quarter of the total sample (n = 246, 24.4%) received post-operative mental health services. In multivariable analyses, high distress (Distress Thermometer score≥4; p = .01), poor social support (p = .01), iADL dependence (p = .04), and longer length of stay (p < .001) were associated with receipt of mental health services after controlling for significant sociodemographic and surgical characteristics and CGA variables. Of patients with high distress, poor social support, or iADL dependence, only one-third (29-33%) received mental health care. Conclusions: Distressed older adults and those with low levels of support pre-operatively were more likely to receive mental health services after surgery, controlling for sociodemographic and surgical characteristics. Yet, only one-third of these patients received mental health care. These findings suggest that barriers to translating distress screening into provision of mental health services remain.
Rapid reduction of peripheral blasts in older patients with refractory acute myeloid leukemia (AML) using reinduction with single agent anti-CD45 targeted iodine (131I) apamistamab [Iomab-B] radioimmunotherapy in the phase III SIERRA trial.
Authors: Tomlinson Ben Kent , Reddy Vijay , Berger Mark S. , Spross Jennifer , Lichtenstein Renee , Gyurkocza Boglarka
Published: February 2020

7048

Background: The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial for patients aged ≥55 years with active, relapsed/refractory (R/R) AML evaluating allogeneic hematopoietic cell transplantation (HCT) versus conventional care (CC). Recent preliminary data demonstrated robust donor engraftment in all patients treated with Iomab-B (Blood 2018 132:1017) despite active disease. We hypothesize that successful engraftment was due to rapid disease reduction with Iomab-B. Methods: Patients are randomized to receive Iomab-B and HCT or to a CC therapy including approved targeted agents followed by HCT if in remission. Majority of patients (79%) in the CC arm did not achieve CR and the study allowed crossover to receive Iomab-B. Results: Data were evaluated for the first 25% of patients (N=38). Twenty-nine patients received Iomab-B, either directly (N=19) or via crossover (N=10). Median baseline marrow blasts were 30% (4-74) for Iomab-B and 24% (6-70%) for CC, which increased to 45% (10-70%) at crossover. Peripheral blast data was available in 16 patients (Iomab 7, Crossover 9). By day 3 post-Iomab, blasts were reduced by 98% with 100% reduction by day 8 (assuming 0% blasts due to lack of differential at WBC 0.1; Table). All patients engrafted with ANC at a median of 13 days (9-22 days). Conclusions: Targeted re-induction radioimmunotherapy with single agent Iomab-B rapidly decreases peripheral blasts in chemotherapy refractory AML. This significant reduction of leukemia burden followed by successful engraftment after HCT is encouraging in this underserved population. Clinical trial information: NCT02665065. [Table: see text]
Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001.
Authors: Wang Michael , Gordon Leo I. , Palomba Maria Lia , Abramson Jeremy S. , Andreadis Charalambos , Ghosh Nilanjan , Lunning Matthew Alexander , Maloney David G. , Farazi Thalia Andrea , Garcia Jacob , Xie Benhuai , Newhall Kathryn J. , Dehner Christine , Siddiqi Tanya
Published: February 2020

7516

Background: Most pts with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. We report initial dose-finding results from pts with R/R MCL treated with liso-cel (JCAR017), an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1 TRANSCEND study. Methods: Eligible pts had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior lines of therapy. After lymphodepleting chemotherapy, liso-cel was administered at 1 of 2 dose levels (DL): DL1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Results: At data cutoff, 9 pts (DL1, n = 6; DL2, n = 3) had received liso-cel. The median (range) age was 66 (58‒78) years; 7 pts were male. Histologies included blastoid (n = 3) and pleiomorphic (n = 1) variants. 8 pts had documented Ki67 > 30% (40%‒80%); 1 pt had TP53 mutation. Pts had received a median of 5 (3‒7) prior therapies; 3 pts had received prior hematopoietic stem cell transplant. All 9 pts had prior ibrutinib; 4 had a best response of progressive disease on ibrutinib. 6/9 pts (67%) received bridging chemotherapy. 4/9 pts (44%) had serious treatment-emergent adverse events (TEAEs). 5/9 pts (56%) had grade (G) 3/4 TEAEs, primarily anemia, neutropenia, and hypophosphatemia (22% each). 3/9 pts (33%) had cytokine release syndrome (CRS); all were G1. Median time to CRS onset was 6 (2‒7) days; median time to resolution was 6 (2‒6) days. 1 pt received tocilizumab and corticosteroids. There were no neurological events. 4 pts died, all in DL1 (3 from disease progression; 1 after receiving new anticancer therapy post liso-cel). Overall response rate was 78% (7/9 pts; 4/6 in DL1, median follow-up 12.4 [95% CI: 9.2–12.4] mo; 3/3 in DL2, median follow-up 1.4 [95% CI: 1.0–1.4] mo). 2 pts in DL1 maintained a durable CR until last follow-up (day 281 and 378, respectively). Median time to peak CAR+ T cell expansion: 9.5 (9–10) days at DL1 and 17.5 (10–27) days at DL2. Conclusions: In this phase 1 study in pts with R/R MCL, liso-cel treatment showed tolerable toxicity and had clinical activity. Updated DL2 data and longer follow-up will be presented. Clinical trial information: NCT02631044.
Patient-reported outcomes (PROs) with ibrutinib-rituximab in Waldenström macroglobulinemia (WM): Results from iNNOVATE.
Authors: Tedeschi Alessandra , Dimopoulos Meletios A. , Trotman Judith , Garcia-Sanz Ramón , MacDonald David , Mahe Beatrice , Herbaux Charles , Heffner Leonard T. , Tam Constantine Si Lun , Varettoni Marzia , Palomba Maria Lia , Matous Jeffrey , Shustik Chaim , Kastritis Efstathios , Treon Steven P. , Li Jianling , Poulsen Erik , Hauns Bernhard , Buske Christian , Leblond Veronique
Published: February 2020

8018

Background: Anemia and fatigue can impair quality of life in patients (pts) with WM. Ibrutinib (ibr) as single agent or in combination with RTX is FDA-approved for WM. In pts with RTX-refractory WM, single-agent ibr induced meaningful improvements in PROs (Trotman, EHA 2017). In iNNOVATE, ibr-RTX (IR) produced higher rates of sustained hemoglobin improvement and meaningful improvements in PROs versus placebo-RTX (R; Dimopoulos NEJM 2018). Here, we report detailed PRO analyses from iNNOVATE. Methods: Pts with symptomatic WM requiring therapy were randomized to daily 420 mg oral ibr or placebo, both with RTX (375 mg/m2/week IV at weeks 1–4 and 17–20). PRO measures included FACIT-Fatigue (FACIT-F), FACT-An total score (TS) and anemia subscale score (AS), and EQ-5D-5L (EuroQol Research Foundation. EQ-5D is a trade mark of the EuroQol Research Foundation) visual analog scale (VAS), and utility score (US). Results: For 150 randomized pts (n=75/arm), most common reasons for initiating therapy were fatigue (61%), constitutional symptoms (32%), and anemia (32%). Baseline PRO scores were comparable in both arms. At a median follow-up of 26.5 mo, numerically more pts showed clinically meaningful improvement in FACIT-F, TS, and AS with IR than R (Table). Median time to PRO improvement was short (1-2 mo) in both arms. At week 25, the Pearson correlation coefficients were 0.28, 0.29, and 0.26 for changes in hemoglobin levels vs changes in FACIT-F, TS and AS, respectively, in the IR arm; no meaningful correlations were observed on R. The correlation coefficients were -0.32, -0.33, -0.35 and -0.26 for changes in IgM levels vs changes in FACIT-F, TS, AS, and EQ-VAS, respectively, for IR and 0.29 and 0.35 vs FACIT-F and TS for R. Conclusions: Clinical response and improvements in anemia with IR are consistent with more pts showing clinically meaningful improvement in PROs versus R. Changes in IgM correlate with improvements in PROs. Clinical trial information: NCT02165397. [Table: see text]
Unique racial patterns in rare T-cell lymphomas: A National Cancer Registry analysis from 2001 to 2015.
Authors: Shah Nishi , Herrera Diego Adrianzen , Shah Urvi , Kolla Bhaskar Chandu , Kaur Gurbakhash , Sica Roberto Alejandro , Shastri Aditi , Mantzaris Ioannis , Verma Amit , Janakiram Murali
Published: February 2020

e19070

Background: Peripheral T-cell lymphomas (PTCL) are a rare heterogenous group of lymphomas and modern studies on incidence patterns of PTCL are lacking. Methods: Using the National Program of Cancer registries (NPCR) database, which covers 99% of the US population, we aim to evaluate the incidence of PTCL according to age, race-ethnicity, and gender; and examine trends over time. We identified PTCL using ICD-O-3 codes and evaluated incidence trends from 2001 to 2015. Results: A total of 78722 PTCL cases were identified, the most common were Mycoses fungoides/Sezary syndrome (MF-SS), PTCL Not Otherwise Specified (NOS), and ALK+ Anaplastic Large Cell Lymphoma (ALK+ ALCL). The age-adjusted incidence rate was 2.1 per 100,000. Incidence of PTCL increased with age (6.7/100,000 in 80+years). PTCL was more common in males than females (incidence rate ratio [IRR] of 0.6, p<0.05). Most PTCL were more common in Non-Hispanic Blacks (NHB). Incidence rates of MF-SS, PTCL NOS, Hepatosplenic TCL (HSL) in NHB were 0.8, 0.8, and 0.02 per 100,000 [IRR 1.7, 1.8, 2.2, p<0.05] respectively which is approximately twice that of Non-Hispanic whites (NHW). Viral related PTCL like Adult T-cell Leukemia Lymphoma (HTLV), Angio-Immunoblastic T-cell Lymphoma [AITL] (EBV), Extranodal NK-TCL nasal type [ENK TCL] (EBV), NK cell leukemia (EBV) are higher in groups at highest predisposition such as NHB and Non-Hispanic Asian Pacific Islanders (NHAPI). Primary cutaneous (PC) gamma-delta TCL occurs exclusively in NHW at an incidence rate of 0.03 per 100,000. There was no increase in overall yearly incidence of PTCL over the study period (0.1%, p=NS) but the incidence increased in NHB (Annual Percent Change [APC] 1.4%, p <0.05). Incidence of ENK TCL and AITL increased in NHAPI (2.2% and 3.7%, respectively [p <0.05]). The incidence of ALK + ALCL, PC CD30+ TCL decreased (APC -4.2%, -2% [p≤0.05] respectively). Conclusions: This is the first study to show unique incidence patterns of PTCL namely higher incidence in males, African Americans (esp. MF, PTCL-NOS and HSL unaccounted for viral etiologies) and exclusivity of primary cutaneous gamma delta TCL in NHW. Further research is needed to understand these differences.
Energy Commons
Authors: Szeman Imre
Published: February 2020

This article argues for the necessity of articulating and struggling for an energy common. An energy common is not intended to substitute for articulations of the common in general. Rather, the specific discussion of energy in relation to the common accomplishes two things. First, it underscores the problematic lack of attention to energy in existing discussions of the common, as in autonomist political philosophy. Second, adding energy to our thinking about the common produces new insights into the political and environmental commitments of existing articulations of the common. The possibilities of a common that is alert to the limits of natural resources and operates in relation to them are described in Ivan Illich’s 1973 essay “Energy and Equity.” This article takes Illich’s essay as a beginning point for creating an energy commons today.
Establishment of chromatin accessibility by the conserved transcription factor Grainy head is developmentally regulated
Authors: Nevil Markus , Gibson Tyler J. , Bartolutti Constantine , Iyengar Anusha , Harrison Melissa M.
Published: February 2020

The dramatic changes in gene expression required for development necessitate the establishment of cis-regulatory modules defined by regions of accessible chromatin. Pioneer transcription factors have the unique property of binding closed chromatin and facilitating the establishment of these accessible regions. Nonetheless, much of how pioneer transcription factors coordinate changes in chromatin accessibility during development remains unknown. To determine whether pioneer-factor function is intrinsic to the protein or whether pioneering activity is developmentally modulated, we studied the highly conserved, essential transcription factor Grainy head (Grh). Prior work established that Grh is expressed throughout Drosophila development and is a pioneer factor in the larva. We demonstrated that Grh remains bound to mitotic chromosomes, a property shared with other pioneer factors. By assaying chromatin accessibility in embryos lacking maternal and/or zygotic Grh at three stages of development, we discovered that Grh is not required for chromatin accessibility in early embryogenesis, in contrast to its essential functions later in development. Our data reveal that the pioneering activity of Grh is temporally regulated and likely influenced by additional factors expressed at a given developmental stage.
Moving neuromuscular disorders research forward: from novel models to clinical studies
Authors: van Putten Maaike , Hmeljak Julija , Aartsma-Rus Annemieke , Dowling James J.
Published: February 2020

Neuromuscular disorders (NMDs) encompass a diverse group of genetic diseases characterized by loss of muscle functionality. Despite extensive efforts to develop therapies, no curative treatment exists for any of the NMDs. For multiple disorders, however, therapeutic strategies are currently being tested in clinical settings, and the first successful treatments have now entered clinical practice (e.g. spinraza for spinal muscular atrophy). Successful clinical translation depends on the quality and translatability of preclinical findings and on the predictive value of the experimental models used in their initial development. This Special Issue of Disease Models & Mechanisms has a particular focus on translational research for NMDs. The collection includes original research focusing on advances in the development of novel in vitro and in vivo models, broader understanding of disease pathology and progression, and approaches to modify the disease course in these models. We also present a series of special articles and reviews that highlight our understanding of cellular mechanisms, biomarkers to tract disease pathology, the diversity of mouse models for NMDs, the importance of high-quality preclinical studies and data validation, and the pitfalls of successfully moving a potential therapeutic strategy to the clinic. In this Editorial, we summarize the highlights of these articles and place their findings in the broader context of the NMD research field.
Limb dynamics in agility jumps of beginner and advanced dogs
Authors: Söhnel Katja , Rode Christian , de Lussanet Marc H. E. , Wagner Heiko , Fischer Martin S. , Andrada Emanuel
Published: February 2020

A considerable body of work has examined the dynamics of different dog gaits, but there are no studies that focused on limb dynamics in jumping. Jumping is an essential part of dog agility, a dog sport in which handlers direct their dogs through an obstacle course in a limited time. We hypothesized that limb parameters like limb length and stiffness indicate the skill level of dogs. We analyzed global limb parameters in jumping for 10 advanced and 10 beginner dogs. In experiments, we collected 3D kinematics and ground reaction forces during dog jumping at high forward speeds. Our results revealed general strategies of limb control in jumping and highlighted differences between advanced and beginner dogs. In take-off, the spatially leading forelimb was 75% (p<0.001) stiffer than the trailing forelimb. In landing, the trailing forelimb was 14% stiffer (p<0.001) than the leading forelimb. This indicates a strut-like action of the forelimbs to achieve jumping height in take-off and to transfer vertical velocity into horizontal velocity in landing (with switching roles of the forelimbs). During landing, the more (24%) compliant forelimbs of beginner dogs (p=0.005), resulted in 17% (p=0.017) higher limb compression during the stance phase. This is associated with a larger amount of eccentric muscle contraction, which might in turn explain the soft tissue injuries that frequently occur in the shoulder region of beginner dogs. For all limbs, length at toe-off was greater for advanced dogs. Hence, limb length and stiffness might be used as objective measures of skill.