bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Trial of the Bruton Tyrosine-Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Waldenström Macroglobulinemia
Authors: An Gang , Zhou Daobin , Cheng Shu , Zhou Keshu , Li Jianyong , Zhou Jianfeng , Xie Liping , Jin Jie , Zhong Liye , Yan Lingzhi , Guo Haiyi , Du Chenmu , Zhong Jinhua , Yu Yiling , Wu Binghao , Qiu Lugui 
Published: July 2021

Abstract

Purpose:
Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM.

Patients and Methods:
Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety.

Results:
Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2–36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88L265P/CXCR4WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred.

Conclusions:
Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit–risk profile for WM.
Integrated Human and Murine Clinical Study Establishes Clinical Efficacy of Ruxolitinib in Chronic Myelomonocytic Leukemia
Authors: Hunter Anthony M. , Newman Hannah , Dezern Amy E. , Steensma David P. , Niyongere Sandrine , Roboz Gail J. , Mo Qianxing , Chan Onyee , Gerds Aaron , Sallman David A. , Dominguez-Viqueira William , Letson Christopher , Balasis Maria E. , Ball Markus , Kruer Traci , Zhang Hailing , Lancet Jeffrey E. , List Alan F. , Sekeres Mikkael A. , Komrokji Rami S. , Padron Eric 
Published: July 2021

Abstract

Purpose:
Chronic myelomonocytic leukemia (CMML) is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies. CMML cells are uniquely hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) and robustly engraft in immunocompromised mice that secrete human cytokines. To leverage these unique biological features, we conducted an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that potently downregulates intracellular GM-CSF signaling.

Patients and Methods:
A total of 50 patients with WHO-defined CMML were enrolled in this open-label, multi-institution phase I/II clinical study, with a ruxolitinib dose of 20 mg twice daily studied in phase II. In parallel, 49 patient-derived xenografts (PDX) derived from 13 study participants were generated and randomized to receive ruxolitinib or vehicle control.

Results:
The most common grade 3/4 treatment-related toxicities observed were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38% by Myelodysplastic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) International Working Group (IWG) criteria and 43% of patients with baseline splenomegaly achieved a spleen response. Profiling of cytokine levels and somatic mutations at baseline failed to identify predictive biomarkers. PDX models derived from screening samples of study participants recapitulated responses seen in humans, particularly spleen responses, and corroborated ruxolitinib's clinical efficacy in a randomized murine study not feasible in human trials.

Conclusions:
Ruxolitinib demonstrated clinical efficacy and an acceptable adverse event profile in patients with CMML, identifying a potential novel therapeutic in this rare malignancy. Furthermore, this study demonstrates proof of concept that PDX modeling can recapitulate responses of patients treated on clinical trial and represents a novel correlative study that corroborates clinical efficacy seen in humans.
See related commentary by Shastri and Adrianzen-Herrera, p. 6069
Molecular Dosimetry of Temozolomide: Quantification of Critical Lesions, Correlation to Cell Death Responses, and Threshold Doses
Authors: Stratenwerth Björn , Geisen Susanne M. , He Yang , Beltzig Lea , Sturla Shana J. , Kaina Bernd 
Published: July 2021

Abstract
Temozolomide (TMZ) is a DNA-methylating agent used in cancer chemotherapy, notably for glioblastoma multiforme (GBM), where it is applied as a front-line drug. One of the DNA alkylation products of TMZ is the minor lesion O6-methylguanine (O6MeG), which is responsible for nearly all genotoxic, cytotoxic, and cytostatic effects induced in the low-dose range relevant for cancer therapy. Here, we addressed the question of how many O6MeG adducts are required to elicit cytotoxic responses. Adduct quantification revealed that O6MeG increases linearly with dose. The same was observed for DNA double-strand breaks (DSB) and p53ser15. Regarding apoptosis, hockeystick modeling indicated a possible threshold for A172 cells at 2.5 μmol/L TMZ, whereas for LN229 cells no threshold was detected. Cellular senescence, which is the main cellular response, also increased linearly, without a threshold. Using a dose of 20 μmol/L, which is achievable in a therapeutic setting, we determined that 14,000 adducts give rise to 32 DSBs (γH2AX foci) in A172 cells. This leads to 12% cell death and 35% of cells entering senescence. In LN229 cells, 20 μmol/L TMZ induced 20,600 O6MeG adducts, 66 DSBs (γH2AX foci), 24% apoptosis, and 52% senescence. The linear dose response and the genotoxic and cytotoxic effects observed at therapeutically relevant dose levels make it very likely that the TMZ target concentration triggers a significant cytotoxic and cytostatic effect in vivo. Despite a linear increase in the O6MeG adduct level, DSBs, and p53 activation, the low curative effect of TMZ results presumably from the low rate of apoptosis compared to senescence.
High Prevalence of Severe Aortic Stenosis in Low-Flow State Associated With Atrial Fibrillation
Authors: Alsidawi Said , Khan Sana , Pislaru Sorin V. , Thaden Jeremy J. , El-Am Edward A. , Scott Christopher G. , Morant Kareem , Oguz Didem , Luis Sushil A. , Padang Ratnasari , Lane Colleen E. , McCully Robert B. , Pellikka Patricia A. , Oh Jae K. , Nkomo Vuyisile T. 
Published: July 2021

Background:
Atrial fibrillation (AF) is a low-flow state and may underestimate aortic stenosis (AS) severity. Single-high Doppler signals (HS) consistent with severe AS (peak velocity ≥4 m/s or mean gradient ≥40 mm Hg) are averaged down in current practice. The objective for the study was to determine the significance of HS in AF low-gradient AS (LGAS).

Methods:

One thousand five hundred forty-one patients with aortic valve area ≤1 cm
2
and left ventricular ejection fraction ≥50% were identified and classified as high-gradient AS (HGAS) (≥40 mm Hg) and LGAS (<40 mm Hg), and AF versus sinus rhythm (SR). Available computed tomography aortic valve calcium scores (AVCS) were retrieved from the medical record. Outcomes were assessed.

Results:

Mean age was 76±11 years, female 47%. Mean gradient was 51±12 in SR-HGAS, 48±10 in AF-HGAS, 31±5 in SR-LGAS, and 29±7 mm Hg in AF-LGAS, all
P
≤0.001 versus SR-HGAS; HS were present in 33% of AF-LGAS. AVCS were available in 34%. Compared with SR-HGAS (2409 arbitrary units; interquartile range, 1581–3462) AVCS were higher in AF-HGAS (2991 arbitrary units; IQR1978–4229,
P
=0.001), not different in AF-LGAS (2399 arbitrary units; IQR1817–2810,
P
=0.47), and lower in SR-LGAS (1593 arbitrary units; IQR945–1832,
P
<0.001); AVCS in AF-LGAS were higher when HS were present (
P
=0.048). Compared with SR-HGAS, the age-, sex-, comorbidity index-, and time-dependent aortic valve replacement-adjusted mortality risk was higher in AF-HGAS (hazard ratio=1.82 [1.40–2.36],
P
<0.001) and AF-LGAS with HS (hazard ratio=1.54 [1.04–2.26],
P
=0.03) but not different in AF-LGAS without HS or SR-LGAS (both
P
=not significant).

Conclusions:
Severe AS was common in AF-LGAS. AVCS in AF-LGAS were not different from SR-HGAS. AVCS were higher and mortality worse in AF-LGAS when HS were present.
Use of Deep Learning for Weather Radar Nowcasting
Authors: Cuomo Joaquin , Chandrasekar V. 
Published: July 2021

AbstractNowcasting based on weather radar uses the current and past observations to make estimations of future radar echoes. There are many types of operationally deployed nowcasting systems, but none of them are currently based on deep learning, despite it being an active area of research in the last few years. This paper explores deep learning models as alternatives to current methods by proposing different architectures and comparing them against some operational nowcasting systems. The methods proposed here, harnessing residual convolutional encoder-decoder architectures, reach a level of performance expected of current systems and in certain scenarios can even outperform them. Finally, some of the potential drawbacks of using deep learning are analyzed. No decay in the performance on a different geographical area from where the models were trained was found. No edge or checkerboard artifact, common in convolutional operations, was found that affects the nowcasting metrics.
Anticipatory Culture in the Bering Sea: Weather, Climate and Temporal Dissonance
Authors: Baker Zeke 
Published: July 2021

AbstractA major implication of climate change is the declining capacity for communities to anticipate future conditions and scenarios. In the Bering Sea region of Western Alaska, this situation is acute and holds manifold consequences, particularly for the region’s primarily Indigenous residents. Based upon interviews and fieldwork in two Bering Sea communities and among regional weather forecasters, this paper explores the intertwined temporalities of weather, climate, and social life. I demonstrate that anticipatory culture, which otherwise structures anticipatory practices regarding climate, local weather, and social life, is beset by temporal dissonance across three timescales. First, dramatic climatic and ecosystem shifts reshape how Indigenous Peoples envision themselves as culturally inhabiting a long-range history and future. Second, changes in weather patterns, ecological cycles, and sea ice dynamics upset evaluations of seasonality, leading to a pervasive sense of unpredictability. Third, on the everyday timescale, social and technological change complicates mariners’ evaluations of risk and economic (commercial and subsistence) decision-making. I conclude by connecting these three socio-environmental temporalities to the temporal frames that primarily characterize weather and climate services, with an emphasis on the US National Weather Service. The paper discusses how such services may further orient toward engaging socially embedded practices of anticipation in addition to formal prediction. Such an orientation can help to shape an anticipatory culture that more closely aligns meteorological and social patterns.
Evaluation of choroidal circulation and stromal features in Graves’ disease
Authors: Aksoy Mustafa , Simsek Mert , Apaydın Mahmut 
Published: July 2021

Purpose: This study aimed to evaluate choroidal thickness (CT) and choroidal vascularity index (CVI) in patients with Graves’ disease (GD) without ocular involvement. Methods: Fifty patients diagnosed with GD and 50 age and gender matched healthy control subjects were retrospectively evaluated. Measurements were taken from five different points on CT images. Choroid images were classified as lumen regions (LA) and stromal regions (SA) using the image binarization method. CVI was calculated by dividing LA by the total choroidal area (TCA). The effects of Thyrotropin Receptor Antibody (TRAb), age, GD duration, blood pressure, axial length measurements, and intraocular pressure were analyzed on CT and CVI measurements. Results: Mean age was 40.1 ± 13.5 years in the patient group and 39.3 ± 13.6 years in the control group ( p = 0.89). There was no significant difference between the GD group and control group in terms of CT measurements. There was a significant difference between the mean CVI measurements of the GD group and control group (68.03 ± 3.41 and 66.62 ± 3.11, respectively) ( p < 0.001). Univariate linear regression analysis revealed a positive correlation between TRAb and CVI ( p = 0.013). Conclusion: While there was no significant difference between the CT measurements of the GD group and the control group, the GD group had significantly higher CVI measurements.
A team mental model approach to understanding team effectiveness in an emergency department: A qualitative study
Authors: Wise Sarah , Duffield Christine , Fry Margaret , Roche Michael 
Published: July 2021

Objectives To demonstrate how the team mental model concept can broaden our understanding of team effectiveness in health care by exploring the knowledge that underpins it, and the workplace conditions that sustain it in a metropolitan emergency department (ED) in Sydney, Australia. Methods This study draws on accounts of 19 ED clinicians (registered nurses, doctors and nurse practitioners) of their teamwork practice and perceptions of their team’s effectiveness through semi-structured interviews. Analysis was conducted in two stages. A thematic analysis was followed by a template analysis using the a priori themes of task, team, team process and goal knowledge to specify the content of the team’s mental model. Results The content of the ED team’s mental model revealed that the knowledge the team employed to coordinate their work was deeply embedded in the team’s tasks and the workplace context. Team effectiveness not only relied on how well team members coordinate, but also their ability to perform their own role effectively and efficiently. Three workplace conditions were identified as enablers to individuals acquiring the knowledge needed to work effectively in the team: stability in team membership; workplace experience; and the spatial-temporal conditions of emergency work where permanent emergency doctors and nurses executed their tasks concurrently, regularly interacted and shared a common goal. Conclusions Getting health care teams ‘on the same page’ is a long-standing challenge. This study suggests that solutions may lay in the organisation of health care work, creating team stability and opportunities for team members to interact that allows a team mental model to emerge.
One-Year Clinical Outcome and Risk Factor Analysis of Directional Atherectomy Followed With Drug-Coated Balloon for Femoropopliteal Artery Disease
Authors: Feng Zibo , Yang Shuofei , Sang Hongfei , Xue Guanhua , Ni Qihong , Zhang Lan , Zhang Wei , Fang Xin , Ye Meng 
Published: July 2021

Purpose: This study investigated the 1-year clinical outcomes of directional atherectomy combined with drug-coated balloon (DA + DCB) in femoropopliteal artery disease (FPAD) from real-world experience. Materials and Methods: A retrospective study was conducted of patients treated between July 2016 and June 2019 using DA + DCB for FPAD. Patients’ demographics, comorbidities, clinical characteristics and outcomes, and angiography and duplex ultrasound findings were analyzed. The 6-month and 1-year primary patency, primary assisted patency, secondary patency, and freedom from clinically-driven target lesion revascularization (CD-TLR) were evaluated. Univariate and multivariate analyses were performed to identify risk factors of primary patency loss or CD-TLR. Results: Seventy-nine consecutive patients (83 lesions, mean age 70.9 years, 52 men) were included. Twenty-seven limbs had lifestyle-limiting claudication and 56 limbs had critical limb ischemia. There were 73 and 10 limbs with de novo lesion and in-stent restenosis, respectively. The mean lesion length of all the patients was 22.1 cm. The mean length of chronic total occlusions (CTOs) was 8.3 cm. Severe calcification was found in 32.5% cases. The 1-year primary patency rate was 80.8% and freedom from CD-TLR was 92.2%. The bailout stenting rate was 2.4%. Patients with CTO >10 cm had significantly lower 1-year primary patency rate and freedom from CD-TLR than did patients with CTO ≤10 cm. Total length of CTO (stratified as ≤5 cm, 5–10 cm, >10 cm) was identified as an independent risk factor of 1-year primary patency loss and CD-TLR. Conclusion: DA + DCB appears to be a safe and effective endovascular therapy to treat FPAD in real-world clinical practice, with a promising 1-year patency rate with a low rate of bailout stenting.
The Surgical Learning Curve for Modified Lapidus Procedure for Hallux Valgus Deformity
Authors: Jackson J. Benjamin , Kennedy Benjamin , Deal Patrick , Gonzalez Tyler 
Published: July 2021

Background Hallux valgus is one of the most common orthopaedic deformities of the foot, affecting as much as 23% of the population age 18 to 65. In addition to its high prevalence, it has a complex multifactorial pathogenesis. Surgical correction options have variable rates of success and new techniques are being developed. The modified Lapidus procedure attempts to correct in 3 planes of deformity, which may create a steeper learning curve for those newly adopting the technique. Methods A retrospective review was performed on patients who underwent hallux valgus reconstruction with a modified Lapidus procedure between March 2018 and July 2020. Exclusion criteria included revision surgery, 6 or more concurrent procedures, or a flexor digitorum longus tendon transfer for adult acquired flatfoot correction. Results There were a total of 81 modified Lapidus procedures for hallux valgus within the study time frame and 68 were included in the study. Over a period of 2 years there was a significant decrease in overall surgery duration from 78.93 minutes at month 0 to 61.80 minutes at 24 months ( P = .036). The average preoperative/postoperative intermetatarsal angles were 15.08° and 4.91°, respectively. There was an average decrease of 10.17°. The rate of nonunion was 4.41% (3/68), and the rate of recurrence at 6 months was 5.88% (4/68). There was not a significant difference in the rate of recurrence ( P = .394) or the rate of nonunion ( P = .817) as the surgeon increased in experience. Conclusion Although there is a significant learning curve for the modified Lapidus procedure, it is largely overcome by the 23rd case. Additionally, experience with the technique does not appear to affect the patient outcomes of nonunion or recurrence. Levels of Evidence Level IV: Retrospective
High concurrent validity between digital and analogue algometers to measure pressure pain thresholds in healthy participants and people with migraine: a cross-sectional study
Authors: Castien René F. , Coppieters Michel W. , Durge Tom S. C. , Scholten-Peeters Gwendolyne G. M. 
Published: July 2021

Abstract
Background
Pressure pain thresholds (PPTs) are commonly assessed to quantify mechanical sensitivity in various conditions, including migraine. Digital and analogue algometers are used, but the concurrent validity between these algometers is unknown. Therefore, we assessed the concurrent validity between a digital and analogue algometer to determine PPTs in healthy participants and people with migraine.

Methods
Twenty-six healthy participants and twenty-nine people with migraine participated in the study. PPTs were measured interictally and bilaterally at the cephalic region (temporal muscle, C1 paraspinal muscles, and trapezius muscle) and extra-cephalic region (extensor carpi radialis muscle and tibialis anterior muscle). PPTs were first determined with a digital algometer, followed by an analogue algometer. Intraclass correlation coefficients (ICC3.1) and limits of agreement were calculated to quantify concurrent validity.

Results
The concurrent validity between algometers in both groups was moderate to excellent (ICC3.1 ranged from 0.82 to 0.99, with 95%CI: 0.65 to 0.99). Although PPTs measured with the analogue algometer were higher at most locations in both groups (p < 0.05), the mean differences between both devices were less than 18.3 kPa. The variation in methods, such as a hand-held switch (digital algometer) versus verbal commands (analogue algometer) to indicate when the threshold was reached, may explain these differences in scores. The limits of agreement varied per location and between healthy participants and people with migraine.

Conclusion
The concurrent validity between the digital and analogue algometer is excellent in healthy participants and moderate in people with migraine. Both types of algometer are well-suited for research and clinical practice but are not exchangeable within a study or patient follow-up.
Air pollution and children’s health—a review of adverse effects associated with prenatal exposure from fine to ultrafine particulate matter
Authors: Johnson Natalie M. , Hoffmann Aline Rodrigues , Behlen Jonathan C. , Lau Carmen , Pendleton Drew , Harvey Navada , Shore Ross , Li Yixin , Chen Jingshu , Tian Yanan , Zhang Renyi 
Published: July 2021

AbstractBackgroundParticulate matter (PM), a major component of ambient air pollution, accounts for a substantial burden of diseases and fatality worldwide. Maternal exposure to PM during pregnancy is particularly harmful to children’s health since this is a phase of rapid human growth and development.MethodIn this review, we synthesize the scientific evidence on adverse health outcomes in children following prenatal exposure to the smallest toxic components, fine (PM2.5) and ultrafine (PM0.1) PM. We highlight the established and emerging findings from epidemiologic studies and experimental models.ResultsMaternal exposure to fine and ultrafine PM directly and indirectly yields numerous adverse birth outcomes and impacts on children’s respiratory systems, immune status, brain development, and cardiometabolic health. The biological mechanisms underlying adverse effects include direct placental translocation of ultrafine particles, placental and systemic maternal oxidative stress and inflammation elicited by both fine and ultrafine PM, epigenetic changes, and potential endocrine effects that influence long-term health.ConclusionPolicies to reduce maternal exposure and health consequences in children should be a high priority. PM2.5levels are regulated, yet it is recognized that minority and low socioeconomic status groups experience disproportionate exposures. Moreover, PM0.1levels are not routinely measured or currently regulated. Consequently, preventive strategies that inform neighborhood/regional planning and clinical/nutritional recommendations are needed to mitigate maternal exposure and ultimately protect children’s health.