bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acoustic analysis of surgeons’ voices to assess change in the stress response during surgical in situ simulation
Authors: Hall Andrew , Kawai Kosuke , Graber Kelsey , Spencer Grant , Roussin Christopher , Weinstock Peter , Volk Mark S 
Published: April 2021

IntroductionStress may serve as an adjunct (challenge) or hindrance (threat) to the learning process. Determining the effect of an individual’s response to situational demands in either a real or simulated situation may enable optimisation of the learning environment. Studies of acoustic analysis suggest that mean fundamental frequency and formant frequencies of voice vary with an individual’s response during stressful events. This hypothesis is reviewed within the otolaryngology (ORL) simulation environment to assess whether acoustic analysis could be used as a tool to determine participants’ stress response and cognitive load in medical simulation. Such an assessment could lead to optimisation of the learning environment.MethodologyORL simulation scenarios were performed to teach the participants teamwork and refine clinical skills. Each was performed in an actual operating room (OR) environment (in situ) with a multidisciplinary team consisting of ORL surgeons, OR nurses and anaesthesiologists. Ten of the scenarios were led by an ORL attending and ten were led by an ORL fellow. The vocal communication of each of the 20 individual leaders was analysed using a long-term pitch analysis PRAAT software (autocorrelation method) to obtain mean fundamental frequency (F0) and first four formant frequencies (F1, F2, F3 and F4). In reviewing individual scenarios, each leader’s voice was analysed during a non-stressful environment (WHO sign-out procedure) and compared with their voice during a stressful portion of the scenario (responding to deteriorating oxygen saturations in the manikin).ResultsThe mean unstressed F0 for the male voice was 161.4 Hz and for the female voice was 217.9 Hz. The mean fundamental frequency of speech in the ORL fellow (lead surgeon) group increased by 34.5 Hz between the scenario’s baseline and stressful portions. This was significantly different to the mean change of −0.5 Hz noted in the attending group (p=0.01). No changes were seen in F1, F2, F3 or F4.ConclusionsThis study demonstrates a method of acoustic analysis of the voices of participants taking part in medical simulations. It suggests acoustic analysis of participants may offer a simple, non-invasive, non-intrusive adjunct in evaluating and titrating the stress response during simulation.
Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers
Authors: Colen Rivka R , Rolfo Christian , Ak Murat , Ayoub Mira , Ahmed Sara , Elshafeey Nabil , Mamindla Priyadarshini , Zinn Pascal O , Ng Chaan , Vikram Raghu , Bakas Spyridon , Peterson Christine B , Rodon Ahnert Jordi , Subbiah Vivek , Karp Daniel D , Stephen Bettzy , Hajjar Joud , Naing Aung 
Published: April 2021

BackgroundWe present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers.MethodsThe study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 “controlled disease” (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance.FindingsThe 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively.ConclusionOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.InterpretationOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.
Longitudinal observational study investigating outcome measures for clinical trials in inclusion body myositis
Authors: Sangha Gina , Yao Bohao , Lunn Daniel , Skorupinska Iwona , Germain Louise , Kozyra Damian , Parton Matt , Miller James , Hanna Michael G , Hilton-Jones David , Freebody Jane , Machado Pedro M 
Published: April 2021

ObjectiveTo describe decline in muscle strength and physical function in patients with sporadic inclusion body myositis (IBM).MethodsManual muscle testing (MMT), quantitative muscle testing (QMT) and disability scoring using the IBM Functional Rating Scale (IBMFRS) were undertaken for 181 patients for up to 7.3 years. The relationship between MMT, QMT and IBMFRS composite scores and time from onset were examined using linear mixed effects models adjusted for gender and age of disease onset. Adaptive LASSO regression analysis was used to identify muscle groups that best predicted the time elapsed from onset. Cox proportional hazards regression was used to evaluate time to use of a mobility aid.ResultsMultilevel modelling of change in percentage MMT, QMT and IBMFRS score over time yielded an average decline of 3.7% (95% CI 3.1% to 4.3%), 3.8% (95% CI 2.7% to 4.9%) and 6.3% (95% CI 5.5% to 7.2%) per year, respectively. The decline, however, was not linear, with steeper decline in the initial years. Older age of onset was associated with a more rapid IBMFRS decline (p=0.007), but did not influence the rate of MMT/QMT decline. Combination of selected muscle groups allowed for generation of single measures of patient progress (MMT and QMT factors). Median (IQR) time to using a mobility aid was 5.4 (3.6–9.2) years, significantly affected by greater age of onset (HR 1.06, 95% CI 1.04 to 1.09, p<0.001).ConclusionThis prospective observational study represents the largest IBM cohort to date. Measures of patient progress evaluated in this study accurately predict disease progression in a reliable and useful way to be used in trial design.
Living with systemic lupus erythematosus in 2020: a European patient survey
Authors: Cornet Alain , Andersen Jeanette , Myllys Kirsi , Edwards Angela , Arnaud Laurent 
Published: April 2021

ObjectiveThe aim of this study was to analyse the 2020 burden of Systemic Lupus Erythematosus (SLE) in Europe, from the patients’ perspective.MethodsIn May 2020, Lupus Europe, the European umbrella patient association for SLE, designed and disseminated a multilingual anonymous online survey to individuals with a self-reported physician’s diagnosis of SLE living in Europe.ResultsData from 4375 SLE survey respondents (95.9% women, median age: 45 (IQR: 36–54) years, 70.7% Caucasians) from 35 European countries were analysed. The median age at SLE diagnosis was 30 years (IQR: 22–40) and the median diagnosis delay was 2 years (IQR: 0–6). The most commonly affected organ-systems included the joints (81.8%) and skin (59.4%), with renal involvement in 30%. Another diagnosis was given before that of SLE in 45.0%, including psychological/mental disorders in 9.1% and fibromyalgia in 5.9%. The median number of symptoms reported was 9 (IQR: 6–11) out of 21, with fatigue most common (85.3%) and most bothersome. The median number of SLE-related medications was 5 (IQR: 3–7), including antimalarials (75%), oral glucocorticoids (52.4%), immunosuppressants (39.8%) and biologics (10.9%). Respondents reported significant impact over their studies, career and emotional/sexual life in 50.7%, 57.9% and 38.2%, respectively. Appropriate access to care was highly variable across countries and care component.ConclusionThis survey underlines the 2020 burden and strong heterogeneity in the care of SLE across Europe, from the patient’s perspective. Altogether, these data may prove crucial to physicians, patients and policy-makers to improve the diagnosis and management of this rare and complex disease.
Spherically symmetric analytic solutions and naked singularities in Einstein–Aether theory
Authors: Chan R. , Silva M. F. A. da , Satheeshkumar V. H. 
Published: April 2021

AbstractWe analyze all the possible spherically symmetric exterior vacuum solutions allowed by the Einstein–Aether theory with static aether. We show that there are three classes of solutions corresponding to different values of a combination of the free parameters, $$c_{14}=c_1+c_4$$

c
14

=

c
1

+

c
4

, which are: $$ 0< c_{14}<2$$

0
<

c
14

<
2

, $$c_{14} < 0$$

c
14

<
0

, and $$c_{14}=0$$

c
14

=
0

. We present explicit analytical solutions for $$c_{14}=3/2, 16/9, 48/25, -16$$

c
14

=
3
/
2
,
16
/
9
,
48
/
25
,
-
16

and 0. The first case has some pathological behavior, while the rest have all singularities at $$r=0$$

r
=
0

and are asymptotically flat spacetimes. For the solutions $$c_{14}=16/9, 48/25\, \mathrm {\, and \,}\, -16$$

c
14

=
16
/
9
,
48
/
25

and

-
16

we show that there exist no horizons, neither Killing horizon nor universal horizon, thus we have naked singularities. This characteristic is completely different from general relativity. We briefly discuss the thermodynamics for the case $$c_{14}=0$$

c
14

=
0

where the horizon exists.
Power Spectrum Features of Acupoint Bioelectricity Signal
Authors: Zhang Jingjing , Yu Renhuan , Zhao Enlu , Zhou Quan , Gai Shuping 
Published: April 2021

Background. Since the 1950s, many studies have been conducted on the electrical properties of acupuncture points (acupoints), especially their bio-resistance characteristics. Results of such studies have been inconclusive due to factors such as sweat gland density and compounding factors of applying electrical stimulation. In this study, a power spectrum instrument was used to assess the power spectrum and power of acupoints and nonacupoints without electrical stimulation. Using such instrumentation, specificity of electrical signals of acupoints was also explored. Methods. Thirty-six subjects (29 females, 7 males) participated in the study. Stainless steel acupuncture needles (diameter 0.35 mm; length 50 mm) were used. Five acupoints were tested: ST 36, SP 6, GB 39, GB 37, and K I9. Four control sites 0.5–1.0 cm adjacent to each acupoint were chosen. After needle insertion into the acupoint and control sites, the needles were attached to the power spectrum instrument to acquire any electrical signals. Acquire signals were analyzed using self-written software. Results. Power spectrum difference between acupoint and nonacupoint signals was 0–2 Hz. Results of t-test or signed rank sum test (α = 0.05) found that electrical signals between acupoints and nonacupoints were markedly different (

P

< 0.05). Conclusion. Acupoint bioelectricity signals are higher than adjacent nonacupoints. The most significant difference is distributed between 0 Hz and 2 Hz.
Correlations between Left Ventricular and Left Atrial Function Assessed by Speckle Tracking Echocardiography in Patients with Treated Well-Controlled Arterial Hypertension
Authors: Uziębło-Życzkowska Beata , Krzesiński Paweł 
Published: April 2021

Introduction. Even in patients with well-controlled arterial hypertension (AH) and without significant comorbidities, left ventricular (LV) and left atrial (LA) strain abnormalities may sometimes be found in speckle-tracking echocardiography. Therefore, the aim of this study was to investigate the correlation between LA strain and LV diastolic and systolic function in a group of patients with treated, well-controlled AH. Material and methods. LA contractile, conduit, and reservoir function, together with echocardiographic signs of LV diastolic function and LV global longitudinal strain (LV GLS), were assessed in 101 patients with treated, well-controlled AH who met the standard criteria of normal LV ejection fraction (LVEF) and normal LV diastolic function. Results. A relevant percentage of study participants presented lower than reference LV (−18.7% for LV GLS) and LA strain (32.9% for LAS during reservoir phase, LASr; −15.9% for LAS during contraction phase, LASct; and −13.9% for LAS during conduit phase, LAScd) values. Moreover, there were statistically significant differences in LA longitudinal strain (LAS) values (LASr (31.43 vs. 36.33;

p

= 0.0007) and LAS LAScd (−13.09 vs. −15.79;

p

= 0.008)) between patients with high (>the absolute value of −20%) and lower (≤the absolute value of −20%) LV GLS, confirmed by significant correlations between LASr, LAScd, and GLS. In the correlations analysis between LAS values and LV diastolic function parameters, statistical significance was obtained for the following: LASct (contraction) versus e’avg, LASct versus E/A, LASct versus A, LAScd versus e’avg, LAScd versus E/A, and LAScd versus A. Conclusions. LV and LA strain abnormalities occurred within a significant percentage of patients with treated, well-controlled AH. Impaired LA strain is associated with lower LV strain and reduced LV diastolic function parameters, reflecting both the passive and active properties of the LA.
Obinutuzumab in Combination with Chemotherapy Enhances Direct Cell Death in CD20-Positive Obinutuzumab-resistant Non-Hodgkin Lymphoma Cells
Authors: Fujimura Takaaki , Yamashita-Kashima Yoriko , Kawasaki Natsumi , Yoshiura Shigeki , Harada Naoki , Yoshimura Yasushi 
Published: April 2021

Abstract
Follicular lymphoma commonly recurs and is difficult to cure. Obinutuzumab is a humanized glycoengineered type II anti-CD20 antibody with a mode of action that includes induction of antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and direct cell death. There is no evidence on the effectiveness of retreatment with obinutuzumab in patients with prior obinutuzumab treatment. Using obinutuzumab-induced direct-cell-death–resistant cells, we investigated the efficacy of obinutuzumab retreatment in combination with chemotherapeutic agents used in follicular lymphoma treatment. Human non-Hodgkin lymphoma SU-DHL-4 cells were sustainably exposed to obinutuzumab in vitro, and 17 resistant clones expressing CD20 and showing 100-fold higher IC50 of obinutuzumab than parental cells were established. The growth inhibition effect of obinutuzumab in combination with bendamustine, 4-hydroperoxy-cyclophosphamide, doxorubicin, vincristine, or prednisolone was estimated using an interaction index based on the Bliss independence model. For each clone, there were various combinations of obinutuzumab and chemotherapeutic agents that showed supra-additive effects. Obinutuzumab combined with doxorubicin enhanced caspase-dependent apoptosis and growth inhibition effect. Obinutuzumab combined with prednisolone enhanced DNA fragmentation and G0–G1 arrest. These combinations also had an antitumor effect in mouse xenograft models. Our results indicate that retreatment with obinutuzumab, when it is combined with chemotherapeutic agents, is effective in the CD20-positive obinutuzumab-induced direct-cell-death–resistant cells.
Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?
Authors: Lentz Robert W. , Colton Meryl D. , Mitra Siddhartha S. , Messersmith Wells A. 
Published: April 2021

Abstract
While immunotherapy has revolutionized the treatment of many types of advanced cancer, most patients still do not derive benefit. The currently available immune checkpoint inhibitors target the adaptive immune system, generating a T-cell antitumor response. However, an antitumor immune response depends on a complex interplay of both innate and adaptive immune cells. The innate immune system is a promising new target, and innate immune checkpoint inhibitors can disrupt inhibitory interactions (“don't eat me” signals) between tumor and both phagocytes and natural killer cells. The checkpoint inhibitor may also provide a stimulatory interaction (“eat me” signal), or this can be achieved through use of combination therapy. This generates antitumor effector functions including phagocytosis, natural cytotoxicity, antibody-dependent effects, and synergistic activation of the adaptive immune system via antigen presentation. This is a rapidly expanding area of drug development, either alone or in combination (with anticancer antibodies or adaptive immune checkpoint inhibitors). Here, we comprehensively review the mechanism of action and up-to-date solid tumor clinical trial data of the drugs targeting phagocytosis checkpoints (SIRPα/CD47, LILRB1/MHC-I, and LILRB2/MHC-I) and natural killer–cell checkpoints (TIGIT/CD112 + CD155, PVRIG/CD112, KIRs/MHC-I, and NKG2A-CD94/HLA-E). Innate immune checkpoint inhibitors could once again revolutionize immune-based cancer therapies.
Abstract IA-001: Genomic architecture and targets in hypoxic tumors
Authors: Bristow Robert G. 
Published: April 2021

Abstract
Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localized setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumors and are associated with many biologic drivers of tumor progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal adaption and evolution and driving an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a "contextual lethal" vulnerability in hypoxic prostate tumors which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to prostate and other cancers, and also characterize the role of hypoxia in driving early metastatic spread. Supported by core funding from Cancer Research UK Manchester Institute and grants within the Cancer Research UK Manchester RadNet Unit, NIHR Manchester Biomedical Research Centre and a Prostate Cancer UK-Movember Centre of Excellence award.
Citation Format: Robert G. Bristow. Genomic architecture and targets in hypoxic tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-001.
Abstract IA-003: Oxygen dependent resistance to PARP inhibitors
Authors: Mehibel Manal , Xu Jimmy , Li Grace , Moon Jung , Thakkar Kaushik , Diep Anh , Kim Ryan , Bloomstein Joshua , Xiao Siren , Bacal Julien , Saldivar Joshua , Le Quynh , Cimprich Karlene , Rankin Erinn , Giaccia Amato 
Published: April 2021

Abstract
Severe hypoxia causes resistance to conventional chemotherapy and has been reported to synergize with PARP inhibitors (PARPi) through suppression of homologous recombination (HR). While this synergistic killing is true at oxygen levels less than 0.5%, our study shows that less severe hypoxia (e.g. 2% oxygen) is instead associated with resistance to PARPi in HR proficient cells. Interestingly, we demonstrate that HR deficient hypoxic tumors are significantly less responsive to PARPi, due to limited ROS-induced intrinsic DNA damage. To determine the contribution of hypoxic cells to PARPi, we used the hypoxic cytotoxin Tirapazamine to target hypoxic tumor cells. We found that the elimination of hypoxic tumor cells by Tirapazamine led to a substantial antitumor response with PARPi compared to PARPi treated tumors alone, without enhancing normal tissue toxicity. These studies indicate that tumor hypoxia reduces the efficacy of PARPi to tumor cells and that eliminating hypoxic tumor cells will enhance the efficacy of PARPi therapy.
Citation Format: Manal Mehibel, Jimmy Xu, Grace Li, Jung Moon, Kaushik Thakkar, Anh Diep, Ryan Kim, Joshua Bloomstein, Siren Xiao, Julien Bacal, Joshua Saldivar, Quynh Le, Karlene Cimprich, Erinn Rankin, Amato Giaccia. Oxygen dependent resistance to PARP inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-003.
Abstract IA-010: Deciphering DNA end resection at DSBs
Authors: Chowdhury Dipanjan 
Published: April 2021

Abstract
Double stranded DNA break (DSB)s are repaired by two major mechanistically distinct pathways, homologous recombination (HR) and non-homologous end joining (NHEJ). A decisive factor in the choice between DSB repair pathways is in the competition between DNA end protection (necessary for NHEJ) and DNA end resection (necessary for HR). As the ‘master regulator’ of DSB repair pathway choice, 53BP1, a chromatin-associated reader of epigenetic marks at DSBs, helps channel DSBs into the NHEJ pathway by restricting BRCA1-dependent end resection. 53BP1 nucleates the assembly of a higher order ensemble that includes the Shieldin complex, CST complex, and DNA polymerase (Pol) a-primase complex. Loss of BRCA1 provides a therapeutic opportunity as these tumors are exquisitely sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP), and are also susceptible to platinum-based drugs. Loss of 53BP1 or any of the 53BP1-interacting proteins restores end resection and causes PARPi resistance in BRCA1-mutant tumors. We recently identified Dynein light chain like protein 1 (DYNLL1) as as anti-resection factor. Loss of DYNLL1 allowed DNA end resection and restored HR, thereby inducing resistance to platinum drugs and PARPi in BRCA1-mutant tumors. At the molecular level, DYNLL1 limited the nucleolytic resection of DNA ends by interacting with the resection machinery. Importantly, purified DYNLL1 interacted with MRE11 and inhibited its exonuclease activity in vitro. Now we observe that 53BP1 loss prevents DYNLL1 recruitment to DSBs and more broadly to chromatin. We hypothesize that 53BP1 inhibits MRE11-mediated DNA end resection by recruiting DYNLL1 and that DYNLL1 functions in parallel of Shieldin-CST to regulate DNA end resection and DSB repair pathway choice. We are investigating the crosstalk between the Shieldin-CST and DYNLL1-MRE11 arms of the 53BP1-dependent anti-DNA end resection machinery.
Citation Format: Dipanjan Chowdhury. Deciphering DNA end resection at DSBs [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-010.