bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Conscious Control of Scapular Orientation in Oral Cancer Survivors With Scapular Dyskinesis: A Randomized Controlled Trial
Authors: Chen Yueh-Hsia , Huang Cheng-Ya , Liang Wei-An , Lin Chi-Rung , Chao Yuan-Hung
Published: August 2021

Objectives:

Spinal accessory nerve dysfunction is one of the complications of neck dissection in patients with oral cancer. This study aimed to explore the effects of long-term scapular-focused exercises and conscious control of scapular orientation on scapular movement and quality of life (QoL).

Methods:

This study was a randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Thirty-six patients with oral cancer were randomly allocated to the motor-control group (scapular-focused exercise + conscious control of scapular orientation) or the regular-exercise group (scapular-focused exercises only). Both groups received conventional physical therapy after neck dissection for 3 months. Shoulder pain intensity, active range of motion (AROM) of shoulder abduction, scapular muscle strength and activity under maximal voluntary isometric contraction (MVIC), scapular muscle activity when performing scapular movements, and QoL were measured at baseline, 1 month after the start of the intervention, and the end of the intervention.

Results:

Both groups showed significant improvement in all outcomes except shoulder pain intensity. After the 3-month intervention, the motor-control group had more significant improvement in AROM of shoulder abduction with a 19° difference (95% CI: 10-29, P < .001), muscle strength of upper trapezius with an 11 N difference (95% CI: 2-20; P = .021), and QoL than the regular-exercise group. When performing shoulder horizontal adduction and flexion, the relative value (%MVIC) of serratus anterior was smaller in the motor-control group with a 106%MVIC difference (95% CI: 7-205, P = .037).

Conclusions:

Scapular-focused exercises have promising effects on spinal accessory nerve dysfunction. Combining scapular-focused exercises with conscious control of scapular orientation has more remarkable benefits on AROM of shoulder abduction, UT muscle strength, and muscle activation pattern than the scapular-focused exercises alone. Conscious control of scapular orientation should be considered to integrate into scapular-focused exercises in patients with oral cancer and scapular dyskinesis. Trial registry name and URL, and registration number: ClinicalTrials.gov (URL: https://clinicaltrials.gov ; Approval No: NCT03545100)
Development of a Chronic Canine Ovariohysterectomy Model to Evaluate Vaginal Cuff Healing Using Two Closure Systems
Authors: Wiseman David , Hanzlik Josa A. , Richardson James A. , Shelton John M. , Evers Bret M. , Diamond Michael P. , Brown Ryan , Mazzucco Dan C.
Published: August 2021

Background and Purpose. This study established a suitable animal model of ovariohysterectomy; characterized the course and pattern of vaginal healing after ovariohysterectomy; and compared healing obtained after closure of the vaginal cuff with a novel cuff-closure device (Zip-stitch® clips) and VICRYL® sutures. Research Design and Study Sample. This prospective, randomized, controlled, blinded animal study was conducted in 27 mongrel hounds according to an IACUC-approved protocol. Each animal underwent ovariohysterectomy followed by vaginal cuff closure with Zip-stitch or VICRYL. At two or six weeks, animals were sacrificed for gross and histological analysis. Data Collection. The primary endpoint was the difference in the fraction of vaginal cuff healed six weeks after application of the closure device. Secondary endpoints included histopathologic cellular and tissue responses, including inflammation, necrosis, infection, and vascular and muscle changes. Results. In the test group, there were two distinct locations where fibrotic or granular tissue fusion between the anterior and posterior vaginal walls was observed: in tissue “captured” by a clip or in tissue around the clip. The fraction of the vaginal cuff healed was similar in animals treated with Zip-stitch clips and those treated with sutures at six weeks (68±10% vs 67±18%; P=.148, test for non-inferiority) after surgery. The test article performed similarly or better than the control article in terms of the intensity or extent of the secondary endpoints. Conclusions. Subject to further confirmation, this study supports Zip-stitch clips as a method to maintain immediate post-operative approximation of the vaginal cuff leading to healing but did not achieve statistical significance in its primary endpoint.
A Study on the Characteristics of Healthy Volunteers who Participate in Phase I Clinical Trials in Korea
Authors: Seo Ji-Hye , Kim Ock-Joo , Yoo Sang-Ho , Choi Eun Kyung , Park Ji-Eun
Published: August 2021

The phase I trial is the first step in administering a drug to humans, but it has no therapeutic purpose. Under the absence of therapeutic purpose, healthy volunteers demonstrated different motivations, unlike the actual patients participating in trials. There were many reported motivations, such as financial motivation, contributing to the health science, accessing ancillary health care benefits, scientific interest or interest in the goals of the study, meeting people, and general curiosity. The aim of this study was to identify the motivation and characteristics of healthy volunteers participating in phase I trials in the Republic of Korea. We gave surveys to 121 healthy volunteers to study their demographic characteristics and the reasons of participation. We identified whether the decision to participate in the research was influenced by demographic factors and whether the perception and attitudes toward the research were influenced by the characteristics of the healthy volunteers. After completion of the first survey, 12 healthy volunteers who had participated in a phase I clinical trial were selected to answer the second interview. According to our survey, most healthy volunteers were unmarried men and economically dependent. Most of them participated in the study because of financial reward. The most important factor to measure financial reward was the research period. Also, 43% of the volunteers were university students, 42% answered “university graduation” and 55% were residing in family-owned houses. Many healthy volunteers were found to be living in family homes and to have a student status or lack of economic independence. Results of the survey showed that 64% of respondents indicated having more than one clinical trial participation. In-depth interviews showed that healthy volunteers had diverse motivation to participate in research and that healthy volunteer perceive the clinical trial positively. The main motivation for healthy volunteers’ participation in research was “financial reward.” Healthy volunteers also considered research schedules, processes, and safety, and had a positive perception of clinical trials, but they thought that the public has a negative perception.
“Punched in the Balls”: Male Intimate Partner Violence Disclosures and Replies on Reddit
Authors: Sivagurunathan Marudan , Walton David M. , Packham Tara , Booth Richard , MacDermid Joy
Published: August 2021

Research on male intimate partner violence (IPV) survivors is limited. The sparse research on male IPV disclosure suggest males receive more negative and less helpful responses from potential sources of formal or informal support. Males may seek support on social networking sites (SNSs), hence, it is important to understand their emerging experiences of virtual disclosures. This study examined the nature and content of responses to IPV disclosures by male IPV survivors on a popular SNS (reddit.com). Search of Reddit submissions related to male IPV were carried out using three IPV related keywords for the calendar month of February 2019, resulting in 917 submissions. Twelve submissions that focused on male IPV disclosure were examined in detail. The 12 submissions were analyzed using quantitative content analysis while associated comments ( n = 569) were analyzed using qualitative approach. Two-thirds of the disclosures (8/12) were of personal IPV experiences. All disclosure narratives identified the sex of perpetrator, most stated the types of abuse (7/12), and some revealed the outcomes of past disclosures (4/12). Six major themes were developed through qualitative analysis of the associated comments: (1) Informational Support, (2) Nurturant Support, (3) Tangible Aid, (4) Negative Response (5) Self-Defence, and (6) Reciprocal Disclosure. Overall, males experienced a majority of supportive responses to IPV disclosures and some negative responses including criticism and minimizing the abuse. Males take risks in disclosure of IPV in person and online.
Biological Responses to Short-Term Maximal Exercise in Male Police Officers
Authors: Dergaa Ismail , Ben Saad Helmi , Romdhani Mohamed , Souissi Amine , Fessi Mohamed Saifeddin , Yousfi Narimen , Masmoudi Tasnim , Souissi Nizar , Ammar Achraf , Hammouda Omar
Published: August 2021

The specifics of short-term physical exercise are similar to the immediate reaction demands placed on police officers. Identifying the physiological predisposition to short-term high-intensity exercise in male law enforcement officers will assist in understanding their metabolism and make a significant contribution to a much more personal and individualized workout program. This will improve physical fitness of individual officers, improving their preparedness for such times of emergency. This cross-sectional study was conducted to investigate the responses of hematological (erythrocytes, hemoglobin, hematocrit, leucocytes, monocytes, neutrophils, lymphocytes), hormonal (testosterone, cortisol, melatonin), biochemical (glucose, uric-acid, lactate, creatine-phosphokinase) data to short-term maximal exercise in male police officers ( n = 20). Blood samples were collected before- and after- the running-based anaerobic sprint test (RAST), and biological values were corrected for fluid shifts. Data were mean ± standard deviation of differences (= after minus before RAST). After the RAST, values of cortisol, lactate, neutrophils, lymphocytes, and monocytes increased significantly by 7.01 ± 37.36 mmol/l, 7.55 ± 1.67 mmol/l, 0.17 ± 0.26 103/µl, 0.61 ± 0.28 103/µl, and 0.10 ± 0.13 103/µl, respectively. After the RAST, values of melatonin, uric-acid, creatine-phosphokinase, hemoglobin, and hematocrit decreased significantly by −13.24 ± 4.60 pg/ml, −13.28 ± 14.35 µmol/l, −10.23 ± 10.13 IU/l, −2.01 ± 0.81 g/dl, and −4.46 ± 0.59%, respectively. Biological data of male police officers were affected by sprint test. Understanding changes in biological data following short-term maximal exercise can further assist in a better understanding of anaerobic metabolism, which will be helpful to find available methods for coaches to quantify training loads.
Proximity hype as a frame attribute in the reporting on North Korea: Frame strength in competitive contexts
Authors: Nowacki Lukasz
Published: August 2021

This study analyses generic frames exhibiting varying strength when in a competitive context in an effort to identify the most recurring and repeated patterns and schemata in the framing of global news. The two-level analysis revealed six recurring attributes (official and/or credible sources, repetition, journalistic lexical bias, proximity hype, episodic nature of frame and negativity bias) that are believed to encompass frames and influence their power of persuasiveness. Special focus is placed on proximity hype with its three dominant angles recurring in the publications, which implies a common use of this aspect in the framing of news content.
Similarities and differences in understanding negative and affirmative counterfactuals and causal assertions: Evidence from eye-tracking
Authors: Orenes Isabel , Espino Orlando , Byrne Ruth MJ
Published: August 2021

Two eye-tracking experiments compared affirmative and negative counterfactuals, “if she had (not) arrived early, she would (not) have bought roses” and affirmative and negative causal assertions, “Because she arrived (did not arrive) early, she bought (did not buy) roses.” When participants heard a counterfactual, they looked on screen at words corresponding to its conjecture (“roses”), and its presupposed facts (“no roses”), whereas for a causal assertion, they looked only at words corresponding to the facts. For counterfactuals, they looked at the conjecture first, and later the presupposed facts, and at the latter more than the former. The effect was more pronounced for negative counterfactuals than affirmative ones because the negative counterfactual’s presupposed facts identify a specific item (“she bought roses”), whereas the affirmative counterfactual’s presupposed facts do not (“she did not buy roses”). Hence, when participants were given a binary context, “she did not know whether to buy roses or carnations,” they looked primarily at the presupposed facts for both sorts of counterfactuals. We discuss the implications for theories of negation, the dual meaning of counterfactuals, and their relation to causal assertions.
Chemoprevention in Barrett’s esophagus and esophageal adenocarcinoma
Authors: Alkhayyat Motasem , Kumar Prabhat , Sanaka Krishna O. , Thota Prashanthi N.
Published: August 2021

There has been a dramatic increase in the incidence of Barrett’s esophagus and esophageal adenocarcinoma over the past several decades with a continued rise expected in the future. Several strategies have been developed for screening and surveillance of patients with Barrett’s esophagus and endoscopic treatment of Barrett’s associated dysplasia and early esophageal cancer; however, they have not made a substantial impact on the incidence of cancer. Herein, chemoprevention becomes an attractive idea for reducing the incidence of cancer in Barrett’s patients. Several agents appear promising in preclinical and observational studies but very few have been evaluated in randomized controlled trials. Strongest evidence to date is available for proton-pump inhibitors and Aspirin that have been evaluated in a large randomized controlled trial. Other agents such as statins, metformin, ursodeoxycholic acid, and dietary supplements have insufficient evidence for chemoprevention in Barrett’s patients.
Exploring attitudes towards use of technology to support stroke survivors living at home: A quantitative and qualitative content analysis study in Spain
Authors: Ortiz-Fernandez Leire , Magnusson Charlotte , Ruiz Agustin Gutierrez , Indart Lorea Martinez , Zabala Joana Sagastagoya , Menica Juan Andres Alava , Arri Eunate Arana
Published: August 2021

Purpose

The aim of this study was to better understand the attitudes towards the use of technology to support chronic stroke survivors in a home-based setting.

Methods

A quantitative study was used on the data obtained from a face to face survey with the sample group, incorporating quantitative statistical analysis.

Results

Participants reported positive attitudes towards using technology for their own independent health management. The purpose of the home-based technology was different: source of information, supporting self-management, pharmacological treatment reminders… and differed according to age, educational level and survivor disability. Installing devices and sharing information remains a challenge.

Conclusions

100% of stroke survivors living in the community with any type of disability, reported that they would like to use technology as a tool to help improve their health status.
Undesirable Epsilon-Based Model DEA Application for Chinese Natural Disaster Mitigation Efficiency
Authors: Li Ying , Cen Hongyi , Lin Tai-Yu , Chiu Yung-ho
Published: August 2021

As natural disasters cause significant damage, many countries have developed disaster mitigation plans to reduce losses. Because China has frequent natural disasters in its geographically diverse territory, over the past few decades, the Chinese government has promulgated regulations and developed plans to mitigate the loss of life and property in natural disasters. To analyze the natural disaster mitigation efficiency in 27 Chinese provinces, this article employed a modified Epsilon-Based Measure (EBM) Data Envelopment Analysis (DEA) model. It was found that while Sichuan, Guangdong, Hebei, Shandong, and Chongqing had good efficiencies, there were significant variances across the provinces, and, in general, significant improvements were needed. Previous natural disaster efficiency research has examined disaster management and performance evaluations, employed static DEA models, and tended to ignore the radial and non-radial characteristics. Therefore, this article is the first comprehensive examination of recent natural disaster mitigation efficiencies in Chinese provinces.
National Identity Construction in Cultural and Creative Tourism: The Double Mediators of Implicit Cultural Memory and Explicit Cultural Learning
Authors: Zhang Shu-Ning , Ruan Wen-Qi , Yang Ting-Ting
Published: August 2021

In light of the gap in the national identity research, this study proposes, constructs, and examines the path to national identity by using a mixed-method approach. Study 1 collected 502 questionnaires from Chinese tourists, and Study 2 conducted semi-structured interviews with 15 tourists. The findings confirm that cultural and creative tourism contributes to the construction of tourists’ national identity. Tourists’ long-term implicit cultural memory and short-term explicit cultural learning are the double guarantees for forming tourists’ cultural identity. Importantly, tourists’ cultural identity plays a critical mediating role in promoting national identity. Moreover, the interactive effect of cultural experience and creative performance accelerates the construction process of tourists’ national identity. This study consolidates the sociopolitical significance of cultural and creative tourism for national identity through a rare mixed method and identifies the specific role of the cultural factors affecting national identity, thereby providing great theoretical contributions and practical value.
A Surgical Algorithm According to Pivot-Shift Grade in Patients With ACL Injury: A Prospective Clinical and Radiological Evaluation
Authors: Akmese Ramazan , Ovali Sancar Alp , Celebi Mehmet Mesut , Malatyali Batu , Kocaoglu Hakan
Published: August 2021

Background:

Some patients have a positive pivot-shift finding and rotational instability after anterior cruciate ligament (ACL) reconstruction (ACLR). Three major pathologies known to affect the pivot-shift examination include ACL tear, anterolateral ligament injury, and loss of posterior lateral meniscus root function.

Purpose:

To describe a surgical algorithm determining indications for lateral extra-articular tenodesis (LET) based on intraoperative pivot-shift examination to prevent postoperative pivot shift and rotational instability and to evaluate the 2-year clinical and functional outcomes.

Study Design:

Case series; Level of evidence, 4.

Methods:

The study included 47 consecutive patients (39 men and 8 women) who underwent operative treatment for ACL injury between 2016 and 2017. Pivot-shift examination was performed under anesthesia, and the pivot shift was graded as grade 1 (glide), grade 2 (clunk), or grade 3 (gross). According to the surgical algorithm, single-bundle ACLR was performed in patients with grade 1 pivot shift. In patients with grade 2 with loss of posterior lateral meniscus root function, concurrent lateral meniscal repair was performed, and in patients with grade 2 with an intact lateral meniscus posterior root, concurrent extra-articular iliotibial band tenodesis was performed. Patients with grade 3 underwent ACLR, lateral meniscal repair, and LET. Clinical and radiographic evaluations were performed.

Results:

The mean age was 27.2 years (range, 16-56 years). In total, 26 (55.3%) patients were evaluated as having pivot-shift grade 1; 16 (34%) patients, grade 2; and 5 (10.6%) patients, grade 3. A total of 7 (14.9%) patients underwent LET in addition to ACLR. Two of these patients had pivot-shift grade 2, and LET was performed since the lateral meniscus posterior root was intact. In 14 of 16 patients with grade 2, lateral meniscus root disruption was detected, and lateral meniscal repair was performed. One patient was excluded from the further follow-up because of graft failure. At a mean postoperative follow-up of 29 months in 46 patients, the pivot-shift examination was negative in all patients. The mean Lysholm and International Knee Documentation Committee subjective scores were 95.35 ± 4.40 and 82.87 ± 9.36, respectively. Radiographic evidence of osteoarthritis was not detected.

Conclusion:

Only 14.9% of patients needed LET. With proper ACL, lateral meniscal, and anterolateral ligament surgery, it was possible to prevent positive pivot-shift findings postoperatively.
“But It’s So Random!”: A Versatile Constrained Creativity Exercise for Application of Business Topics
Authors: Meilich Ofer , de Pillis Emmeline
Published: August 2021

In this exercise, participants create a fictional business based on a set of randomly generated words. This challenge requires participants to exercise creativity, while reinforcing the business concepts learned in class. The exercise has four steps: (1) generating a prompt of three random words, (2) designing a fictional business based on this prompt, (3) answering questions applying the concepts being taught, and (4) making presentations and discussion. The exercise is followed by a debrief that includes group discussions and critical thinking activities. We illustrate the exercise with examples from a strategic management course. The exercise can be applied in a variety of topics in business and organizations, student levels, and modes of instruction. Students report that the exercise is challenging, enjoyable, and effective in increasing understanding of the concepts taught.
Prognostic Impact of the Presence of Barrett’s Esophagus and Intestinal Metaplasia on Esophageal Adenocarcinoma Survival
Authors: Kolb Jennifer M. , Fox Charlie , Friedman Chloe , Scott Frank I. , Han Samuel , Marsh Megan , McCarter Martin , Kaplan Jeffrey , Lieu Christopher H. , Gleisner Ana , Katzka David A. , Wani Sachin
Published: August 2021

Background/Aims:

Barrett’s esophagus (BE), defined by the presence of intestinal metaplasia (IM) on histology, is thought to be the only identifiable precursor lesion for esophageal adenocarcinoma (EAC). Recent studies have suggested the possibility of an alternate, non-IM associated EAC that is a more aggressive form of EAC with worse survival. Among EAC patients, we aimed to compare survival of patients with and without IM at the time of diagnosis.

Methods:

This was a retrospective cohort study of all patients with histologic confirmed EAC evaluated at a tertiary care center from 2013 to 2019. Cases were categorized according to the presence or absence of IM on histologic specimens (Group I—IM-EAC and Group II—non-IM-EAC). We compared demographic characteristics, clinical stage, therapy, and survival between the 2 groups using the Chi-square and ANOVA tests (for categorical and continuous variables, respectively). We used Cox proportional hazards regression to determine the association of IM with overall survival, adjusting for sex, age at diagnosis, tumor location, histologic grade, and clinical stage.

Results:

A total of 475 patients were included in this analysis (mean age 64.8 years [SD 10.8], 89% white) and 109 (23.0%) had no evidence of IM. Compared with IM-EAC (Group I), individuals in the non-IM-EAC group were younger ( P = .01) and had a greater proportion of patients diagnosed with advanced disease (49.5 vs 20.2% for stage 4, P < .001). These patients were less likely to undergo endoscopic therapy alone (0.92% vs 29.78%, P < .001) or surgery alone (0 vs 9.84%, P = .001). On multivariable analysis, the presence of IM-EAC was associated with improved overall survival compared to non-IM-EAC (HR 0.69, 95% CI 0.49-0.96). Additional factors associated with poor survival was increasing stage of diagnosis (HR 6.49: 95% CI 3.77-11.15 for stage 4, HR 2.19: 95% CI 1.25-3.84 for stage 3, HR 2.04: 95% CI 0.98-4.25 for stage 2 compared to stage 1) and more advanced histologic stage (HR 2.00, 95% CI 1.26-3.19) for poorly/undifferentiated compared to well differentiated).

Conclusions:

EAC without the presence of IM on histology was associated with worse survival compared to those with IM. Future prospective studies with detailed molecular sequencing are required to clarify if 2 separate phenotypes of EAC exist (IM-EAC and non-IM-EAC). If confirmed, this may have significant implications for screening and management strategies.
Vision 2020: A Review of 20 Years of Inclusion Studies in Music Education
Authors: Allan Amalia A.
Published: August 2021

Inclusion has been a prominent topic in music education since the passage of the Education for All Handicapped Children Act of 1974 (now known as the Individuals with Disabilities Education Act or IDEA 2004). In 2000, music educators at the Housewright Symposium presented a list of goals for music education for the year 2020 in a document called Vision 2020, and one of those goals stated that barriers would be removed for the inclusion of all students. The purpose of this literature review was to examine the past 20 years of music education research (1999–2019) to determine how well the inclusion goal of Vision 2020 has been met. Four themes emerged: Perceptions in Schools, Practices in Schools, University Coursework, and Unique Topics. A concluding section summarizes findings and presents implications for meeting the Vision 2020 inclusion goal as it pertains to students with disabilities.
Music for a Lifetime: How Are We Doing? A Review of Literature on Adult Participation in Large Community Music Ensembles
Authors: Boswell Matthew A.
Published: August 2021

A common rationale for the continued existence and support of music education in schools has been the development of skills and attitudes leading to a lifetime of music-making for all students. Therefore, the purpose of this review of literature was to examine previous research on adult participation in large ensemble (i.e., band, choir, or orchestra) community music settings. The research literature included in this study was summarized and presented according to three broad categories: (a) status studies of both demographic information and the music backgrounds of large ensemble community music participants; (b) the motivations encouraging or discouraging such participation; and (c) potential issues, both concrete and philosophical, in what Jellison (2000) termed the transition between school-based music and that of the adult world. Implications for music educators and potential ideas for future research are discussed.
Complement and the prothrombotic state
Authors: Schmidt Christoph Q. , Schrezenmeier Hubert , Kavanagh David
Published: August 2021

In 2007 and 2009, the regulatory approval of the first-in-class complement inhibitor eculizumab revolutionized the clinical management of 2 rare, life-threatening clinical conditions: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Although being completely distinct diseases affecting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology and clinical presentation. An imbalance between complement activation and regulation at host surfaces underlies both diseases precipitating in severe thrombotic events that are largely resistant to anticoagulant and/or antiplatelet therapies. Inhibition of the common terminal complement pathway by eculizumab prevents the frequently occurring thrombotic events responsible for the high mortality and morbidity observed in patients not treated with anticomplement therapy. Although many in vitro and ex vivo studies elaborate numerous different molecular interactions between complement activation products and hemostasis, this review focuses on the clinical evidence that links these 2 fields in humans. Several noninfectious conditions with known complement involvement are scrutinized for common patterns concerning a prothrombotic statues and the occurrence of certain complement activation levels. Next to PNH and aHUS, germline-encoded CD59 or CD55 deficiency (the latter causing the disease complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy), autoimmune hemolytic anemia, (catastrophic) antiphospholipid syndrome, and C3 glomerulopathy are considered. Parallels and distinct features among these conditions are discussed against the background of thrombosis, complement activation, and potential complement diagnostic and therapeutic avenues.
Biomaterial and cellular implants: foreign surfaces where immunity and coagulation meet
Authors: Kizhakkedathu Jayachandran N. , Conway Edward M.
Published: August 2021

Exposure of blood to a foreign surface in the form of a diagnostic or therapeutic biomaterial device or implanted cells or tissue elicits an immediate, evolutionarily conserved thromboinflammatory response from the host. Primarily designed to protect against invading organisms after an injury, this innate response features instantaneous activation of several blood-borne, highly interactive, well-orchestrated cascades and cellular events that limit bleeding, destroy and eliminate the foreign substance or cells, and promote healing and a return to homeostasis via delicately balanced regenerative processes. In the setting of blood-contacting synthetic or natural biomaterials and implantation of foreign cells or tissues, innate responses are robust, albeit highly context specific. Unfortunately, they tend to be less than adequately regulated by the host’s natural anticoagulant or anti-inflammatory pathways, thereby jeopardizing the functional integrity of the device, as well as the health of the host. Strategies to achieve biocompatibility with a sustained return to homeostasis, particularly while the device remains in situ and functional, continue to elude scientists and clinicians. In this review, some of the complex mechanisms by which biomaterials and cellular transplants provide a “hub” for activation and amplification of coagulation and immunity, thromboinflammation, are discussed, with a view toward the development of innovative means of overcoming the innate challenges.
The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia
Authors: Hu Eileen Y. , Do Priscilla , Goswami Swagata , Nunes Jessica , Chiang Chi-ling , Elgamal Sara , Ventura Ann M. , Cheney Carolyn , Zapolnik Kevan , Williams Erich , Mani Rajeswaran , Frissora Frank , Mo Xiaokui , Waldmeier Lorenz , Beerli Roger R. , Peng Haiyong , Rader Christoph , Long Meixiao , Grawunder Ulf , Byrd John C. , Muthusamy Natarajan
Published: August 2021

Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody–based therapies. Herein we describe a humanized, first-in-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR1+ malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR1+ leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.
Development and characterization of prototypes for in vitro and in vivo mouse models of ibrutinib-resistant CLL
Authors: Aslan Burcu , Kismali Gorkem , Chen Lisa S. , Iles LaKesla R. , Mahendra Mikhila , Peoples Michael , Gagea Mihai , Fowlkes Natalie W. , Zheng Xiaofeng , Wang Jing , Vellano Christopher P. , Marszalek Joseph R. , Bertilaccio Maria Teresa Sabrina , Gandhi Varsha
Published: August 2021

Although ibrutinib improves the overall survival of patients with chronic lymphocytic leukemia (CLL), some patients still develop resistance, most commonly through point mutations affecting cysteine residue 481 (C481) in Bruton’s tyrosine kinase (BTKC481S and BTKC481R). To enhance our understanding of the biological impact of these mutations, we established cell lines that overexpress wild-type or mutant BTK in in vitro and in vivo models that mimic ibrutinib-sensitive and -resistant CLL. MEC-1 cell lines stably overexpressing wild-type or mutant BTK were generated. All cell lines coexpressed GFP, were CD19+ and CD23+, and overexpressed BTK. Overexpression of wild-type or mutant BTK resulted in increased signaling, as evidenced by the induction of p-BTK, p-PLCγ2, and p-extracellular signal–related kinase (ERK) levels, the latter further augmented upon IgM stimulation. In all cell lines, cell cycle profiles and levels of BTK expression were similar, but the RNA sequencing and reverse-phase protein array results revealed that the molecular transcript and protein profiles were distinct. To mimic aggressive CLL, we created xenograft mouse models by transplanting the generated cell lines into Rag2−/−γc−/− mice. Spleens, livers, bone marrow, and peripheral blood were collected. All mice developed CLL-like disease with systemic involvement (engraftment efficiency, 100%). We observed splenomegaly, accumulation of leukemic cells in the spleen and liver, and macroscopically evident necrosis. CD19+ cells accumulated in the spleen, bone marrow, and peripheral blood. The overall survival duration was slightly lower in mice expressing mutant BTK. Our cell lines and murine models mimicking ibrutinib-resistant CLL will serve as powerful tools to test reversible BTK inhibitors and novel, non–BTK-targeted therapeutics.
Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis
Authors: Pemmaraju Naveen , Carter Bing Z. , Bose Prithviraj , Jain Nitin , Kadia Tapan M. , Garcia-Manero Guillermo , Bueso-Ramos Carlos E. , DiNardo Courtney D. , Bledsoe Sharon , Daver Naval G. , Popat Uday , Konopleva Marina Y. , Zhou Lingsha , Pierce Sherry , Estrov Zeev E. , Borthakur Gautam M. , Ohanian Maro , Qiao Wei , Masarova Lucia , Wang Xuemei , Mak Po Yee , Cortes Jorge , Jabbour Elias , Verstovsek Srdan
Published: August 2021

Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.
Brain multimodal co-alterations related to delay discounting: a multimodal MRI fusion analysis in persons with and without cocaine use disorder
Authors: Meade Christina S. , Li Xiang , Towe Sheri L. , Bell Ryan P. , Calhoun Vince D. , Sui Jing
Published: August 2021

Background

Delay discounting has been proposed as a behavioral marker of substance use disorders. Innovative analytic approaches that integrate information from multiple neuroimaging modalities can provide new insights into the complex effects of drug use on the brain. This study implemented a supervised multimodal fusion approach to reveal neural networks associated with delay discounting that distinguish persons with and without cocaine use disorder (CUD).

Methods

Adults with (n = 35) and without (n = 37) CUD completed a magnetic resonance imaging (MRI) scan to acquire high-resolution anatomical, resting-state functional, and diffusion-weighted images. Pre-computed features from each data modality included whole-brain voxel-wise maps for gray matter volume, fractional anisotropy, and regional homogeneity, respectively. With delay discounting as the reference, multimodal canonical component analysis plus joint independent component analysis was used to identify co-alterations in brain structure and function.

Results

The sample was 58% male and 78% African–American. As expected, participants with CUD had higher delay discounting compared to those without CUD. One joint component was identified that correlated with delay discounting across all modalities, involving regions in the thalamus, dorsal striatum, frontopolar cortex, occipital lobe, and corpus callosum. The components were negatively correlated with delay discounting, such that weaker loadings were associated with higher discounting. The component loadings were lower in persons with CUD, meaning the component was expressed less strongly.

Conclusions

Our findings reveal structural and functional co-alterations linked to delay discounting, particularly in brain regions involved in reward salience, executive control, and visual attention and connecting white matter tracts. Importantly, these multimodal networks were weaker in persons with CUD, indicating less cognitive control that may contribute to impulsive behaviors.
Comparative analysis of carbapenemases, RND family efflux pumps and biofilm formation potential among Acinetobacter baumannii strains with different carbapenem susceptibility
Authors: Zhang Yanpeng , Fan Bing , Luo Yong , Tao Zhiyuan , Nie Yongbo , Wang Yongtao , Ding Fanglin , Li Yanwu , Gu Dayong
Published: August 2021

Aim

This study has conducted a comparative analysis of common carbapenemases harboring, the expression of resistance-nodulation-cell division (RND) family efflux pumps, and biofilm formation potential associated with carbapenem resistance among Acinetobacter baumannii (A. baumannii) strains with different carbapenem susceptibility. Methods: A total of 90 isolates of A. baumannii from two tertiary hospitals of China were identified and grouped as carbapenem susceptible A. baumannii (CSAB) strains and carbapenem non-susceptible A. baumannii (CnSAB) strains based on the susceptibility to imipenem. Harboring of carbapenemase genes, relative expression of RND family efflux pumps and biofilm formation potential were compared between the two groups. Result: Among these strains, 12 (13.3 %) strains were divided into the CSAB group, and 78 (86.7 %) strains into the CnSAB group. Compared with CSAB strains, CnSAB strains increased distribution of blaOXA−23 (p < 0.001) and ISAba1/blaOXA−51−like (p = 0.034) carbapenemase genes, and a 6.1-fold relative expression of adeB (p = 0.002), while CSAB strains led to biofilm formation by 1.3-fold than CnSAB strains (p = 0.021).

Conclusions

Clinically, harboring more blaOXA−23−like and ISAba1/blaOXA−51−like complex genes and overproduction of adeABC are relevant with carbapenem resistance, while carbapenem susceptible strains might survive the stress of antibiotic through their ability of higher biofilm formation.
Action for better brain health among people living with HIV: protocol for a randomized controlled trial
Authors: Quigley Adria , Brouillette Marie-Josée , Fellows Lesley K. , Mayo Nancy
Published: August 2021

Background

Lifestyle changes can protect or improve brain health in older adults. However, sustained lifestyle change is difficult for everyone and may be more difficult for those with executive dysfunction, including some people living with HIV. Thus, the key question is how we can improve adherence to the most promising interventions among people living with HIV experiencing cognitive difficulties. Goal management training is a cognitive rehabilitation program that targets executive dysfunction by teaching goal-directed behaviour and self-management. It is a promising means to improve adherence to lifestyle interventions.

Objective

To estimate the extent to which goal management training before a healthy lifestyle program is associated with greater adherence to health recommendations, achievement of health-related goals, and better brain health and health outcomes compared to the healthy lifestyle program alone among people living with HIV.

Methods

Brain Health Now cohort participants with cognitive difficulties or are not aging successfully are eligible. All participants will be given health resources, a health coach, a goal-setting digital application, and access to an online goal-setting workshop. The intervention group will participate in nine 2-h goal management training sessions and then will enter the healthy lifestyle program. Control participants will enter the healthy lifestyle program directly. A total sample of 100 participants will participate for 12 months. The main outcome is adherence to the healthy lifestyle program, defined as the number of weeks where physical activity adherence targets were met (150 min per week, measured with an activity monitor). Weekly social activities will be captured via self-report with confidential photo validation. We will send weekly health state reports to the participants. Downstream outcomes include cognitive ability, health-related quality of life, mobility, vascular risk profile, and social network size. We will analyze the data using a linear regression model.

Discussion

This project is the first to test whether goal management training can augment adherence to health recommendations among individuals with cognitive difficulties. If successful, behavioural interventions such as goal management training could be implemented as an adjunct to lifestyle interventions in other clinical populations.

Trial registration: This trial was registered on clinicaltrials.gov (NCT04345484) on April 14, 2020, https://clinicaltrials.gov/ct2/show/NCT04345484?term=NCT04345484&draw=2&rank=1.
Commentary: Implications of SARS-Cov-2 infection for pregnancy with diabetes: achievements and open questions for feto-maternal medicine
Authors: Göbl Christian S. , Bozkurt Latife , Henrich Wolfgang
Published: August 2021

SARS-Cov-2 (Severe Acute Respiratory Coronavirus 2) infection confers a non-negligible risk for younger pregnant women with diabetes, which is still less well investigated. This topic was recently addressed by a systematic scoping review in BMC Pregnancy and Childbirth, aiming to summarize the complex interaction between SARS-Cov-2 infection, pregnancy and diabetes. This commentary will summarize and discuss the main findings of this article and its implications for future research.
Should international borders re-open? The impact of travel restrictions on COVID-19 importation risk
Authors: Liebig Jessica , Najeebullah Kamran , Jurdak Raja , Shoghri Ahmad El , Paini Dean
Published: August 2021

Background

Novel coronavirus disease (COVID-19) has spread across the world at an unprecedented pace, reaching over 200 countries and territories in less than three months. In response, many governments denied entry to travellers arriving from various countries affected by the virus. While several industries continue to experience economic losses due to the imposed interventions, it is unclear whether the different travel restrictions were successful in reducing COVID-19 importations.

Methods

Here we develop a comprehensive probabilistic framework to model daily COVID-19 importations, considering different travel bans. We quantify the temporal effects of the restrictions and elucidate the relationship between incidence rates in other countries, travel flows and the expected number of importations into the country under investigation.

Results

As a cases study, we evaluate the travel bans enforced by the Australian government. We find that international travel bans in Australia lowered COVID-19 importations by 87.68% (83.39 - 91.35) between January and June 2020. The presented framework can further be used to gain insights into how many importations to expect should borders re-open.

Conclusions

While travel bans lowered the number of COVID-19 importations overall, the effectiveness of bans on individual countries varies widely and directly depends on the change in behaviour in returning residents and citizens. Authorities may consider the presented information when planning a phased re-opening of international borders.