bluuebunny/crossref_metadata_2025 huggingface dataset:
Migration Studies: How Should We Approach Them? Learning Through Participatory Practices. The So-Close Case Study
Authors: Gunella Chiara , Rodrigo Javier
Published: December 2022

Community members such as migrants are involved to collect data but not included in the actual research process, for example, in developing research guidelines or in using research tools such as data analysis. Participatory methodology enables investigating a specific issue while including the community involved. In the So-Close project, we applied this approach to investigate how we study migration and the role of the cultural heritage of forced migration through four multi-stakeholders participatory focus groups (FGs) in Spain (involving Refugees, NGO and Cultural Institutions representatives, Academics and Policy-Makers). From the FGs, emerged the need to investigate complex issues from various angles and contexts to create sustainable, community-approved, and shared solutions.
Presidential versus Civil Power: Public Opinion, Second-Wave Feminism, and Party Politics in the USA
Authors: Sachs Willa , Alexander Jeffrey C
Published: December 2022

This article theorizes the relationship between social movements, public opinion, and presidential power. While sociologists and social movement scholars have long neglected these interconnections, we argue that they form a key foundation of American political life. Drawing on civil sphere theory, we show that, at least in formally democratic regimes, the exercise of state power is continuously subject to public opinion, via social movements that pressure states in the public’s name. We demonstrate how social movements compete with one another to speak on behalf of ‘public opinion.’ In giving expression to the desires of ‘the public’, imagined as a putative whole, movements exercise what we call ‘civil power.’ Taking the second-wave feminist movement and the countermovements that arose against it as our empirical case study, we examine their interaction with three particularly illustrative presidential administrations: that of Richard Nixon, Jimmy Carter, and Ronald Reagan. While presidents organize state power, we argue, the effective functioning of this formal power is enabled by the civil power of social movements, whose roots are located in collective meanings and whose generation occurs outside the state.
Assessment of chest pain
Authors: Stone Catherine
Published: December 2022

In general practice, chest pain is a common presentation, with a wide range of potential causes, some of which are potentially life-threatening. It is essential that GPs, often the first point of contact for patients, can assess and differentiate causes of chest pain to provide appropriate management in a timely manner. This article aims to provide readers with a diagnostic framework for assessing the patient presenting with chest pain and summarises the management of some key diagnoses.
Clinical and paraclinical features, outcome, and prognosis of ovarian granulosa cell tumor: A retrospective study of 28 Vietnamese women
Authors: Le Duc Thanh , Do Tu Anh , Nguyen Linh Ly Thi , Do Kien Hung , Van Nguyen Chu
Published: December 2022

Background: Granulosa cell tumor of the ovary is a rare disease and presents with two clinically and molecularly distinct subtypes: the juvenile and the adult type. GCT is considered as a malignant tumor with an indolent course and a tendency toward late recurrence. Purpose: To assess the clinical and paraclinical features, treatment findings, survival outcomes, and explored the prognostic factors in the granulosa cell tumor. Methods: The current study was conducted on 28 GCT patients who had surgical operations and adjuvant chemotherapy (stage IC-IV) by applying a retrospective cohort analysis. The clinical and paraclinical characteristics were recorded. Recurrent status was evaluated for analysis with clinical and paraclinical features and survival. All GCT patients’ survival were analyzed by using Kaplan-Meier and Log-Rank models. Results: 17.9% of patients experienced a relapse and two patients died due to disease. The mean time from initial diagnose to recurrence was 40.21 months. The 5-year OS and DFS of stage I-II were 100% and 80.8%, and of stage III were 50% and 25%, respectively. In survival analyses, using the log-rank test, age ≥50 years, irregular menstruation, stage I-II, and absence of residual lesion were all significant predictors for the improved DFS. Stage I-II and absence of residual lesion were associated significantly with better OS. Mean of age, FIGO stage, and residual lesion during surgery had significant differences to recurrent rate (p < <0.05). The multivariate model revealed that these factors didn’t remain as an independent prognostic variable. Conclusion: FIGO stage and residual lesion during surgery had significant differences in survival and recurrent rate.
In vitro elastic cartilage reconstruction using human auricular perichondrial chondroprogenitor cell–derived micro 3D spheroids
Authors: Oba Takayoshi , Okamoto Satoshi , Ueno Yasuharu , Matsuo Megumi , Tadokoro Tomomi , Kobayashi Shinji , Yasumura Kazunori , Kagimoto Shintaro , Inaba Yutaka , Taniguchi Hideki
Published: December 2022

Morphologically stable scaffold-free elastic cartilage tissue is crucial for treating external ear abnormalities. However, establishing adequate mechanical strength is challenging, owing to the difficulty of achieving chondrogenic differentiation in vitro; thus, cartilage reconstruction is a complex task. Auricular perichondrial chondroprogenitor cells exhibit high proliferation potential and can be obtained with minimal invasion. Therefore, these cells are an ideal resource for elastic cartilage reconstruction. In this study, we aimed to develop a novel in vitro scaffold-free method for elastic cartilage reconstruction, using human auricular perichondrial chondroprogenitor cells. Inducing chondrogenesis by using microscopic spheroids similar to auricular hillocks significantly increased the chondrogenic potential. The size and elasticity of the tissue were maintained after craniofacial transplantation in immunodeficient mice, suggesting that the reconstructed tissue was morphologically stable. Our novel tissue reconstruction method may facilitate the development of future treatments for external ear abnormalities.
Health service - A click away
Authors: Sadrul Huda Syed SM , Akhtar Afsana , Uddin MD Ishtiak , Mowla Syeda Madeha , Syeda Aida Mowla
Published: December 2022

This case study examines digital health service provider Doctorola’s business strategy, competitive advantage, and challenges. The case is developed primarily on secondary sources, e.g., journal articles, newspapers, and authentic websites. The case presents the journey of the first online-based doctor appointment business - Doctorola, and its subsequent development as a full-fledged e-health service delivery provider. The case finds that Doctorola has designed effective service system to deliver patient centric services and captures a significant market share. This case shows its’ service evolution and illustrates the challenges it would face in the market to sustain in digital health market.
Governance in the transformational journey toward integrated healthcare: The case of Ontario
Authors: Dong Linying , Sahu Roshan , Black Rod
Published: December 2022

Ontario, the most populous province and the main driver of economic growth in Canada, has been plagued by rising healthcare costs and declining health quality. Firmly believing that care integration is integral to health quality and efficiency of the healthcare system, the Ontario government has embarked on its journey of healthcare system transformation. The case, by taking a snapshot of its transition from the Local Health Integration Network (LHIN) model to the Ontario Health Team model, offers insights into the governance of the LHIN model as well as the initiative of integrating a myriad of healthcare information systems to support care integration. After 12 years’ controversial operation of LHINs, the government dissolved the organization and announced its plan to switch to the Ontario Health Team model. Under the new model, Ontario Health Teams would be responsible for providing a full and coordinated spectrum of care for patients, especially those with complex care needs. Would this round of transformation and emphatic focus on digital health lead Ontario one step closer to integrated care that Ontarians have been chasing for so long?
Reliability and minimal detectable difference of pressure pain thresholds in a pain-free population
Authors: Koh Ryan GL , Paul Tracy M , Nesovic Karlo , West Daniel , Kumbhare Dinesh , Wilson Richard D
Published: December 2022

The objective of this work was to evaluate the inter-rater and intra-rater reliability and minimal detectable difference (MDD) of pressure pain thresholds (PPTs) in pain-free participants with two examiners over two consecutive days in a cross-sectional study design. Examiners used a standardized method to measure and locate a specific testing site over tibialis anterior for PPT testing with a hand-held algometer. The mean of each examiner’s three PPT measurements was used to calculate the intraclass correlation coefficient, inter-rater reliability, and intra-rater reliability. The minimal detectable difference (MDD) was calculated. Eighteen participants were recruited (11 female). The inter-rater reliability was 0.94 and 0.96 on day 1 and day 2, respectively. Intra-rater reliability for the examiners was 0.96 and 0.92 on day 1 and day 2, respectively. The MDD on day 1 was 1.24 kg/cm2 (CI: 0.76–2.03) and the MDD on day 2 was 0.88 kg/cm2 (CI: 0.54–1.43). This study demonstrates high inter- and intra-rater reliability and the MDD values for this method of pressure algometry.
Granulomatous mastitis: A case report
Authors: Oze Koudouhonon Rita , Yehouenou Tessi Romeo Thierry , Mendes Papys , Allali Nazik , Chat Latifa , El Haddad Siham
Published: December 2022

Idiopathic granulomatous mastitis is a rare chronic benign inflammatory mastopathy occurring mainly in young women. With a non-specific imagery, it is considered as a diagnosis by exclusion and has a challenging treatment. Histologically, it is characterized by the predominance of polynuclear neutrophils and the absence of caseous necrosis. The breast carcinoma is the main differential diagnosis at the clinical stage, and imagery plays an essential role in its diagnostic approach. Its treatment combines antibiotics, anti-inflammatories, corticosteroid therapy, and surgery. We report a 42-year-old woman who presented a breast lesion diagnosis as granulomatous mastitis based on magnetic resonance imaging, ultrasound, and histology examinations. She received a treatment with different drugs (antibiotics, anti-inflammatories). The outcome treatment was successful with a good healing of breast lesions.
The rules of trust between individuals: An ethnography of transactions on Leboncoin.fr
Authors: Stenger Thomas , Garcia-Bardidia Renaud , Bailly Adrien
Published: December 2022

Online C to C platforms rely on multiple evaluation tools (ratings, calculated reputation, and online reviews) to generate the trust that is essential for transactions. What are the sources of trust when these tools are absent (or not used)? From an ethnography of private transactions via leboncoin.fr, this contribution reveals the mechanisms of trust in this context. The Goffmanian approach adopted enables us to highlight the rules of trust and their role in maintaining and repairing trust situations (commitment, normality, proximity, readability, and unveiling). This research contributes to the marketing literature by supplementing the work on the evaluative and calculated character of trust and by proposing a cross-channel analysis incorporating online trust. It opens up alternative perspectives for framing C to C exchanges and studying cross-channel consumer behavior.
Governing teachers through datafication: Physical–virtual hybridity and language interoperability in teacher accountability
Authors: Holloway Jessica , Lewis Steven
Published: December 2022

In this paper, we draw on Foucault's and Deleuze's theorisations of discipline and control, respectively, to understand a teacher accountability system in the US state of Texas: the Texas Teacher Evaluation and Support System (hereafter, T-TESS). Specifically, we focus on the interplay of physical and virtual modes of governance – which we develop here as physical– virtual hybridity – and the techniques that make these physical and virtual domains compatible via language interoperability, with T-TESS deployed as a representative empirical case to show how such technologies work to govern teacher subjectivity. First, in-person appraiser meetings and observations re-code teachers’ linguistic behaviours, so their physical bodies and practices can become legible to and interoperable with the hybrid T-TESS system. This avoids any possible syntax errors between the linguistic expression of physical teacher speech and the digital coding language of T-TESS. Second, these digital bodies of data can now be viewed as proxies for the physical teacher body in the classroom, allowing the constant modulation in physical space (teacher bodies) and digital space (bodies of data). This is the physical–virtual hybridity of T-TESS, whereby discipline and control work symbiotically to govern both the physical and the digital expressions of teachers and their teaching. In this way, the disciplining of teachers’ language has profound effects on teachers’ bodies, both corporeal and digital.
Telemedicine in Thai-otorhinolaryngology patients in COVID-19 situation; primary surveys
Authors: Koopirom Phoom , Wiriyaamornchai Pannapa , Santeerapharp Alena
Published: December 2022

Introduction

COVID-19 pandemic has put a strain on various aspects of hospital management due to high rates of infection and increased preventive measures around the world. Physicians and patients alike are susceptible to the ongoing virus causing concern leading to loss or postpone of follow up. Thailand has just start integration of digital solutions such as telemedicine which expected similar level of medical care and efficiency while reducing risk of exposure during the COVID-19 pandemic.

Objective

Evaluation the willingness to accept telemedicine in otorhinolaryngology patients during the peak COVID-19 outbreaks in our institution.

Methods

Collected data from all patients who had a schedule follow up for otorhinolaryngology department between the months of June to August, 2021 at out-patient Center.

Results

Total of 299 otorhinolaryngology patients included, 213 patients (71.2%) denied a virtual medical visit whereas 86 patients (28.8%) accepted. The obstructive sleep apnea (OSA) was the only group to have more acceptance of telemedicine, 79.5% than denying 20.5% with statistical significance ( p < 0.01). Age difference between the accepting and declining group also showed statistical significance, 48.5 years and 56 years respectively ( p < 0.01). Main Reasons for their decision, 48% of patients accepted due to experiencing clinical improvement and stability. The main reason for not accepting telemedicine was 80% of patients preferred a special otorhinolaryngologic examination on follow up.

Conclusions

This primary surveys among Thai otorhinolaryngology patients about telemedicine. The greater number of patients not interested in telemedicine due to requirement of otorhinolaryngologic examination. Which OSA follow-up patients have more attention in telemedicine.
The “Ups and Downs” of Living With Type 2 Diabetes Among Working Adults in the Rural South
Authors: Glenn Lynn E. , Thurlow Christine B. , Enriquez Maithe
Published: December 2022

The purpose of this qualitative study was to gain a better understanding of the spheres of influence on engagement in recommended diabetes preventive health services among rural, working adults. Additionally, this study sought to understand the unique factors that influence diabetes self-management among rural, working adult populations. The sample included mostly African-American, low-income females with self-reported diabetes, who scored low on the Patient Activation Measure (PAM-10). Semi-structured interviews (N = 20) revealed that most participants struggled with the “ups and downs” of living with diabetes. Four major themes emerged from the data: “the struggle,” “doing things together,” “diabetes is not the priority,” and “we’re lucky to have what we have.” Most participants were developing individual responsibility and motivation for a healthy future, but were overwhelmed by inconsistency in self-management, diabetes distress, lack of effective coping strategies, and lack of social and economic capital. The findings of this study indicate the need to further address psychological well-being among rural, working adults, yet rural populations often lack sufficient access to mental health care and formalized psychological support. Psychological support and resources are essential to facilitate engagement in diabetes self-management and preventive health services for rural, working adults.
Nurses’ Experiences of Caring for Patients with COVID-19: A Qualitative Study
Authors: Almomani Maysa H. , Khater Wejdan A. , Akhu-Zaheya Laila M. , Alloubani Aladeen , AlAshram Safa A. , Azab Mohammed , Al-malkawi Adeeb K.
Published: December 2022

The purpose of this study was to explore nurses’ experiences, abilities, and willingness to care for patients with Coronavirus Disease 2019 (COVID-19). A descriptive qualitative study was conducted among 12 nurses working with patients with COVID-19. Purposive sampling was used to recruit participants from two national hospitals in Jordan. Semi-structured interviews (45–90 minutes each) with open-ended questions were held via Zoom to collect data. Four major themes emerged from the data analysis. The first theme, uncertainty, consisted of two subthemes: new experience and lack of training. The second theme was related to social stigma by society and other staff members. The third theme of front-line fighters consisted of two subthemes: empowering the main health caregiver and community acknowledgment. The fourth theme was related to challenges and consisted of two subthemes: physical and psychological challenges. At the beginning of the outbreak of COVID-19, the nurses had experienced a lack of certainty, physical and psychological challenges, and social stigmatization, which had negatively affected their willingness and ability to fight the outbreak. However, the nurses reported growing professionally and psychologically with time and becoming more knowledgeable, skillful, powerful, and confident care providers during the pandemic. Being able to fulfill their responsibilities and being acknowledged by others gave the nurses a sense of achievement. Early education and training about COVID-19, clear infection control protocols and guidelines, psychological counseling, and adequate social support are essential steps for enhancing nurses’ mental well-being and willingness and ability to fight COVID-19.
Characteristics of Nursing Facilities and Staff Willingness to Implement a Non-Pharmacological Intervention
Authors: Inoue Megumi , Li Meng-Hao , Layman Shannon , Tompkins Catherine J. , Ihara Emily S.
Published: December 2022

While non-pharmacological interventions could positively impact mood and behaviors of nursing-home residents who are living with dementia, some facilities are more willing to adopt such interventions than others. This study investigated the characteristics of Medicaid-funded nursing facilities that were associated with their willingness to implement a non-pharmacological intervention, personalized music. Using the publicly-available dataset (aka LTCfocus) from Brown University, this study examined characteristics of nursing homes in Virginia that have implemented or are in the process of implementing a personalized music intervention ( n = 59) and that have decided not to implement it ( n = 216). The findings indicate that nursing facilities with a higher proportion of long-term residents are more likely to implement the intervention. The findings can inform future research recruitment strategies. In addition, a greater understanding of the use of non-pharmacological interventions in relation to the characteristics of nursing facilities offers insight to policymakers and public health officials regarding resource allocations to facilities.
14-day Holter monitoring for atrial fibrillation after ischemic stroke: The yield of guideline-recommended monitoring duration
Authors: Himmelreich Jelle CL , Lucassen Wim AM , Coutinho Jonathan M , Harskamp Ralf E , de Groot Joris R , CPM van Weert Henk
Published: December 2022

Introduction:

Current European Stroke Organisation (ESO) guidelines recommend >48 h of continuous electrocardiographic monitoring for atrial fibrillation (AF) in all patients with ischemic stroke or transient ischemic attack (TIA) with undetermined origin. We assessed the yield of the guideline-recommended monitoring for AF, as well as of extending monitoring up to 14 days.

Patients and methods:

We included consecutive patients with stroke/TIA without AF in an academic hospital in The Netherlands. We reported AF incidence and number needed to screen (NNS) in the overall sample after 48 h and 14 days of Holter monitoring.

Results:

Among 379 patients with median age 63 years (IQR 55–73), 58% male, Holter monitoring detected 10 cases of incident AF during a median of 13 (IQR 12–14) days of monitoring. Seven AF cases were detected within the first 48 hours (incidence 1.85%, 95% CI 0.74–3.81; NNS 54), and three additional AF cases were recorded among the 362 patients with >48 h of monitoring and without AF ⩽ 48 h (incidence 0.83%, 95% CI: 0.17–2.42; NNS 121). All AF cases were detected within the first 7 days of monitoring. Our sample was subject to sampling bias favoring inclusion of participants with low AF risk.

Discussion:

Strengths of this work were the broad inclusion criteria as recommended by ESO guidelines, and high Holter adherence among participants. The analysis was limited by inclusion of lower-risk cases and a relatively small sample size.

Conclusion:

In low-risk patients with recent stroke or TIA, ESO guideline-recommended screening for AF resulted in a low AF yield, with limited additional value of monitoring up to 14 days. Our results underline the need for a personalized approach in determining a patient’s optimum duration for post-stroke non-invasive ambulatory monitoring.
The Statistical Fragility of Platelet-Rich Plasma as Treatment for Plantar Fasciitis: A Systematic Review and Simulated Fragility Analysis
Authors: Gupta Arjun , Ortiz-Babilonia Carlos , Xu Amy L. , Rogers Davis , Vulcano Ettore , Aiyer Amiethab A.
Published: December 2022

Background:

Plantar fasciitis (PF) is the most common cause of heel pain and can be a source of extensive physical disability and financial burden. Platelet-rich plasma (PRP) offers a potentially definitive, regenerative treatment modality that, if effective, could change the current paradigm of PF care. However, randomized controlled trials (RCTs) on the clinical benefits of PRP for refractory PF offer inconsistent conclusions, potentially because of the broader limitations of using P value thresholds to declare statistical and clinical significance. In this study, we use the Continuous Fragility Index (CFI) and Quotient (CFQ) to appraise the statistical robustness of data from RCTs evaluating PRP for treatment of PF.

Methods:

RCTs comparing outcomes after PRP injection vs alternative treatment in patients with chronic PF were evaluated. Representative simulated data sets were generated for each reported outcome event using summary statistics. The CFI was determined by manipulating each data set until reversal of significance (α=0.05) was achieved. The corresponding CFQ was calculated by dividing the CFI by the sample size.

Results:

Of 259 studies screened, 20 studies (59 outcome events) were included in this analysis. From these simulations, the median CFI for all events was 9, suggesting that varying the treatment of 9 patients would be required to reverse trial significance. The corresponding CFQ was 0.177. Studies with reported P value <.05 were more statistically fragile (CFI=10, CFQ=0.122) than studies with reported P value >.05 (CFI=5, CFQ=0.179). Of 36 outcome events reporting lost to follow-up data, 10 events (27.8%) lost ≥9 patients.

Conclusion:

Our findings suggest that, on average, the statistical fragility of RCTs evaluating PRP for nonoperative PF therapy is at least comparable to that of the sports medicine literature. However, several included studies had concerningly low simulated fragility scores. Orthopaedic surgeons may benefit from preferentially relying on studies with higher CFI and CFQ values when evaluating the utility of PRP for chronic PF in their own clinical practice. Given the importance of RCT data in clinical decision making, fragility indices could help give context to the stability of statistical findings.

Level of Evidence:

Level I, systematic review.
Latissimus Dorsi Tendon Repair
Authors: Belk John W. , Bravman Jonathan T. , Frank Rachel M. , Seidl Adam J. , McCarty Eric C.
Published: December 2022

Background:

Latissimus dorsi tendon ruptures are rare injuries that can occur in overhead or throwing motions and are almost always sports related.

Indications:

Latissimus dorsi tendon ruptures are largely treated nonoperatively, although surgical repair is indicated for the young active patient looking to return to a high level of sport and for those with complete avulsion injuries or mid-substance tendon tears.

Technique Description:

Depending on the degree of tendon retraction, anteroinferior or posteroinferior axillary incision is made. After the tendon is mobilized, sutures are placed in a Krackow fashion through the bulk of the tendon, and the tendon footprint is prepared by gently decorticating the surface of the humerus, just anterior and inferior to the teres major insertion point. Two Arthrex Pec Buttons are then loaded into the superior and inferior limbs of the suture tape and 2 unicortical holes are drilled into the footprint of the insertion site. The superior button is placed first and then tensioned to allow the latissimus dorsi to be pulled to the bone. Next, the second button is placed, though this is not tensioned until later at the time of the biceps tenodesis. Finally, the procedure is visualized and well inspected to ensure appropriate location of the tendon and securing hardware.

Results:

After an appropriate rehabilitation protocol is followed for up to 6 months postoperatively, acute repair of a ruptured latissimus dorsi tendon allows for near to complete restoration of patient functionality and strength, with return to full activity possible within 6 to 8 months.

Conclusion:

Surgical repair of a ruptured latissimus dorsi tendon is effective in restoring upper extremity strength and functionality and is associated with high patient satisfaction. The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.
The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell–mediated graft-versus-host disease
Authors: Cheng Qiao , Wang Dong , Lai Xiaoxuan , Liu Yin , Zuo Yibo , Zhang Wenli , Lei Lei , Chen Jia , Liu Hong , Wang Ying , Liu Haiyan , Zheng Hui , Wu Depei , Xu Yang
Published: December 2022

Disorders of the ubiquitin-proteasome system (UPS) are known to influence the incidence and mortality of various diseases. It remains largely unknown whether and how the UPS affects the onset and progression of acute graft-verus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study demonstrated that the deubiquitinase OTUD1 is an essential regulator of aGVHD. Activation of CD4+ T cells after allo-HSCT, elevated the protein levels of OTUD1, which in turn interacted with the Notch2-ICD (NICD) to cleave the ubiquitin of NICD at the K1770 site, thereby inducing NICD protein accumulations in T cells. OTUD1-driven NICD signaling promoted the differentiation and functions of Th1 and Th17 cells and amplified the cascade of aGVHD. Moreover, by screening a FDA-approved drugs library the study identified dapagliflozin as an inhibitor targeting the OTUD1/NICD axis. Dapagliflozin administration significantly prolonged the survival of aGVHD mice. This study characterized a previously unknown role of OTUD1 in T cell–mediated allogeneic responses and provided a promising therapeutic strategy to target OTUD1 for the alleviation of aGVHD.
Proximity proteomics identifies septins and PAK2 as decisive regulators of actomyosin-mediated expulsion of von Willebrand factor
Authors: El-Mansi Sammy , Robinson Christopher L. , Kostelnik Katja B. , McCormack Jessica J. , Mitchell Tom P. , Lobato-Márquez Damián , Rajeeve Vinothini , Cutillas Pedro , Cutler Daniel F. , Mostowy Serge , Nightingale Thomas D.
Published: December 2022

In response to tissue injury, within seconds the ultra-large glycoprotein von Willebrand factor (VWF) is released from endothelial storage organelles (Weibel−Palade bodies) into the lumen of the blood vasculature, where it leads to the recruitment of platelets. The marked size of VWF multimers represents an unprecedented burden on the secretory machinery of endothelial cells (ECs). ECs have evolved mechanisms to overcome this, most notably an actomyosin ring that forms, contracts, and squeezes out its unwieldy cargo. Inhibiting the formation or function of these structures represents a novel therapeutic target for thrombotic pathologies, although characterizing proteins associated with such a dynamic process has been challenging. We have combined APEX2 proximity labeling with an innovative dual loss-of-function screen to identify proteins associated with actomyosin ring function. We show that p21 activated kinase 2 (PAK2) recruits septin hetero-oligomers, a molecular interaction that forms a ring around exocytic sites. This cascade of events controls actomyosin ring function, aiding efficient exocytic release. Genetic or pharmacological inhibition of PAK2 or septins led to inefficient release of VWF and a failure to form platelet-catching strings. This new molecular mechanism offers additional therapeutic targets for the control of thrombotic disease and is highly relevant to other secretory systems that employ exocytic actomyosin machinery.
A nanobody against the VWF A3 domain detects ADAMTS13-induced proteolysis in congenital and acquired VWD
Authors: Kizlik-Masson Claire , Peyron Ivan , Gangnard Stéphane , Le Goff Gaelle , Lenoir Solen M , Damodaran Sandra , Clavel Marie , Roullet Stéphanie , Regnault Véronique , Rauch Antoine , Vincent Flavien , Jeanpierre Emmanuelle , Dupont Annabelle , Ternisien Catherine , Donnet Thibault , Christophe Olivier D. , van Belle Eric , Denis Cécile V. , Casari Caterina , Susen Sophie , Lenting Peter J.
Published: December 2022

von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site. Although KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2 domain modulates exposure of its epitope in the A3 domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact VWF could be detected using this nanobody. By comparing plasma from volunteers to that from congenital von Willebrand disease (VWD) patients, intact-VWF levels were significantly reduced for all VWD types, and most severely in VWD type 2A–group 2, in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD type 1 and VWD type 2M. A significant correlation (r = 0.51, P < .0001) between the relative amount of high–molecular weight multimers and levels of intact VWF was observed. Reduced levels of intact VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3 domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis.
Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial
Authors: Panopoulou Aikaterini , Cairns David A. , Holroyd Amy , Nichols Isabel , Cray Nikita , Pawlyn Charlotte , Cook Gordon , Drayson Mark , Boyd Kevin , Davies Faith E. , Jenner Matthew , Morgan Gareth J. , Owen Roger , Houlston Richard , Jackson Graham , Kaiser Martin F.
Published: December 2022

Prediction of individual patient benefit from lenalidomide (Len) maintenance after autologous stem cell transplant (ASCT) remains challenging. Here, we investigated extended molecular profiling for outcome prediction in patients in the National Cancer Research Institute Myeloma XI (MyXI) trial. Patients in the MyXI trial randomized to Len maintenance or observation after ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q), and del(17p) and co-occurrence of risk markers was computed. Progression-free survival (PFS), subsequent progression (PFS2), and overall survival (OS) were calculated from maintenance randomization, and groups were compared using Cox proportional hazards regression. Of 556 patients, 17% with double-hit multiple myeloma (MM) (≥2 risk markers), 32% with single-hit (1 risk marker), and 51% without risk markers were analyzed. Single-hit MM derived the highest PFS benefit from Len maintenance, specifically, isolated del(1p), del(17p), and t(4;14), with ∼40-fold, 10-fold, and sevenfold reduced risk of progression or death (PFS), respectively, compared with observation. This benefit translated into improved PFS2 and OS for this group of patients compared with observation; median PFS was 10.9 vs 57.3 months for observation vs Len maintenance. Patients with isolated gain(1q) derived no benefit, and double-hit MM limited benefit (regardless or risk lesions involved) from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway. This trial was registered at www.isrctn.com/ISRCTN49407852 as # ISRCTN49407852.
Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo
Authors: Ramos Teresa L. , Bolivar-Wagers Sara , Jin Sujeong , Thangavelu Govindarajan , Simonetta Federico , Lin Po-Yu , Hirai Toshihito , Saha Asim , Koehn Brent , Su Leon L. , Picton Lora K. , Baker Jeanette , Lohmeyer Juliane K. , Riddle Megan , Eide Cindy , Tolar Jakub , Panoskaltsis-Mortari Angela , Wagner John E. , Garcia K. Christopher , Negrin Robert S. , Blazar Bruce R.
Published: December 2022

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex–disparate GVHD model of lethally irradiated BALB/c mice given T cell–depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ–transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.
INR and vitamin K–dependent factor levels after vitamin K antagonist reversal with 4F-PCC or plasma
Authors: Hood Christopher , Goldstein Joshua N. , Milling Truman J. , Refaai Majed A. , Bajcic Paolo , Goldstein Brahm , Sarode Ravi
Published: December 2022

Restoration of the international normalized ratio (INR) to values <1.5 is commonly targeted to achieve hemostasis in patients with major bleeding or undergoing urgent surgery who are treated using vitamin K antagonists (VKAs). However, the relationship between corrected INR and vitamin K–dependent factor (VKDF) levels for hemostasis is uncertain. We aim to examine the impact of 4-factor prothrombin complex concentrate (4F-PCC) or plasma on INR correction and VKDF restoration and evaluate the relationship between INR values and VKDF levels in patients with acute major bleeding or patients requiring an urgent surgical procedure. Adult patients treated with VKA with an elevated INR (≥2.0 within 3 hours before study treatment) who received 4F-PCC or plasma after major bleeding or before an urgent surgery or invasive procedure were included in this retrospective analysis of data from 2 prospective phase 3b randomized controlled trials. Of the 370 patients included in this analysis, 185 received 4F-PCC, and 185 received plasma. In the 4F-PCC group, 159 of 185 (85.9%) had an INR ≤1.5 at 30 minutes after the end of infusion compared with only 72 of 184 (39.1%) in the plasma group. After 4F-PCC treatment, all VKDF levels exceeded 50% activity regardless of the postinfusion INR value. However, after plasma administration, mean activity levels for factors II and X were <50% at all time points assessed within 3 hours after starting the infusion, regardless of the postinfusion INR value. This retrospective analysis demonstrated that treatment with 4F-PCC among patients treated with VKA rapidly restores VKDFs to hemostatic levels irrespective of the postinfusion INR value, whereas treatment with plasma does not.
A Novel Braking Control Strategy for Hybrid Electric Buses Based on Vehicle Mass and Road Slope Estimation
Authors: Liu Zijun , Cheng Shuo , Liu Jinzhao , Wu Qiong , Li Liang , Liang Huawei
Published: December 2022

Proper braking force distribution strategies can improve both stability and economy performance of hybrid electric vehicles, which is prominently proved by many studies. To achieve better dynamic stable performance and higher energy recovery efficiency, an effective braking control strategy for hybrid electric buses (HEB) based on vehicle mass and road slope estimation is proposed in this paper. Firstly, the road slope and the vehicle mass are estimated by a hybrid algorithm of extended Kalman filter (EKF) and recursive least square (RLS). Secondly, the total braking torque of HEB is calculated by the sliding mode controller (SMC), which uses the information of brake intensity, whole vehicle mass, and road slope. Finally, comprehensively considering driver's braking intention and regulations of the Economic Commission for Europe (ECE), the optimal proportional relationship between regenerative braking and pneumatic braking is obtained. Furthermore, related simulations and experiments are carried out on the hardware-in-the-loop test bench. Results show that the proposed strategy can effectively improve the braking performance and increase the recovered energy through precise control of the braking torque.
The Critical Biomarkers Identification of Insulin Signaling Involved in Initiating cAMP Signaling Mediated Salivary Secretion in Sjogren Syndrome: Transcriptome Sequencing in NOD Mice Model
Authors: Chen Bo , Zhou Jiannan , Mao Tianjiao , Cao Tingting , Hu Shilin , Zhang Wenqi , Li Xueyang , Qin Xiuni , Liu Xintong , Watanabe Nobumoto , Li Jiang
Published: December 2022

Background

Sjogren’s syndrome (SS) is an autoimmune disorder characterized by the destruction of exocrine glands, resulting in dry mouth and eyes. Currently, there is no effective treatment for SS, and the mechanisms associated with inadequate salivary secretion are poorly understood.

Methods

In this study, we used NOD mice model to monitor changes in mice’s salivary secretion and water consumption. Tissue morphology of the submandibular glands was examined by H&E staining, and Immunohistochemical detected the expression of AQP5 (an essential protein in salivary secretion). Global gene expression profiling was performed on submandibular gland tissue of extracted NOD mice model using RNA-seq. Subsequently, a series of bioinformatics analyses of transcriptome sequencing was performed, including differentially expressed genes (DEGs) identification, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, PPI network construction, hub gene identification, and the validity of diagnostic indicators using the dataset GSE40611. Finally, IFN-γ was used to treat the cells, the submandibular gland tissue of NOD mice model was extracted, and RT-qPCR was applied to verify the expression of hub genes.

Results

We found that NOD mice model had reduced salivary secretion and increased water consumption. H&E staining suggests acinar destruction and basement membrane changes in glandular tissue. Immunohistochemistry detects a decrease in AQP5 immunostaining within acinar. In transcriptome sequencing, 42 overlapping DEGs were identified, and hub genes (REN, A2M, SNCA, KLK3, TTR, and AZGP1) were identified as initiating targets for insulin signaling. In addition, insulin signaling and cAMP signaling are potential pathways for regulating salivary secretion and constructing a regulatory relationship between target-cAMP signaling-salivary secretion.

Conclusion

The new potential targets and signal axes for regulating salivary secretion provide a strategy for SS therapy in a clinical setting.
Analysis of differentially expressed long non-coding RNAs in LPS-induced human HMC3 microglial cells
Authors: Baek Mina , Chai Jin Choul , Choi Hae In , Yoo Eunyoung , Binas Bert , Lee Young Seek , Jung Kyoung Hwa , Chai Young Gyu
Published: December 2022

Background

Long non-coding RNAs (lncRNAs) are emerging as key modulators of inflammatory gene expression, but their roles in neuroinflammation are poorly understood. Here, we identified the inflammation-related lncRNAs and correlated mRNAs of the lipopolysaccharide (LPS)-treated human microglial cell line HMC3. We explored their potential roles and interactions using bioinformatics tools such as gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG), and weighted gene co-expression network analysis (WGCNA).

Results

We identified 5 differentially expressed (DE) lncRNAs, 4 of which (AC083837.1, IRF1-AS1, LINC02605, and MIR3142HG) are novel for microglia. The DElncRNAs with their correlated DEmRNAs (99 total) fell into two network modules that both were enriched with inflammation-related RNAs. However, treatment with the anti-inflammatory agent JQ1, an inhibitor of the bromodomain and extra-terminal (BET) protein BRD4, neutralized the LPS effect in only one module, showing little or even enhancing effect on the other.

Conclusions

These results provide insight into, and a resource for studying, the regulation of microglia-mediated neuroinflammation and its potential therapy by small-molecule BET inhibitors.
OpenGenomeBrowser: a versatile, dataset-independent and scalable web platform for genome data management and comparative genomics
Authors: Roder Thomas , Oberhänsli Simone , Shani Noam , Bruggmann Rémy
Published: December 2022

Background

As the amount of genomic data continues to grow, there is an increasing need for systematic ways to organize, explore, compare, analyze and share this data. Despite this, there is a lack of suitable platforms to meet this need.

Results

OpenGenomeBrowser is a self-hostable, open-source platform to manage access to genomic data and drastically simplifying comparative genomics analyses. It enables users to interactively generate phylogenetic trees, compare gene loci, browse biochemical pathways, perform gene trait matching, create dot plots, execute BLAST searches, and access the data. It features a flexible user management system, and its modular folder structure enables the organization of genomic data and metadata, and to automate analyses. We tested OpenGenomeBrowser with bacterial, archaeal and yeast genomes. We provide a docker container to make installation and hosting simple. The source code, documentation, tutorials for OpenGenomeBrowser are available atopengenomebrowser.github.ioand a demo server is freely accessible atopengenomebrowser.bioinformatics.unibe.ch.

Conclusions

To our knowledge, OpenGenomeBrowser is the first self-hostable, database-independent comparative genome browser. It drastically simplifies commonly used bioinformatics workflows and enables convenient as well as fast data exploration.
Carotenoid biosynthesis is associated with low-temperature adaptation in Rhodosporidium kratochvilovae
Authors: Guo Rui , Liu Tao , Guo Caina , Chen Gongshui , Fan Jingdie , Zhang Qi
Published: December 2022

Background

Low temperatures greatly limit the growth of microorganisms. Low-temperature adaptation in microorganisms involves multiple mechanisms. Carotenoids are naturally occurring lipid-soluble pigments that act as antioxidants and protect cells and tissues from the harmful effects of free radicals and singlet oxygen. However, studies on the regulation of carotenoid biosynthesis at low temperatures in microorganisms are limited. In this study, we investigated the correlation between carotenoids and low-temperature adaptation in the cold-adapted strain of Rhodosporidium kratochvilovae YM25235.

Results

Carotenoid biosynthesis in YM25235 was inhibited by knocking out the bifunctional lycopene cyclase/phytoene synthase gene (RKCrtYB) using the established CRISPR/Cas9 gene-editing system based on endogenous U6 promoters. The carotenoids were extracted with acetone, and the content and composition of the carotenoids were analyzed by spectrophotometry and HPLC. Then, the levels of reactive oxygen species (ROS) and the growth rate in YM25235 were determined at a low temperature. The results indicated that the carotenoid biosynthesis and ROS levels were increased in the YM25235 strain at a low temperature and inhibition of carotenoid biosynthesis was associated with higher ROS levels and a significant decrease in the growth rate of YM25235 at a low temperature.

Conclusions

The regulation of carotenoid biosynthesis was associated with low-temperature adaptation in YM25235. Our findings provided a strong foundation for conducting further studies on the mechanism by which YM25235 can adapt to low-temperature stress.