bluuebunny/crossref_metadata_2025 huggingface dataset:
The randomized trial of mammography screening that was not—A cautionary tale
Authors: Yaffe Martin J , Seely Jean M. , Gordon Paula B. , Appavoo Shushiela , Kopans Daniel B.
Published: November 2021

Two randomized trials were conducted in Canada in the 1980s to test the efficacy of breast cancer screening. Neither of the trials demonstrated benefit. Concerns were raised regarding serious errors in trial design and conduct. Here we describe the conditions that could allow subversion of randomization to occur and the inclusion of many symptomatic women in a screening trial. We examine anomalies in data where the balance would be expected between trial arms. “Open book” randomization and performance of clinical breast examination on all women before allocation to a trial arm allowed women with palpable findings to be mis-randomized into the mammography arm. Multiple indicators raising suspicion of subversion are present including a large excess in poor-prognosis cancers in the mammography trial arm at prevalence screen. Personnel described shifting of women from the control group into the mammography group. There is compelling evidence of subversion of randomization in Canadian National Breast Screening Study. Mis-randomization of even a few women with advanced breast cancer could markedly affect measured screening efficacy. The Canadian National Breast Screening Study trials should not influence breast screening policies.
Effects of Export Orientation, Exchange Rates and Leverage on Firm Productivity: Evidence from Pakistan
Authors: Rashid Abdul , Khan Afaq , Fraz Ahmad
Published: November 2021

This article empirically scrutinizes the effect of exchange rate changes, exchange rate uncertainty and firm leverage on firm-level productivity growth. It also examines the differential effects of these variables, conditional on the levels of exports. Finally, it investigates whether a firm’s heterogeneity in terms of its share of exports in total sales matters in determining the response of a firm’s productivity growth to these variables. The empirical analysis is based on an unbalanced panel data set with annual observations of 222 exporting firms listed on the Pakistan Stock Exchange over the 2009–2017 period. We find that both exchange rate changes and exchange rate uncertainty have significant, negative effects on the firm’s productivity growth, and exporting further makes intense these effects. Yet, we show that export activities are positively related to firms’ productivity growth. We also reveal that there is a significant heterogeneity in the effects of exchange rate changes, its uncertainty and leverage, which is attributed to export intensity. Specifically, we observe that the effects are more prominent in firms that export more shares of their output to foreign markets.
Telepsychiatry and face-to-face psychiatric consultations during the first year of the COVID-19 pandemic in Australia: patients being heard and seen
Authors: Looi Jeffrey CL , Allison Stephen , Bastiampillai Tarun , Pring William , Kisely Stephen R
Published: November 2021

Objective:

The Australian federal government introduced additional Medicare Benefits Schedule (MBS) telehealth-items to facilitate care by private psychiatrists during the COVID-19 pandemic.

Method:

We analysed private psychiatrists’ uptake of video and telephone-telehealth, as well as total (telehealth and face-to-face) consultations for April 2020–April 2021. We compare these to face-to-face consultations for April 2018–April 2019. MBS-Item service data were extracted for COVID-19-psychiatrist-video- and telephone-telehealth item numbers and compared with face-to-face consultations for the whole of Australia.

Results:

Psychiatric consultation numbers (telehealth and face-to-face) were 13% higher during the first year of the pandemic compared with 2018–2019, with telehealth accounting for 40% of this total. Face-to-face consultations were 65% of the comparative number of 2018–2019 consultations. There was substantial usage of telehealth consultations during 2020–2021. The majority of telehealth involved short telephone consultations of ⩽15–30 min, while video was used more, in longer consultations.

Conclusions:

Private psychiatrists and patients continued using the new telehealth-items during 2020–2021. This compensated for decreases in face-to-face consultations and resulted in an overall increase in the total patient contacts compared to 2018–2019.
Electromechanical impedance based debond localisation in a composite sandwich structure
Authors: Sikdar Shirsendu , Singh Shishir Kumar , Malinowski Paweł , Ostachowicz Wiesław
Published: November 2021

An electromechanical impedance (EMI) based structural health monitoring (SHM) approach is proposed for the localisation of skin-core debonds in composite sandwich structure (CSS). Towards this, laboratory experiments and numerical simulations of EMI in a CSS with core to bottom face-sheet debond have been carried out using a network of piezoelectric transducers (PZTs). The frequency-domain analysis of the registered EMI signals shows that the presence of inter-facial debonds in the CSS significantly influences the conductance magnitudes of the registered EMI data. It was also noticed that the conductance magnitudes of the signals are dependent on the debond-to-PZT distances. In all the study cases, an agreement between the simulation and experimental results is observed. Eventually, a simulated SHM approach is proposed that uses a debond detection algorithm to calculate the changes in conductance magnitudes to effectively locate such debonds in CSS. The study is further extended for the detection of debonds at different locations in the CSS, including a debond located at the edge to assess the potential of the proposed SHM approach.
3-Dimensional Craniofacial Imaging: A Template for Systematic Radiologic Evaluation for Alveolar Cleft Assessment and Planning
Authors: Preston Kathryn , Mallya Sanjay M.
Published: November 2021

Background

Imaging findings are central to the diagnosis and treatment planning decisions when managing craniofacial differences. However, limited information is published on protocols for systematic cleft imaging assessment and for effective communication of these findings.

Solution

A template is presented to help guide radiologic imaging reports to acquire the relevant clinical information needed to manage patients with alveolar cleft.
Cadaveric Study and Micro-Computed Tomography of the Anatomy of Palatine Aponeurosis and its Link to the Soft Palate Muscles and Pharyngeal Muscles
Authors: Zhao Jiuli , Ma Hengyuan , Wang Yongqian , Song Tao , Wu Di , Yin Ningbei
Published: November 2021

Objective

There have been few studies on the anatomy of palatine aponeurosis (PA). Herein, we elucidated the relationship between the PA and soft palate muscles and pharyngeal muscles.

Design

Two cadaveric specimens were dissected to observe the gross anatomy of the PA. Six cadaveric specimens were processed and scanned by micro-computed tomography to determine the elaborate anatomy. Images were exported to Mimics software to reconstruct a three-dimensional model.

Results

The PA covered the anterior (32.1%-38.8%) of the soft palate, extending from the tensor veli palatini (TVP) and connecting to 3 muscles: palatopharyngeus (PP), uvula muscle, and superior pharyngeal constrictor (SC). The SC and PP are attached to the PA on the medial side of the pterygoid hamulus. SC muscle fibers were attached to the hamulus, forming a distinct gap between the hamulus. Some muscle fibers of the PP and uvula originated from the PA. The PA extended from the TVP to the midline and the posterior edge of the hard palate. The PA was not uniformly distributed, which was complementary to the attached muscles in thickness.

Conclusions

PA, as a flexible fibrous membrane, maintains the shape of the soft palate. It extends from the TVP and covers anteriorly about one-third of the soft palate. The PA provides a platform for the soft palate muscles and pharyngeal muscles, connecting to the PP, uvula muscle, and SC. These muscles are important for palatopharyngeal closure and middle-ear function. It is necessary to minimize the damage to the PA during surgical interventions.
Candida keratitis and endopthalmitis after corneal transplantation; two case reports, a novel regimen and literature overview of therapeutic options
Authors: van der Wekken-Pas LC , de Haas PJ , Wisse R , Rados M , van der Elst KCM
Published: November 2021

Purpose

To evaluate treatment options for candida keratitis and endopthalmitis after corneal transplantation.

Methods

Case reports and literature review.

Results

Two patients with keratitis due to Candida glabrata/ parapsilosis after corneal transplantation were successfully treated with a combination of topical voriconazole, intracameral voriconazole and amphotericin B, and systemic treatment with flucytosine.

Conclusions

Natamycine and voriconazole topically are preferred therapeutic options for the treatment of fungal keratitis. Systemic flucytosine is a useful alternative additive, particularly for countries where natamycine is not registered as a pharmaceutical agent.
The use of peripherally inserted central catheter reduced the incidence of phlebitis in heart failure patients: A randomized trial
Authors: Silva Eunice Vieira Cavalcante , Ochiai Marcelo Eidi , Vieira Kelly Regina Novaes , Pereira Barretto Antonio Carlos
Published: November 2021

Background:

During decompensated heart failure, the use of intravenous inotropes can be necessary. With peripheral venous access, prolonged inotrope infusion can cause phlebitis. However, traditional central venous catheters have possible complications. Peripherally inserted central catheters (PICCs) may be an alternative to traditional catheters.

Aim:

Our objective was to compare the incidence of phlebitis between patients with PICC and those with peripheral venous access catheter indwelling.

Methods:

In a randomized clinical trial, the patients were randomized to PICC and control groups, with 40 patients in each group. The inclusion criteria were hospitalized patients with advanced heart failure, ejection fraction of <0.45, and platelet count of >50,000/mm3 and current use of continuous intravenous infusion of dobutamine. The patients were randomly assigned to receive a PICC or keep their peripheral venous access. The primary end point was the occurrence of phlebitis.

Results:

The PICC and control groups included 40 patients each. The median age was 61.5 years; ejection fraction, 0.24; and dobutamine dose, 7.73 µg/(kg min). Phlebitis occurred in 1 patient (2.5%) in the PICC group and in 38 patients (95.0%) in the control group, with an odds ratio of 0.10% (95% confidence interval: 0.01%–1.60%, p < 0.001).

Conclusion:

In conclusion, in severe heart failure patients who received intravenous dobutamine, PICC use reduced the incidence of phlebitis when compared to patients with peripheral venous access. Therefore, the PICC use should considered over peripheral venous access for prolonged intravenous therapy in heart failure patients.
Relationships Among Toilet Sharing, Water Source Locations, and Handwashing Places Without Observed Soap: A Cross-Sectional Study of the Richest Households in Bangladesh
Authors: Ahamad Mazbahul G , Burbach Mark , Tanin Fahian
Published: November 2021

Background:

A high percentage of the richest households in Bangladesh lack soap at their handwashing places, a problem that is typically considered to be one of the poor.

Objective:

We investigated toilet sharing practices, locations of water sources, and relevant sociodemographic factors associated with the observed handwashing places that lack soap in the richest (ninth wealth decile) households in Bangladesh.

Methods:

We used data from the 2017-18 Bangladesh Demographic and Health Survey (BDHS). Logistic regression technique was used to investigate how toilet sharing practices, water source locations, and different sociodemographic factors were associated with observed handwashing places without soap.

Results:

We found that 25.8% of the richest households were observed to have no soap at their handwashing places. Of these households, those that shared their toilets with another household were 4.6 times (95% CI 3.15-6.60) more likely to observe handwashing places without soap as compared with those that did not share their toilets. Further, the richest households were 4.2 times (95% CI 2.38-7.33) more likely to observe handwashing places without soap if they collected water from their own yard or plot, and 7.1 times (95% CI 3.61-13.97) more likely to observe handwashing places without soap if they collected water from elsewhere in comparison to the reference group that collected water from their own dwelling.

Conclusion:

Sharing toilet with other households and location of main water source are associated with handwashing places without observed soap in the richest households in Bangladesh. These results can inform discussions of water availability and soap-handwashing-related policy and program development.
Presenting the People's Republic: what drives images of China in the press?
Authors: Zhu Runping , Wei Jinrui , Krever Richard , Huang Yu
Published: November 2021

Citizens’ views of the political, social and economic character of foreign countries is largely based on the valence frames – positive, neutral or negative – established in newspaper articles consumed directly from the press or indirectly through republication. Looking at stories on China's one-child policy in the Australian press, the study used a mixed qualitative and quantitative methodology to investigate together all extrinsic factors that might drive the tone of articles on foreign countries. An analysis of factors including newspaper ownership, format, audience, market reach and reporter gender or location suggests a primary driver might be the newspaper audience – owners provide stories that retain their audience (and advertisers).
Ageless play: Sustaining intergenerational playgroup programmes
Authors: Stanley Maree , Allen Penny , Tunks Terry-Ann , Davenport Melinda , Cartmel Jennifer
Published: November 2021

Intergenerational playgroups purposively bring older people, young children and their caregivers together to engage in play and develop reciprocal relationships. Intergenerational research focuses on the benefits for participants, with much less known about how these programmes sustain. This paper discusses and explores programme sustainability through the examination of two playgroups established through Playgroup Queensland’s Ageless Play programme. Through qualitative interviewing with playgroup practitioners and participants we aimed to understand how each of these playgroups had sustained beyond 3 years. The findings included the importance of mutual benefit for stakeholders, knowledge and skills of the playgroup facilitator and use of strategies to ensure ongoing interaction and engagement within the group. These findings are important for ensuring the continuation of intergenerational playgroup programmes.
A generalized meshing analysis method and its application to toroidal surface enveloping conical worm drive
Authors: Huai Chongfei , Chen Chunlin , Zhao Yaping
Published: November 2021

A generalized method for the meshing analysis of conical worm drive is proposed, whose mathematical model is more general and whose application scope is expanded. A universal mathematical model, which can be conveniently applied to left-handed and right-handed conical worm pairs and their tooth flanks on different sides, is established by introducing the helical spin coefficient and tooth side coefficient of the conical worm. The pressure angle at the reference point, which is a key parameter for calculating the curvature parameters and lubrication angle, is determined based on the unit normal vector of the worm helical surface and is no longer determined by the tooth profile angle in the worm shaft section. The above improvement breaks away from the limitation of the classic meshing analysis method based on the reference-point-based meshing theory and thus expands its application scope. The toroidal surface enveloping conical worm drive is taken as an instance to illustrate the proposed method and the numerical example studies are conducted. The approaches to determine the reference point, the normal unit vector, and the curvature parameters at the reference point are all demonstrated in detail. The numerical results all manifest that the method presented in the current work is correct and practicable.
Transitioning to telehealth during the coronavirus disease 2019 pandemic: Perspectives from partners of women with cystic fibrosis and healthcare providers
Authors: Corcoran Jessica , Marley Campbell Caitlin , Ladores Sigrid
Published: November 2021

Objectives

Cystic fibrosis is a chronic, genetic disease that primarily affects the respiratory system. The coronavirus disease 2019 pandemic has altered how people with cystic fibrosis receive healthcare. This paper explores the perceptions of cystic fibrosis healthcare providers and partners of women with cystic fibrosis regarding the use of telehealth in routine cystic fibrosis healthcare in the US.

Methods

As part of a larger study examining fertility counseling for women with cystic fibrosis, we conducted qualitative, semi-structured interviews. Participants included partners of women with cystic fibrosis (n = 20) and cystic fibrosis healthcare providers (n = 20). We completed the interviews before and during the global coronavirus disease 2019 pandemic. We analyzed the data using thematic analysis.

Results

When in-person healthcare could not be achieved safely, partners and healthcare providers found new value in telehealth. Three themes emerged: (1) increased connection between healthcare team and family, (2) increased efficiency of healthcare appointments, and (3) improved interdisciplinary collaboration. Partners found that telehealth allowed for more engagement in their significant others’ healthcare. Providers reported enhanced efficiency and opportunities for collaboration across specialties that improved healthcare delivery and care coordination.

Discussion

Results from this study highlighted the positive value of telehealth. Telehealth presents as a potential alternative to delivering outpatient care for people with chronic illnesses beyond the pandemic
Bergamottin alleviates LPS-induced acute lung injury by inducing SIRT1 and suppressing NF-κB
Authors: An Ning , Yang Tao , Zhang Xiao-Xia , Xu Mei-xia
Published: November 2021

Acute lung injury (ALI) is associated with a high mortality due to inflammatory cell infiltration and lung edema. The development of ALI commonly involves the activation of NF-κB. Since bergamottin is a natural furanocoumarin showing the ability to inhibit the activation of NF-κB, in this study we aimed to determine the effect of bergamottin on ALI. RAW264.7 mouse macrophages were pre-treated with bergamottin and then stimulated with LPS. Macrophage inflammatory responses were examined. Bergamottin (50 mg/kg body mass) was intraperitoneally administrated to mice 12 h before injection of LPS, and the effect of bergamottin on LPS-induced ALI was evaluated. Our results showed that LPS exposure led to increased production of TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1), which was impaired by bergamottin pre-treatment. In vivo studies confirmed that bergamottin pre-treatment suppressed LPS-induced lung inflammation and edema and reduced the levels of pro-inflammatory cytokines in lung tissues and bronchoalveolar lavage fluids. Mechanistically, bergamottin blocked LPS-induced activation of NF-κB signaling in lung tissues. Additionally, bergamottin treatment reduced NF-κB p65 protein acetylation, which was coupled with induction of SIRT1 expression. In conclusion, our results reveal the anti-inflammatory property of bergamottin in preventing ALI. Induction of SIRT1 and inhibition of NF-κB underlies the anti-inflammatory activity of bergamottin.
Advances in dementia with Lewy bodies
Authors: Armstrong Melissa J.
Published: November 2021

Dementia with Lewy bodies (DLB) is a clinical diagnosis representing a specific presentation of a pathological α-synucleinopathy (Lewy body disease). DLB is one entity under the broader term Lewy body dementia, which also includes Parkinson’s disease dementia. Recent advances in DLB include publication of updated diagnostic criteria and recognition of prodromal DLB states, including mild cognitive impairment, delirium-onset, and psychiatric-onset forms. Research criteria for the mild cognitive impairment form of DLB were published in 2020. Increasing research shows that concomitant Alzheimer’s disease pathology in individuals with DLB is common in addition to the α-synucleinopathy pathology. This has implications for biomarker use and expected progression. Identifying biomarkers for DLB is an area of active research. Cerebrospinal fluid and skin biopsy tests are now commercially available in the United States, but their role in routine clinical care is not yet established. Additional research and biomarkers are needed. Research suggests that median survival after DLB diagnosis is 3–4 years, but there are rapidly and slowly progressive forms. Most individuals with DLB die of complications of the disease. Clinical trials for individuals with DLB have increased over the last 5 years, targeting both symptoms and underlying pathology. Effective therapies remain an unmet need, however. This review focuses on recent advances with an emphasis on literature that informs clinical care.
A Transgenic Rat for Noninvasive Assessment of Chondrogenesis in Vivo
Authors: Ferreira Elisabeth , Gatrell Landon B. , Childress Luke , Wu Hong , Porter Ryan M.
Published: November 2021

Objective

To support the preclinical evaluation of therapeutics that target chondrogenesis, our goal was to generate a rat strain that can noninvasively report endogenous chondrogenic activity.

Design

A transgene was constructed in which the dual expression of bioluminescent (firefly luciferase) and fluorescent (mCherry) reporters is controlled by regulatory sequences from rat Col2a1. Candidate lines were established on a Lewis background and characterized by serial bioluminescence imaging as well as ex vivo measurement of molecular reporter levels in several tissues. The sensitivity and specificity of the reporter strain were assessed in models of orthotopic and ectopic chondrogenesis.

Results

Substantial bioluminescence signal was detected from cartilaginous regions, including the appendicular synovial joints, spine, sternum, nose, and pinnae. Bioluminescent radiance was intense at 1 month of age, rapidly declined with continued development, yet remained detectable in 2-year-old animals. Explant imaging and immunohistochemistry confirmed that both molecular reporters were localized to cartilage. Implantation of wild-type bone marrow stromal cells into osteochondral defects made in both young adult and aged reporter rats led to a time-dependent elevation of intra-articular reporter activity concurrent with cartilaginous tissue repair. To stimulate ectopic, endochondral bone formation, bone morphogenetic protein 2 was overexpressed in the gastrocnemius muscle, which led to bioluminescent signal that closely preceded heterotopic ossification.

Conclusions

This strain can help develop strategies to stimulate cartilage repair and endochondral bone formation or to inhibit chondrogenesis associated with heterotopic ossification.
New perspectives on the treatment of hidradenitis suppurativa
Authors: Amat-Samaranch Victoria , Agut-Busquet Eugènia , Vilarrasa Eva , Puig Lluís
Published: November 2021

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by the presence of painful nodules, abscesses, chronically draining fistulas, and scarring in apocrine gland-bearing areas of the body. The exact pathogenesis of HS is not yet well understood, but there is a consensus in considering HS a multifactorial disease with a genetic predisposition, an inflammatory dysregulation, and an influence of environmental modifying factors. Therapeutic approach of HS is challenging due to the wide clinical manifestations of the disease and the complex pathogenesis. This review describes evidence for effectiveness of current and emerging HS therapies. Topical therapy, systemic treatments, biological agents, surgery, and light therapy have been used for HS with variable results. Adalimumab is the only US Food and Drug Administration (FDA) approved biologic agent for moderate-to-severe HS, but new therapeutic options are being studied, targeting different specific cytokines involved in HS pathogenesis. Comparing treatment outcomes between therapies is difficult due to the lack of randomized controlled trials. Treatment strategy should be selected in concordance to disease severity and requires combination of treatments in most cases.
Bridging Digital Divide Amidst Educational Change for Socially Inclusive Learning During the COVID-19 Pandemic
Authors: Liu Ji
Published: November 2021

During the coronavirus disease-19 (COVID-19) outbreak, many education systems were forced to shut down and move learning and instruction online. The future of learning is here before we know it. While the combination of distance learning and educational technology presents a timely solution combating adverse consequences of school disruptions, there is a real risk of channeling learning opportunities through already-existing forms of digital disparity, especially for marginalized populations. China, as one of the first education systems to experience system-wide school closures due to COVID-19, faces critical challenges of digital divide. To examine pandemic ramifications and effective policy strategies taken to mitigate its unintended consequences, this study leverages an original student learning experience survey collected during the pandemic, and documents national and provincial-level COVID-19 education policy responses in China since the initial outbreak. The study uncovers saliency of access to distance learning and educational technology in shaping student learning experiences, and identifies three compelling policy takeaways from the “Disrupted Classes, Undisrupted Learning” initiative, and discuss emerging lessons drawn for crafting an undivided future for remote distance learning.
Return-to-Play Rates and Clinical Outcomes of Baseball Players After Concomitant Ulnar Collateral Ligament Reconstruction and Selective Ulnar Nerve Transposition
Authors: Rao Somnath , D’Amore Taylor , Willier Donald P. , Gawel Richard , Jack Robert A. , Cohen Steven B. , Ciccotti Michael G.
Published: November 2021

Background:

Injury to the ulnar collateral ligament (UCL) leading to medial elbow instability and possible ulnar neuritis is common in overhead-throwing athletes. Treatment may require UCL reconstruction (UCLR) and concomitant ulnar nerve transposition (UNT) for those with preoperative ulnar neuritis.

Purpose:

To evaluate the return-to-play (RTP) rates, clinical outcomes, and rates of persistent ulnar neuritis after concomitant UCLR and UNT in a cohort of baseball players with confirmed preoperative ulnar neuritis.

Study Design:

Case series; Level of evidence, 4.

Methods:

Eligible patients were those who underwent concomitant UCLR and UNT at a single institution between January 2008 and June 2018 and who had a minimum of 2 years of follow-up. Additional inclusion criteria were athletes who identified as baseball players and who had a confirmed history of ulnar neuritis. Patients were contacted at a minimum of 2 years from surgery and assessed with the Kerlan-Jobe Orthopaedic Clinic (KJOC) Shoulder and Elbow Score, Andrew-Timmerman (A-T) Elbow Score, Mayo Elbow Performance Score (MEPS), Single Assessment Numeric Evaluation (SANE) score, and a custom RTP questionnaire.

Results:

Included were 22 male baseball players with a mean age of 18.9 ± 2.1 years (range, 16-25 years). The mean follow-up was 6.1 ± 2.4 years (range, 2.5-11.7 years). Preoperatively, all 22 patients reported ulnar nerve sensory symptoms, while 4 (18.2%) patients reported ulnar nerve motor symptoms. At the final follow-up, 7 (31.8%) patients reported persistent ulnar nerve sensory symptoms, while none of the patients reported persistent ulnar nerve motor symptoms. Overall, 16 (72.7%) players were able to return to competitive play at an average of 11.2 months. The mean postoperative patient-reported outcome scores for the KJOC Shoulder and Elbow Score, MEPS, A-T Elbow Score, and SANE score were 77.9 ± 20.9 (range, 14-100), 92.7 ± 12.7 (range, 45-100), 86.1 ± 17.1 (range, 30-100), and 85.5 ± 14.8 (range, 50-100), respectively.

Conclusion:

This study demonstrated that after concomitant UCLR and UNT for UCL insufficiency and associated ulnar neuritis, baseball players can expect reasonably high RTP rates and subjective outcomes; however, rates of persistent sensory ulnar neuritis can be as high as 30%.
Collective Mindfulness: The Key to Organizational Resilience in Megaprojects
Authors: Wang Linzhuo , Müller Ralf , Zhu Fangwei , Yang Xiaotian
Published: November 2021

The complexity, internal and external risks, and significant social impact of megaprojects make their organizational resilience particularly important. To survive potential adversities, megaproject organizational resilience depends on collective mindfulness. Drawing on an attention-based view, this study investigates the mechanisms of collective mindfulness for megaproject organizational resilience as a process that functions prior to, during, and after recovery from crises. The results from analyzing six embedded crisis events in two megaprojects indicate that collective mindfulness influences organizational resilience processes through the mechanisms of awareness allocation, emotional detachment, and attention alignment. The study's theoretical and practical implications are discussed.
Blood Type Does Not Affect Morbidity or Mortality in COVID-19 Infections, As Assessed By a Clinical Severity Scoring System
Authors: Thomas Katharine E , Dauchy Erin Marie , Karamanis Amber , Chapple Andrew G. , Loch Michelle M
Published: November 2021

Introduction:

Coronavirus disease (COVID-19), caused by the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), continues to lead to worldwide morbidity and mortality. This study aimed to determine if there was an association between blood type and clinical outcomes measured by a calculated morbidity score and mortality rates in patients infected with SARS-CoV-2 at our institution. The secondary aim was to investigate the association between patient characteristics (specifically age, gender, comorbid conditions, and race) and clinical outcomes and mortality in patients with confirmed SARS-COV-2 infection.

Methods:

Logistic regression was used to determine what factors were associated with death. A total morbidity score was constructed based on overall patient's COVID-19 clinical course. This score was modeled using Quasi-Poisson regression. Bayesian variable selection was used for the logistic regression to obtain a posterior probability that blood type is important in predicting worsened clinical outcomes and death.

Results:

Patients with blood type B were more likely to be African American, and patients with blood type AB were less likely to be male. Neither Blood type nor Rh+ status was a significant moderator of death or total morbidity score in regression analyses. Deviance based tests showed that blood type and Rh+ status could be omitted from each regression without a significant decrease in prediction accuracy. Bayesian variable selection showed that the posterior probability that any blood type related covariates were important in predicting death was .10. Increased age (aOR = 3.37, 95% CI = 2.44 - 4.67), male gender (aOR = 1.35, 95% CI = 1.08-1.69), and number of comorbid conditions (aOR = 1.28, 95% CI = 1.01-1.63) were the only covariates that were significantly associated with death. The only significant factors in predicting total morbidity score were age (aOR = 1.45; 95% CI = 1.349-1.555) and gender (aOR = 1.17; 95% CI = 1.109-1.243).

Conclusion:

In a large cohort of COVID-19 positive patients treated at a tertiary care hospital serving a low income population in New Orleans, there is strong evidence that blood type was not a significant predictor of clinical course or death in patients hospitalized with COVID 19. Older age and male gender led to worse clinical outcomes and higher rates of death; whereas older age, male gender, and comorbidities predicted a worse clinical course and higher morbidity score. Race was not a predictor of clinical course or death.

Disclosures

No relevant conflicts of interest to declare.
Tim-3 Mutation Might Play in the Pathophysiology of Acute Myeloid Leukemia
Authors: Huang Junwei , Liu Qifa , Jin Hua
Published: November 2021

Genetic polymorphisms and expression of T-cell immunoglobulin mucin-3 (Tim-3) were associated with susceptibility and prognosis in some tumors, but the relationship between Tim-3 mutation and acute myeloid leukemia (AML) was rarely reported. This study explored the effects of Tim-3 mutations on AML. Four hundred and ninety-one de novo newly diagnosed AML patients were enrolled in this exploratory study. A genomic panel of 167 gene targets were detected by next-generation sequencing (NGS). A matched-pair analysis was designed for prognosis based on 1:2 ratio. 26 patients carried Tim-3 mutations, including 20 Tim-3 p.Y82C and other 6 mutations of p.E273K, p.E182N190del, p.Ter302E, p.A28V, p.R184W, p.G54fs. The median number of somatic mutations apart from Tim-3 was 6 and 7 in Tim-3 + and Tim-3 - groups (P=0.543), respectively. Tim-3 expression was lower, and white blood cell (WBC) at diagnose was higher (P=0.045) in Tim-3 + than Tim-3 - groups. The 2-year cumulative incidence of relapse was 50.8% and 28.7% (P=0.043), overall survival (OS) was 42.6% and 68.5% (P=0.048), and event-free survival (EFS) was 26.8% and 49.6% (P=0.028) in both groups, respectively. Multivariate analysis showed that WBC at diagnose was the risk factor (P=0.004, 0.011 and 0.000, respectively) while transplantation was the protective factor (P=0.015，0.000 and 0.000) for relapse, OS and EFS, and Tim-3 mutation was the risk factor for relapse (P=0.006) in the normal karyotype patients. In vitro, AML cell lines with Tim-3 p.Y82C overexpression revealed lower Tim-3 expression and apoptotic rate as well as lower sensitivity to cytarabine. The bioinformatic analysis also indicated Tim-3 low expression was associated with lower survival in AML patients (P=0.0009). Our findings provide new viewpoint that Tim-3 mutation results in Tim-3 lower expression and is a poor prognostic factor in AML.

Disclosures

No relevant conflicts of interest to declare.
SAXS Analysis of the Intrinsic Tenase Complex Bound to Lipid Nanodisc Highlights Intermolecular Contacts between Factors VIIIa/IXa
Authors: Childers Kenneth C , Peters Shaun , Lollar John S. , Spencer H. Trent , Doering Christopher B , Spiegel Paul Clinton
Published: November 2021

The intrinsic tenase (Xase) complex is formed by activated clotting factors VIII (fVIIIa) and IX (fIXa) on activated platelet surfaces and catalyzes the activation of factor X to promote blood coagulation. The structural organization of the membrane-bound Xase complex remains largely unknown, hindering a mechanistic understanding of how mutations to fVIIIa or fIXa lead to thrombotic disorders. In the present study, we aimed to structurally characterize the Xase complex bound to a lipid nanodisc using biolayer interferometry and small-angle X-ray scattering. By immobilizing lipid nanodiscs, we measured binding rates and nanomolar affinities for fVIIIa, fIXa, and the Xase complex. An ab initio molecular envelope of the nanodisc-bound Xase complex allowed us to computationally model fVIIIa and fIXa docked onto a flexible lipid membrane and identify protein-protein interactions. Our results suggest that interactions between the Gla and catalytic domains of fIXa and the C2 and A2 domains of fVIIIa, respectively, mediate Xase complex assembly. Additionally, our computational modelling highlighted a novel interaction between fIXa residue K80 and an acidic patch formed at the fVIIIa A1/A3 domain interface. Our model of the Xase complex sheds light on how hemophilia A/B-related mutations with varying severities disrupt Xase complex assembly. We also speculate on how gain-of-function mutations to fIXa residue R338, such as the Padua (R338L) and Shanghai (R338Q) variants, bind to the fVIIIa A2 domain and stabilize the Xase complex, leading to excessive blood clotting. Together, our results support the use of SAXS as an emergent tool to investigate the membrane-bound Xase complex and illustrate how mutations at the fVIIIa/fIXa dimer interface may disrupt or stabilize the activated enzyme complex.

Disclosures

Lollar: Expression Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties. Spencer: Expression Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Doering: Expression Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months.
The Impact of Tocilizumab Treatment for Cytokine Release Syndrome on the Incidence of Blood Stream Infections after Peripheral Blood Haploidentical Hematopoietic Cell Transplantation
Authors: De Togni Elisa , Wan Fei , Slade Michael , Abboud Ramzi
Published: November 2021

Introduction: Cytokine release syndrome (CRS) is a potentially fatal systemic inflammatory response that can occur in patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT). IL-6 inhibitors, such as tocilizumab, are effective therapy in moderate to severe cases. Several studies have shown there to be a significant increase in infections with the use of tocilizumab in patients with rheumatoid arthritis, where it is given on a long term basis unlike in the post-haplo-HCT setting, where tocilizumab is rarely given for more than a few days. Severe CRS has been associated with increased infection risk in prior studies. However, the effect of anti-IL-6 therapy on infection risk has not been well established in the early haplo-HCT setting.

In this study, we examined the effect of tocilizumab for treatment of CRS on the incidence of blood stream infections (BSIs) in the early post peripheral blood haplo-HCT setting.

Patients and Methods: We performed a retrospective analysis of 235 patients who underwent T cell-replete peripheral blood haplo-HCTs from 2013 to 2020, stratified on CRS grade (graded by Lee criteria) and tocilizumab administration, for incidence of BSI. Positive blood cultures during days +2 to +28 post-haplo-HCT were included. Patients with positive blood cultures during the immediate peri-transplant period (days -5 to +1) were excluded as infection preceded CRS and tocilizumab administration. Patients who had positive blood cultures within 48 hours of CRS diagnosis were excluded as sepsis cannot be distinguished from CRS.

Results: The overall incidence of bloodstream infection was 17% with 41 out of the total 235 patients having positive blood cultures. Patients with mild CRS had lower incidence of infection than patients with severe CRS (OR 0.31, 95% CI 0.13-0.74, p=0.0086). In the tocilizumab group, 31% (15/49) of patients had positive blood cultures compared with 14% (26/186) in the non-tocilizumab group (OR 1.61, 95% CI 0.30-8.60, p=0.58). However, after controlling for CRS grade, tocilizumab administration was not associated with higher rates of BSIs for any grade of CRS.

Conclusions: Severe CRS after haplo-HCT is associated with higher risk of early BSI. However, tocilizumab therapy does not further increase risk of BSI in the early post-haplo-HCT setting. These data suggest that tocilizumab, a potentially life saving therapy, can be given without increasing risk of blood stream infections after haplo-HCT.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Loss of iqgap1 (IQ Motif Containing GTPase Activating Protein 1) in Zebrafish Leads to Intracerebellar Hemorrhage, Morphological Abnormalities and Activates Hematopoietic Response
Authors: Prykhozhij Sergey , Caceres Lucia , Ban Kevin , McMaster Christopher , Robitaille Johane M , Berman Jason N
Published: November 2021

Defects in multiple cell signaling molecules lead to disruptions of vascular integrity given the need for fine-tuned regulation of the cell adhesion complexes. These genetic defects have been linked to the development of intracerebral hemorrhage (ICH). There is genetic evidence in humans for ICH due to some genetic variants, while other variants have been identified in preclinical animal models. Signaling adaptor proteins play a crucial role in cell signaling by promoting interactions between effector proteins and even enabling integration of different pathways. IQGAP1 is a conserved signaling adaptor known for its roles in cell adhesion, cancer and for other cell biological effects. We engineered a zebrafish null mutant in the zebrafish iqgap1 gene by introducing an 11-bp deletion using a CRISPR/Cas9 genome editing method and characterized its phenotype. Homozygous mutants exhibit severe brain hemorrhage and morphological abnormalities, which are ultimately lethal, in about 30-40% of cases, whereas the other embryos survive to adulthood. We visualized the expression pattern of iqgap1 relative to the established fli1a vascular marker and found that iqgap1 strongly overlapped with fli1a expression, but was expressed much more broadly in tissues, such as muscle, branchial arches, and the caudal hematopoietic tissue (equivalent to the mammalian fetal liver).

Critically, iqgap1 exhibited co-localization with fli1a in the blood vessels of the central nervous system, whose disruption is likely responsible for the brain hemorrhage. Whole embryo RNA sequencing-based comparison of hemorrhage-positive iqgap1-/- embryo pools with wild-type embryos at 52 hours post-fertilization (hpf) shortly after the onset of hemorrhage identified approximately 800 differentially regulated genes. The most striking feature of this dataset was up-regulation of hematopoietic markers especially those of erythrocytes, neutrophils, mast cells and HSPCs (hematopoietic stem and progenitor cells), but not macrophages. We have confirmed by in situ hybridization with marker gene probes that erythrocyte and neutrophil production is up-regulated most strongly in iqgap1-/- embryos undergoing some level of hemorrhage. By contrast, fli1a endothelial and stem cell marker was downregulated. This animal model provides a compelling genotype-phenotype correlation, implicating IQGAP1 as a new player in vascular disorders such as ICH and identifying a previously unrecognized relationship between IQGAP and regulation of hematopoiesis. Furthermore, this model is now poised to identify ameliorating and exacerbating modifier lesions and potential therapeutic agents that restore normal vascular integrity and prevent ICH.

Disclosures

Robitaille: Novartis: Consultancy. Berman: Oxford Immune Algorithmics: Membership on an entity's Board of Directors or advisory committees.
Protein Structure Prediction and Bioinfamatic Analysis of Novel Fusion Gene IKZF1/Pfas in BPDCN
Authors: Le Yin , Yu Qian , Zhu Hongkai , Jiang Yi , Wang Zhihua , Li Ruijuan , Li Heng , Sheng Yue , Cheng Zhao , Peng Hongling
Published: November 2021

A novel fusion gene, IKAROS Family Zinc Finger 1 (IKZF1)/Phosphoribosylformylglycinamidine Synthase (PFAS), was identified in a patient diagnosed with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Secondary protein structure analysis, 3D protein structure determination and domain analysis revealed loss of the ZnF-C2H2 domains of IKZF1 caused by premature translation termination at amino acid (AA) residue 55, which might cause dysfunction of IKZF1.

Bioinformatic analysis was conducted using RNA-seq data for 37 BPDCN samples from the GSE database (GSE62014 and GSE89565) to elucidate the role of IKZF1 in BPDCN. WGCNA showed that IKZF1 expression could be used to categorize BPDCN samples into two distinct clusters (IKZF1 high and IKZF1 low). Differentially expressed genes (DEGs) were identified in these two subgroups and subjected to GO and KEGG analyses. Mitochondrial function-related pathways and ubiquitin-mediated proteolysis were the most enriched pathways in the GO and KEGG analyses, respectively. A PPI network of the DEGs was constructed, and 10 key genes were identified (CSTF2, SF3B1, U2AF2, HNRNPH1, SF3B3, SNRNP200, LSM2, SLU7, CPSF4 and UPF3B). Most of these genes are related to tumorigenesis, cancer metastasis, and hematopoietic malignancies.

In conclusion, the novel IKZF1/PFAS fusion gene could cause dysfunction of the IKZF1. The bioinformatic analysis results emphasized the role of IKZF1 in BPDCN and identified 10 key genes closely related to IKZF1, most of which are tumorigenesis-related.

Disclosures

No relevant conflicts of interest to declare.
Next-Generation Sequencing Reveals Molecular Heterogeneity in Primary Testicular DLBCL
Authors: Liu Shuozi , Yang Ping , Wang Jing , Zhang Weilong , Jing Hongmei
Published: November 2021

Background:

Primary testicular lymphomas (PTLs) are extra-nodal large B-cell lymphomas (LBCLs) that respond poorly to current empirical treatment options. To date, no PTL whole-exome sequencing analysis based on the Chinese population has been reported. The main objective of this study was to explore the genomic landscape of PTDLBCL, correlating the results with clinical, histological, and immunogenetic features.

Methods:

We retrospectively analyzed the disease characteristics in a series of 20 patients (13 paired data and 7 unpaired data). In all cases, the diagnosis of PTL was made using appropriate diagnostic criteria for the 2008 WHO classification of lymphoid tumors with combinations of histologic, immunohistochemical, flow cytometric, and genetic evaluation. Medical records were reviewed for demographic and clinical data. We performed whole-exome next-generation sequencing (NGS) and mapped the mutational landscape. Based on the differential gene results, we performed KEGG and GO enrichment analysis, and five potential new pathogenic genes for DLBCL were obtained based on the Polyphen score.

Results:

A total of 20 DLBCL samples were collected. All samples were subjected to whole-exome sequencing (WES). A standard bioinformatics analysis process was used to identify somatic mutations in each sample, and an average of 1200 somatic mutations was identified, involving an average of 420 mutated genes. (Figure 1.) More than 85% of the somatic mutations were found in only 1 sample, indicating that somatic mutations are highly heterogeneous. In the matched 13 cases, we validated common gene mutations that have been reported, including PIM1 53.84% (7/13), CD79B 38.46% (5/13), CDKN2A 15.38% (2/13), and MYD88 15.38% (2/13). Venn diagram shows that 25% of the mutated genes were specific to the relapsed sample. GO analysis (Figure 2) shows the functional enrichment and differences between relapsed and non-relapsed samples. Non-relapsed samples are enriched in the herpes simplex virus 1 infection pathway. (Figure 3). Focusing on relapsed/non-relapsed samples, we identified 12 mutated genes specific to relapsed samples. Mutation Polyphen scores were calculated to assess mutation deleteriousness. Five potential new pathogenic genes for DLBCL were obtained.

Conclusions:

Based on whole-sequencing data, we validated the previously reported common genes for PTDLBCL. In addition, we performed GO and KEGG analysis according to the relapsed and non-relapsed groups. In addition, based on the difference in enrichment results, 12 significantly enriched mutated genes in relapsed DLBCL samples are obtained, and mutation Polyphen scores are calculated to assess mutation deleteriousness. And 5 potential new pathogenic genes of DLBCL are identified.

Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.