bluuebunny/crossref_metadata_2025 huggingface dataset:
Behind the Mask: An Exploratory Assessment of Female Surgeons’ Experiences of Gender Bias
Authors: Barnes K. Lauren , Dunivan Gena , Sussman Andrew L. , McGuire Lauren , McKee Rohini
Published: July 2020

Though overt sexism is decreasing, women now experience subtle, often unconscious, gender bias as microaggressions. The authors sought to explore the prevalence and impact of the sexist microaggressions female surgeons experience, using a sequential exploratory mixed methods approach (January 2018–April 2018), to identify opportunities for education and prevention. First, all resident, fellow, and attending female surgeons at the University of New Mexico Health Sciences Center (UNM HSC) were invited to participate in focus groups conducted by experienced moderators using a semistructured interview guide based on the 7 Sexist Microaggressions Experiences and Stress Scale (Sexist MESS) domains. Qualitative analysis was performed using line-by-line manual coding to identify themes aligned with the Sexist MESS domains as well as other gender bias experiences of female surgeons. Next, a survey was sent to all resident, fellow, and attending female surgeons at the UNM HSC, which included the Sexist MESS questionnaire and questions related to surgeon-specific experiences of gender bias that the authors developed based on major thematic categories from the focus groups.

Four focus groups of 23 female surgeons were conducted, revealing 4 themes: exclusion, increased effort, adaptation, and resilience to workplace slights. The survey response rate was 64% (65/101 surgeons). Across Sexist MESS domains, the frequency and severity of microaggressions was higher for trainees than attendings. The variables of non-White race/ethnicity, having children under 18, and fellowship training generally did not demonstrate statistical significance. This exploratory study adds to the growing body of evidence that gender bias in surgery continues and frequently manifests as microaggressions. Trainees reported the highest rates and severity of microaggressions and bias experiences. Further research should investigate how to address microaggressions, the experiences of male surgeons, the perspectives of medical students and groups who were reported as often perpetuating gender bias, and the efficacy of possible interventions.
Increased aortic augmentation index is associated with reduced exercise capacity after heart transplantation
Authors: Chun Kyeong-Hyeon , Lee Chan Joo , Oh Jaewon , Won Chihyeong , Lee Taeyoon , Park Sungha , Lee Sang-Hak , Kang Seok-Min
Published: July 2020

Objective:

Exercise capacity is often reduced after heart transplantation. We aimed to investigate the association between aortic stiffness and exercise capacity after heart transplantation.

Methods:

We retrospectively analyzed the data of patients who underwent a cardiopulmonary exercise test and central hemodynamic measurements over 1 year following heart transplantation, from Janary 2011 to June 2018.

Results:

A total of 54 patients (mean age, 49 years; 72% men) were analyzed. The median peak oxygen uptake level was 21.1 ml/kg per min at a median time of 13 months after heart transplantation. In univariate linear regression, recipient age, pulmonary arterial pressure, pulmonary capillary wedge pressure, hemoglobin level, estimated glomerular filtration rate, aortic augmentation index, and pulse wave velocity were significant predictors for peak oxygen uptake level. After adjustment for other confounding variables, heart rate-corrected aortic augmentation index was a significant predictor for peak oxygen uptake (β = −0.141, 95% confidence interval, −0.263 to −0.058, P = 0.003).

Conclusion:

In the present study, increased aortic augmentation index was associated with reduced exercise capacity after heart transplantation. Therefore, this simple measurement of aortic stiffness should be periodically used for the evaluation of exercise capacity after heart transplantation.
Quality of life and satisfaction among physicians after wavefront-optimized vs topography-guided laser vision correction
Authors: Ma Jeffrey , Pillar Angelique , Krueger Ronald
Published: July 2020

Purpose:

To assess satisfaction, quality of life, occupational impact, and clinical outcomes of physicians who have undergone laser vision correction (LVC) using either wavefront-optimized (WFO) or topography-guided (TG) excimer laser ablation profile with femtosecond laser flap creation.

Setting:

Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Design:

Retrospective survey study.

Methods:

A 12-question survey was sent to all physicians who underwent laser in situ keratomileusis or photorefractive keratectomy at the Cole Eye Institute between 2011 and 2018 on the WaveLight Allegretto Wave Eye-Q Laser (Alcon Laboratories, Inc.). Visual outcomes were obtained from patient charts.

Results:

Two hundred thirty-five physicians (454 eyes) met the study's inclusion criteria, including 181 physicians (353 eyes) who underwent WFO LVC and 54 physicians (101 eyes) who underwent TG LVC. One hundred seventeen physicians (49.8%) responded to the survey and reported an overall satisfaction rate of 98.3% among all physicians receiving LVC with 96.6% reporting they would have the procedure again. Visual outcomes showed a high level of surgical predictability, efficacy, and safety among WFO and TG eyes, with a higher percentage of eyes that received TG ablation achieving 20/10 vision (22% vs 4%, P < .0001) and 20/15 vision (87% vs 69%, P < .01) when compared with WFO eyes.

Conclusions:

Physicians who had undergone LVC with either WFO or TG excimer laser ablation reported high satisfaction and quality-of-life improvements. Both groups achieved excellent visual outcomes, with a higher percentage of TG eyes achieving 20/10 and 20/15 vision.
Insomnia and Insomnia Symptoms in Persons With Heart Failure
Authors: Gharzeddine Rida , McCarthy Margaret M. , Yu Gary , Dickson Victoria Vaughan
Published: July 2020

Background/Objective

Insomnia and insomnia symptoms are highly prevalent in persons with heart failure (HF), and they are associated with several untoward outcomes. The purpose of this integrative review is to describe the correlates, predictors, and outcomes of insomnia and insomnia symptoms in persons with HF.

Methods

Using integrative review methods, an extensive electronic search of 5 databases was conducted for the period of 2000–2019. Sixteen studies were identified that met the inclusion criteria for review and investigated insomnia or insomnia symptoms in HF.

Results

Various sociodemographic factors, chronic comorbidities, clinical factors, and cognitive-behavioral factors are correlates and predictors of insomnia and insomnia symptoms in persons with HF. Depression, fatigue, daytime sleepiness, poor self-reported physical functioning, decreased exercise capacity, cardiac events, and poor health-related quality of life are significant outcomes of insomnia and insomnia symptoms in persons with HF. The associations of insomnia and insomnia symptoms with age, sex, sleep-disordered breathing, and cognition were not consistent across all studies.

Conclusion

Larger studies with diverse age and race groups as well as longitudinal studies and designs that test mediation effects are needed to disentangle complex relationships between insomnia and insomnia symptoms and several of their potential predictors and correlates in HF.
Equity in Genomics
Authors: Scott Jewel , Cousin Lakeshia , Woo Jennifer , Gonzalez-Guarda Rosa , Simmons Leigh Ann
Published: July 2020

Background

African Americans are more likely to die from cardiovascular disease (CVD) than all other populations in the United States. Although technological advances have supported rapid growth in applying genetics/genomics to address CVD, most research has been conducted among European Americans. The lack of African American representation in genomic samples has limited progress in equitably applying precision medicine tools, which will widen CVD disparities if not remedied.

Purpose

This report summarizes the genetic/genomic advances that inform precision health and the implications for cardiovascular disparities in African American adults. We provide nurse scientists recommendations for becoming leaders in developing precision health tools that promote population health equity.

Conclusions

Genomics will continue to drive advances in CVD prevention and management, and equitable progress is imperative. Nursing should leverage the public's trust and its widespread presence in clinical and community settings to prevent the worsening of CVD disparities among African Americans.
Neurogenic Orthostatic Hypotension: An Underrecognized Complication of Parkinson Disease
Authors: Sin Mo-Kyung , Khemani Pravin
Published: July 2020

BACKGROUND: Neurogenic orthostatic hypotension (nOH) is a common source of disability but is an often untreated nonmotor symptom of Parkinson disease. The key manifestations of nOH include lightheadedness, dizziness, weakness, and fatigue when standing and engaging in activities in the upright position and result in falls, impaired activities of living, decreased quality of life, and short-term cognitive impairment. Early diagnosis and treatment of nOH are necessary to mitigate its adverse effects and reduce nOH-related symptom burden. CASE STUDY: The management of nOH is illustrated through a case study. MANAGEMENT CONSIDERATIONS: Alerting providers about the impact and treatment of nOH, accurate measurement of orthostatic blood pressure, and educating patients and caregivers about nonpharmacological treatment options are important strategies to manage nOH. The goal of nOH treatment is to mitigate symptoms and improve the patient's quality of life. CONCLUSIONS: Nurses can play a crucial role in the recognition and management of nOH. Nurses who are educated about nOH are well suited to partner with care providers to treat disabling motor and nonmotor symptoms of Parkinson disease.
What Can Social Media Tell Us About Patient Symptoms
Authors: Lee Young Ji , Park Albert , Roberge Mary , Donovan Heidi
Published: July 2020

Background

Ovarian cancer (OvCa) patients suffer from symptoms that severely affect quality of life. To optimally manage these symptoms, their symptom experiences must be better understood. Social media have emerged as a data source to understand these experiences.

Objective

The objective of this study was to use topic modeling (ie, latent Dirichlet allocation [LDA]) to understand the symptom experience of OvCa patients through analysis of online forum posts from OvCa patients and their caregivers.

Interventions/Methods

Ovarian cancer patient/caregiver posts (n = 50 626) were collected from an online OvCa forum. We developed a symptom dictionary to identify symptoms described therein, selected the top 5 most frequently discussed symptoms, extracted posts that mentioned at least one of those symptoms, and conducted LDA on those extracted posts.

Results

Pain, nausea, anxiety, fatigue, and skin rash were the top 5 most frequently discussed symptoms (n = 4536, 1296, 967, 878, and 657, respectively). Using LDA, we identified 11 topic categories, which differed across symptoms. For example, chemotherapy-related adverse effects likely reflected fatigue, nausea, and rash; social and spiritual support likely reflected anxiety; and diagnosis and treatment often reflected pain.

Conclusion

The frequency of a symptom discussed on a social media platform may not include all symptom experience and their severity. Indeed, users, who are experiencing different symptoms, mentioned different topics on the forum. Subsequent studies should consider the influence of additional factors (eg, cancer stage) from discussions.

Implications for Practice

Social media have the potential to prioritize and answer the questions about clinical care that are frequently asked by cancer patients and their caregivers.
Small Cell Neuroendocrine Carcinoma of Paranasal Sinuses: Radiologic Features in 14 Cases
Authors: Lin Naier , Qi Meng , Wang Zhengyue , Luo Siqi , Pan Yucheng , Zhang Fang , Sha Yan
Published: July 2020

Purpose

The purpose of this study was to explore the characteristic computed tomography (CT) and magnetic resonance (MR) features of small cell neuroendocrine carcinoma (SNEC) of paranasal sinuses.

Materials and Methods

Computed tomography (n = 8) and MR (n = 14) images and clinical findings from 14 patients with SNEC of paranasal sinuses were retrospectively reviewed.

Results

Eight lesions were located in the ethmoidal sinus, 4 in the maxillary sinus, and 2 in the sphenoid sinus. Small cell neuroendocrine carcinoma of the sphenoid sinus showed bilateral asymmetry patterns. On CT images, bony changes were visible in all 8 cases. On MR, 4 cases contained hemorrhage, and 10 cases contained cystic or necrotic areas. All cases demonstrated marked heterogeneous enhancement, with half showing a “cribriform-like” or “geographic” appearance. The nasal cavity was the most common site invaded by SNEC of paranasal sinuses, followed by the orbits. A time-signal intensity curve examination showed a washout-type pattern in all but 1 case. The mean ± SD apparent diffusion coefficient value was 0.702 ± 0.112 (×10−3 mm2/s). According to the Dulguerov staging system, 9 tumors were staged as N0 (1 T1, 1 T2, 5 T3, and 2 T4). The recurrence rate was 64.3%.

Conclusions

Some characteristics of radiological findings can provide important clues for preoperative diagnosis.
Well-Being, Burnout, and Resiliency Among Early-Career Rheumatologists
Authors: Kumar Bharat , Swee Melissa L. , Suneja Manish , Iyer Priyanka
Published: July 2020

Background/Objective

Physician well-being is being increasingly recognized for its important role in high-quality patient care, integrity of the healthcare system, and vitality of the workforce. However, little is known about well-being, resiliency, and burnout among rheumatologists, particularly early-career rheumatologists. In this qualitative study, the investigators explore these concepts among early-career rheumatologists.

Methods

We performed a qualitative study using semistructured phone interviews of rheumatologists who completed fellowship in 2017. Participants were recruited through purposive sampling. Twenty questions were devised by the investigators, covering sample demographics, exploring definitions of well-being, resiliency, and burnout, and probing potential solutions.

Interviews were recorded and transcribed independently and verified for consistency. The investigators used grounded theory to code the transcripts and iteratively derive categories, subthemes, and themes until reaching theoretical sufficiency.

Results

Sixty-four rheumatologists were interviewed, accounting for 30.6 hours of material. Seven major themes were identified: (1) well-being as a holistic state where an individual is able to translate one's potential to maximal performance, (2) work-family balance as a dynamic equilibrium changing over time, (3) inadequacy of training in addressing self-doubt over autonomy, (4) uncertainty over career development and progression, (5) excessive administrative burdens, (6) protective nature of longitudinal relationships, and (7) addressing burnout requires a multifaceted approach at multiple levels.

Conclusions

New rheumatologists face a series of challenges as they enter the workforce. Investments into well-being can help reduce the risk of burnout and enlarge our community. Our results highlight drivers and potential solutions, as identified by recent fellowship graduates.
Contrast Saline Mixture DualFlow Injection Protocols for Low-Kilovolt Computed Tomography Angiography
Authors: Overhoff Daniel , Jost Gregor , McDermott Michael , Wichtmann Barbara , Schoenberg Stefan O. , Pietsch Hubertus , Attenberger Ulrike
Published: July 2020

Objective

The aim of this study was to evaluate a contrast media (CM)–saline mixture administration with DualFlow (DF) to adapt injection protocols to low-kilovolt (kV) computed tomography angiography (CTA).

Materials and Methods

In both a circulation phantom and animal model (5 Goettingen minipigs), 3 injection protocols were compared in dynamic thoracic CTA: (a) DF injection protocol at 80 kV with a iodine delivery rate (IDR) of 0.9 gI/s, a flowrate of 5 mL/s injected with a 60%/40% ratio of iopromide (300 mgI/mL) and saline (dose contrast medium 180 mgI/kg body weight [BW]); (b) reference CTA was performed at 120 kV and a 40% higher iodine dose applied at higher IDR (1.5 gI/s, 5 mL/s iopromide [300 mgI/mL]; no simultaneously administered saline; 300 mgI/kg BW); and (c) conventional single-flow (SF) protocol with identical IDR as the DF protocol at 80 kV (0.9 gI/s, 3 mL/s iopromide [300 mgI/mL]; no simultaneously administered saline; 180 mgI/kg BW). All 3 injection protocols are followed by a saline chaser applied at the same flow rate as the corresponding CM injection. Time attenuation curves representing the vascular bolus shape were generated for pulmonary trunk and descending aorta.

Results

In the circulation phantom, pulmonary and aortic time attenuation curves for the 80 kV DF injection protocols do not significantly differ from the 80 kV SF and the 120 kV SF reference. In the animal model, the 80 kV DF protocol shows similar pulmonal and aortic peak enhancement when compared with the 120 kV SF and 80 kV SF protocols. Also, the bolus length above an attenuation level of 300 HU reveals no significant differences between injection protocols. However, the time to peak was significantly shorter for the 80 kV DF when compared with the 80 kV SF protocol (15.78 ± 1.9 seconds vs 18.24 ± 2.0 seconds; P = 0.008).

Conclusion

DualFlow injection protocols can be tailored for low-kV CTA by reducing the IDR while overall flow rate remains unchanged. Although no differences in attenuation were found, DF injections offer a shorter time to peak closer to the reference 120 kV protocol.

This allows the use of DF injection protocols to calibrate bolus density in low-kV CTA and yields the potential for a more individualized CM administration.
Two-Minute Quantitative Susceptibility Mapping From Three-Dimensional Echo-Planar Imaging
Authors: Wicaksono Krishna Pandu , Fushimi Yasutaka , Nakajima Satoshi , Yokota Yusuke , Oshima Sonoko , Otani Sayo , Sakurama Azusa , Shima Atsushi , Sawamoto Nobukatsu , Okada Tomohisa , Nakamoto Yuji
Published: July 2020

Objectives

The aim of this study was to assess the accuracy, reliability, and cerebral microbleed (CMB) detection performance of 2-minute quantitative susceptibility mapping (QSM) from 3-dimensional echo-planar imaging (3D-EPI).

Materials and Methods

Gadolinium phantom study was conducted using 3D-EPI, single–echo time (TE), and multi-TE gradient-recalled echo (GRE) sequences on two 3-T magnetic resonance (MR) scanners to assess the accuracy between measured and theoretical susceptibility values. The institutional review board approved this prospective study, and 40 healthy volunteers were enrolled with written consent between April 2018 and October 2019. Each underwent 3D-EPI, single-TE, and multi-TE GRE sequences consecutively on one 3-T MR scanner, and QSMs were calculated to assess the reliability of 3D-EPI QSM. Intraclass correlation coefficient (ICC), linear regression, and Bland-Altman plots were calculated. Patients with CMB who underwent both 3D-EPI and GRE QSM scans were retrospectively enrolled. Two radiologists evaluated images independently, and Cohen κ coefficients were calculated to compare CMB detection performance.

Results

Phantom study showed excellent validity of 3D-EPI QSM on both MR scanners: Skyra, R
2 = 0.996, P < 0.001, ICC = 0.997, mean difference, −2 ppb (95% confidence interval [CI], −45 to 40 ppb); Prisma, R
2 = 0.992, P < 0.001, ICC = 0.988, mean difference, 15 ppb (95% CI, −67 to 97 ppb). A human study of 40 healthy volunteers (59 ± 13 years, 25 women) showed excellent reliability with 3D-EPI QSM for both single-TE and multi-TE GRE (R
2 = 0.981, P < 0.001, ICC = 0.988; R
2 = 0.983, P < 0.001, ICC = 0.990, respectively), supported by a Bland-Altman mean difference of 4 ppb (95% CI, −15 to 23 ppb) for single-TE GRE and 3 ppb (95% CI, −15 to 20 ppb) for multi-TE GRE. The CMB detection performance evaluation from 38 patients (51 ± 20 years, 20 women) showed almost perfect agreement between 3D-EPI and GRE QSM for both raters (κ = 0.923 and 0.942, P < 0.001).

Conclusions

Faster QSM from 3D-EPI demonstrated excellent accuracy, reliability, and CMB detection performance.
Association Between Compensatory Overaction of the Non-Injured Eye, Measured by HESS Chart and Postoperative Diplopia in Blow-Out Fracture
Authors: Nakajima Yuta , Iwasawa Motonao , Mishima Yoshito , Yuzuriha Shunsuke
Published: July 2020

In orbital floor fracture, diplopia often persists post-operatively. This study evaluated the association between pre-operative parameters concerning the extent of the injury and post-operative diplopia, using multivariate analysis. A retrospective computed tomography analysis and chart review was performed for patients with punched out orbital floor fracture, who underwent operations during the period from April 2011 to March 2018. Five parameters were evaluated: the number of upward arrows on the Hess chart (representing compensatory overaction of the non-injured eye), time interval to surgery, muscular subscores, fracture area, and swelling rate of the inferior rectus muscle. Of the 32 patients, 9 (28%) had post-operative diplopia; pre-operative diplopia was completely restored in 23 (72%) patients by 6 months after surgery. Univariate analysis found statistically significant differences in the number of upward arrows on the Hess chart, time interval to surgery, muscular subscores, and fracture area. Logistic regression analysis demonstrated that only the number of upward arrows displayed a significantly increased risk for post-operative diplopia (odds ratio, 15.3; 95% confidence interval, 2.0–117.0; P = 0.008). Excessive overaction of the non-injured eye predicted persistent diplopia by 6 months post-operatively. Surgical intervention may be insufficient to achieve full recovery from diplopia and disturbances of ocular motility in some patients.
Overexpressed lncRNA AC068039.4 Contributes to Proliferation and Cell Cycle Progression of Pulmonary Artery Smooth Muscle Cells Via Sponging miR-26a-5p/TRPC6 in Hypoxic Pulmonary Arterial Hypertension
Authors: Qin Yuhan , Zhu Boqian , Li Linqing , Wang Dong , Qiao Yong , Liu Bo , Luo Erfei , Hou Jiantong , Yan Gaoliang , Tang Chengchun
Published: July 2020

Background:

Hypoxic pulmonary hypertension (HPH) is a devastating and incurable disease characterized by pulmonary vascular remodeling, resulting in right heart failure and even death. Accumulated evidence has confirmed long coding RNAs (lncRNAs) are involved in hypoxia-induced pulmonary vascular remodeling in HPH. The exact mechanism of lncRNA in hypoxic pulmonary hypertension remains unclear.

Methods:

Microarray analysis was applied to investigate the profiles of lncRNA expression in pulmonary artery smooth muscle cells (PASMCs) cultured under hypoxia and normoxia condition. qRT-PCR was performed for the expression of lncRNAs, miRNA, and mRNAs, western blot analysis was employed for the detection of the expression of proteins. CCK-8 and transwell chamber assay were applied for the assessment of PASMC proliferation and migration, respectively. Besides, flow cytometry was performed for assessments of cell cycle progression. The binding between AC068039.4 and miR-26a-5p, miR-26a-5p, and TRPC6 3’UTR was detected by dual luciferase reporter assay.

Results:

A total of 1,211 lncRNAs (698 up-regulated and 513 down-regulated) were differently expressed in hypoxia-induced PASMCs. Consistent with microarray analysis, quantitative PCR verified that AC068039.4 was obviously up-regulated in hypoxia-induced PASMCs. Knocking down AC068039.4 alleviated proliferation and migration of PASMCs and regulated cell cycle progression through inhibiting cells entering the G0/G1 cell cycle phase. Further experiment indicated AC068039.4 promoted hypoxic PASMCs proliferation via sponging miR-26–5p. In addition, transient receptor potential canonical 6 (TRPC6) was confirmed to be a target gene of miR-26a-5p.

Conclusion:

In conclusion, downregulation of lncRNA AC068039.4 inhibited pulmonary vascular remodeling through AC068039.4/miR-26a-5p/TRPC6 axis, providing new therapeutic insights for the treatment of HPH.
The Cardiac Physiology Underpinning Exsanguination Cardiac Arrest: Targets for Endovascular Resuscitation
Authors: Madurska Marta J. , Abdou Hossam , Leung Lai Yee , Richmond Michael J. , Elansary Noha N. , Scalea Thomas M. , Hu Peter , Morrison Jonathan J.
Published: July 2020

Exsanguination leading to cardiac arrest is the terminal phase of uncontrolled hemorrhage. Resuscitative interventions have focused on preload and afterload support. Outcomes remain poor due to several factors but poor coronary perfusion undoubtedly plays a role. The aim of this study is to characterize the relationship between arterial pressure and flow during hemorrhage in an effort to better describe the terminal phases of exsanguination.

Male swine weighing 60 kg to 80 kg underwent splenectomy and instrumentation followed by a logarithmic exsanguination until asystole. Changes in hemodynamic parameters over time were compared using one-way, repeated measures analysis of variance.

Nine animals weighing 69 ± 15 kg were studied. Asystole occurred at 53 ± 13 min when 52 ± 11% of total blood volume has been shed. The greatest fall in mean hemodynamic indices were noted in the first 15 min: SBP (80–42 mm Hg, P = 0.02), left ventricular end-diastolic volume (94–52 mL, P = 0.04), cardiac output (4.8–2.4 L/min, P = 0.03), coronary perfusion pressure (57–30 mm Hg, P = 0.01), and stroke volume (60–25 mL, P = 0.02). This corresponds to the greatest rate of exsanguination. Organized cardiac activity was observed until asystole without arrythmias. Coronary flow was relatively preserved throughout the study, with a precipitous decline once mean arterial pressure was less than 20 mm Hg, leading to asystole.

In this model, initial hemodynamic instability was due to preload failure, with asystole occurring relatively late, secondary to failure of coronary perfusion. Future resuscitative therapies need to directly address coronary perfusion failure if effective attempts are to be made to salvage these patients.
Early Hemoglobin Status as a Predictor of Long-Term Mortality for Sepsis Patients in Intensive Care Units
Authors: Qi Desheng , Peng Milin
Published: July 2020

Objectives:

It is still not clear what influences hemoglobin has on the outcomes of patients with sepsis. The intention of this research is to investigate the impact of early hemoglobin levels on clinical outcomes for sepsis.

Methods:

In this single-center, cohort study, each patient was put into one of four groups dependent on hemoglobin levels of 70 g/L, 80 g/L, or 90 g/L in the first 48 h of being admitted to intensive care unit (ICU). Adjustments for baseline/confounding factors were made using the multiple Cox regression model.

Results:

In all, 235 septic patients were examined in this research. The non-survivors exhibited significantly higher levels for early hemoglobin status at or below 80 g/L (33.7% vs. 19.4%, P = 0.016) than survivors. Survival curve demonstrated that septic patients with early hemoglobin levels at or below 80 g/L survived at significantly lower rates than those with hemoglobin above 80 g/L. Multivariate Cox analysis demonstrated that levels of 1-year mortality rose as early hemoglobin levels fell in the first 48 h after ICU admission, with relative risks for 80 g/L to 90 g/L, 70 g/L to 80 g/L, and at or below 70 g/L being respectively 1.11 (95% CI: 0.654–1.882), 1.742 (95% CI: 0.969–3.133), 1.981 (95% CI: 1.124–3.492) times higher than those for hemoglobin levels above 90 g/L.

Conclusions:

Hemoglobin levels at or below 80 g/L in the first 48 h after ICU admission are an alternative indicator for predicting long-term mortality of sepsis. Awareness should be encouraged of the importance of targeting early hemoglobin levels when treating sepsis to improve prognosis.
Molecular recognition at septin interfaces: the switches hold the key
Authors: Rosa Higor Vinícius Dias , Leonardo Diego Antonio , Brognara Gabriel , Brandão-Neto José , Pereira Humberto D’Muniz , Araújo Ana Paula Ulian , Garratt Richard Charles
Published: July 2020

The assembly of a septin filament requires that homologous monomers must distinguish between one another in establishing appropriate interfaces with their neighbours. To understand this phenomenon at the molecular level, we present the first four crystal structures of heterodimeric septin complexes. We describe in detail the two distinct types of G-interface present within the octameric particles which must polymerize to form filaments. These are formed between SEPT2 and SEPT6 and between SEPT7 and SEPT3, and their description permits an understanding of the structural basis for the selectivity necessary for correct filament assembly. By replacing SEPT6 by SEPT8 or SEPT11, it is possible to rationalizeKinoshita’s postulatewhich predicts the exchangeability of septins from within a subgroup. Switches I and II, which in classical small GTPases provide a mechanism for nucleotide-dependent conformational change, have been repurposed in septins to play a fundamental role in molecular recognition. Specifically, it is switch I which holds the key to discriminating between the two different G-interfaces. Moreover, residues which are characteristic for a given subgroup play subtle, but pivotal, roles in guaranteeing that the correct interfaces are formed.

HIGHLIGHTS

High resolution structures of septin heterodimeric complexes reveal new interactions

Switches of small GTPases are repurposed in septins to play key roles in interface contacts

The GTP present in catalytically inactive septins participates in molecular recognition

Conservation of interface residues allows for subunit exchangeability from within septin subgroups

Specific residues for each septin subgroup provide selectivity for proper filament assembly

GRAPHICAL ABSTRACT
RHEB/mTOR-hyperactivity causing cortical malformations drives seizures through increased axonal connectivity
Authors: Onori Martina Proietti , Koene Linda M.C. , Schafer Carmen B. , Nellist Mark , de Brito van Velze Marcel , Gao Zhenyu , Elgersma Ype , van Woerden Geeske M.
Published: July 2020

Dominant-active mutations inRas Homolog Enriched in Brain 1(RHEB), such as the recently identified RHEBp.P37L mutation, can cause malformations of cortical development (MCD) with associated epilepsy and intellectual disability through a yet unknown mechanism. We found that focal expression of RHEBp.P37L in mouse somatosensory cortex results in an MCD-like phenotype, with increased mammalian target of rapamycin (mTOR) signaling, ectopic localization of neurons and generalized seizures. In addition, the RHEBp.P37L expressing neurons showed increased axonal length and branching. By temporally controlling RHEBp.P37L expression, we found that the cortical malformation by itself was neither necessary nor sufficient to generate seizures. Rather, seizures were contingent on persistent mTOR activation and enhanced axonal connectivity of RHEBp.P37L expressing neurons, causing hyperexcitability of distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, that can lead to generalized epilepsy.
Oviposition of the mosquitoAedes aegyptiin forest and domestic habitats in Africa
Authors: Xia Siyang , Dweck Hany K. M. , Lutomiah Joel , Sang Rosemary , McBride Carolyn S. , Rose Noah H. , Ayala Diego , Powell Jeffrey R.
Published: July 2020

The theory of ecological divergence provides a useful framework to understand the adaptation of many species to anthropogenic (‘domestic’) habitats. The mosquitoAedes aegypti, a global vector of several arboviral diseases, presents an excellent study system.Ae. aegyptioriginated in African forests, but the populations that invaded other continents have specialized in domestic habitats. In its African native range, the species can be found in both forest and domestic habitats like villages. A crucial behavioral change between mosquitoes living in different habitats is their oviposition choices. ForestAe. aegyptilay eggs in natural water containers like tree holes, while their domestic counterparts heavily rely on artificial containers such as plastic buckets. These habitat-specific containers likely have different environmental conditions, which could drive the incipient divergent evolution of oviposition in AfricanAe. aegypti. To examine this hypothesis, we conducted field research in two African locations, La Lopé, Gabon and Rabai, Kenya, whereAe. aegyptilive in both forests and nearby villages. We first characterized a series of environmental conditions of natural oviposition sites, including physical characteristics, microbial density, bacterial composition, and volatile profiles. Our data showed that in both locations, environmental conditions of oviposition sites did differ between habitats. To examine potential behavioral divergence, we then conducted field and laboratory oviposition choice experiments to compare the oviposition preference of forest and village mosquitoes. The field experiment suggested that forest mosquitoes readily accepted artificial containers. In laboratory oviposition assays, forest and village mosquito colonies did not show a differential preference towards several conditions that featured forest versus village oviposition sites. Collectively, there is little evidence from our study that environmental differences lead to strong and easily measurable divergence in oviposition behavior betweenAe. aegyptithat occupy nearby forest and domestic habitats within Africa, despite clear divergence between African and non-AfricanAe. aegypti.
Genetic information insecurity as state of the art
Authors: Schumacher Garrett J. , Sawaya Sterling , King Demetrius , Hansen Aaron J.
Published: July 2020

Genetic information is being generated at an increasingly rapid pace, offering advances in science and medicine that are paralleled only by the threats and risk present within the responsible ecosystem. Human genetic information is identifiable and contains sensitive information, but genetic data security is only recently gaining attention. Genetic data is generated in an evolving and distributed cyber-physical ecosystem, with multiple systems that handle data and multiple partners that utilize the data. This paper defines security classifications of genetic information and discusses the threats, vulnerabilities, and risk found throughout the entire genetic information ecosystem. Laboratory security was found to be especially challenging, primarily due to devices and protocols that were not designed with security in mind. Likewise, other industry standards and best practices threaten the security of the ecosystem. A breach or exposure anywhere in the ecosystem can compromise sensitive information. Extensive development will be required to realize the potential of this emerging field while protecting the bioeconomy and all of its stakeholders.
A unifying concept of animal breeding programs
Authors: Simianer H. , Ganesan A. , Buettgen L. , Ha N.T. , Pook T.
Published: July 2020

Modern animal breeding programs are constantly evolving with advances in breeding theory, biotechnology and genetics. Surprisingly, there seems to be no generally accepted succinct definition of what exactly a breeding program is, neither is there a unified language to describe breeding programs in a comprehensive, unambiguous and reproducible way. In this work, we try to fill this gap by suggesting a general definition of breeding programs that also pertains to cases where genetic progress is not achieved through selection, but e.g. through transgenic technologies, or the aim is not to generate genetic progress, but e.g. to maintain genetic diversity. The key idea of the underlying concept is to represent a breeding program in modular form as a directed graph that is composed of nodes and edges, where nodes represent cohorts of breeding units, usually individuals, and edges represent breeding activities, like ‘selection’ or ‘reproduction’. We claim, that by defining a comprehensive set of nodes and edges it is possible to represent any breeding program of arbitrary complexity by such a graph, which thus comprises a full description of the breeding program. This concept is implemented in a web-based tool (MoBPSweb, available atwww.mobps.de) which is described in a companion paper, and has a link to the R-package MoBPS (Modular Breeding Program Simulator) to simulate the described breeding programs. The approach is illustrated by showcasing three different breeding programs of increasing complexity. Finally, potential limitations of the concept are indicated and extensions to other fields, like plant breeding, are discussed.
Fast and sensitive diffuse correlation spectroscopy with highly parallelized single photon detection
Authors: Liu Wenhui , Qian Ruobing , Xu Shiqi , Konda Pavan Chandra , Harfouche Mark , Borycki Dawid , Jönsson Joakim , Berrocal Edouard , Cooke Colin , Wang Haoqian , Dai Qionghai , Horstmeyer Roarke W.
Published: July 2020

Diffuse correlation spectroscopy (DCS) is a well-established method that measures rapid changes in scattered coherent light to identify blood flow and functional dynamics within tissue. While its sensitivity to minute scatterer displacements leads to a number of unique advantages, conventional DCS systems become photon-limited when attempting to probe deep into tissue, which leads to long measurement windows (∼1 sec). Here, we present a high-sensitivity DCS system with 1024 parallel detection channels integrated within a single-photon avalanche diode (SPAD) array, and demonstrate the ability to detect mm-scale perturbations up to 1 cm deep within a tissue-like phantom at up to 33 Hz sampling rate. We also show that this highly parallelized strategy can measure the human pulse at high fidelity and detect behaviorally-induced physiological variations from above the human prefrontal cortex. By greatly improving detection sensitivity and speed, highly parallelized DCS opens up new experiments for high-speed biological signal measurement.
X-ray structural analysis of single adult cardiomyocytes: tomographic imaging and micro-diffraction
Authors: Reichardt M. , Neuhaus C. , Nicolas J-D. , Bernhardt M. , Toischer K. , Salditt T.
Published: July 2020

We present a multi-scale imaging approach to characterize the structure of isolated adult murine cardiomyocytes based on a combination of full-field three-dimensional (3d) coherent x-ray imaging and scanning x-ray diffraction. Using these modalities, we probe the structure from the molecular to the cellular scale. Holographic projection images on freeze-dried cells have been recorded using highly coherent and divergent x-ray waveguide radiation. Phase retrieval and tomographic reconstruction then yield the 3d electron density distribution with a voxel size below 50 nm. In the reconstruction volume, myofibrils, sarcomeric organisation and mitochondria can be visualized and quantified within a single cell without sectioning. Next, we use micro-focusing optics by compound refractive lenses to probe the diffraction signal of the acto-myosin lattice. Comparison between recordings of chemically fixed and untreated, living cells indicate that the characteristic lattice distances shrink by approximately 10% upon fixation.

SIGNIFICANCE

Diffraction with synchrotron radiation has played an important role to decipher the molecular structure underlying force generation in muscle. In this work, the diffraction signal of the actomyosin contractile unit has for the first time been recorded from living cardiomyocytes, bringing muscle diffraction to the scale of single cells. In addition to scanning diffraction, we use coherent optics at the same synchrotron endstation to perform holographic imaging and tomography on a single cardiomyocyte. By this hard x-ray microscopy modality, we extend the length scales covered by scanning diffraction and reconstruct the electron density of an entire freeze-dried cardiomyocyte, visualizing the 3d architecture of myofibrils, sarcomers, and mitochondria with a voxel size below 50 nm.
Investigation of cell nucleus heterogeneity
Authors: Reynolds Noel , McEvoy Eoin , Ghosh Soham , Pérez Juan Alberto Panadero , Neu Corey P. , McGarry Patrick
Published: July 2020

Nucleus deformation has been shown to play a key role in cell mechanotransduction and migration. Therefore, it is of wide interest to accurately characterize nucleus mechanical behavior. In this study we present the first computational investigation of the in-situ deformation of a heterogeneous cell nucleus. A novel methodology is developed to accurately reconstruct a three-dimensional finite element spatially heterogeneous model of a cell nucleus from confocal microscopy z-stack images of nuclei stained for nucleus DNA. The relationship between spatially heterogeneous distributions microscopic imaging-derived greyscale values, shear stiffness and resultant shear strain is explored through the incorporation of the reconstructed heterogeneous nucleus into a model of a chondrocyte embedded in a PCM and cartilage ECM. Externally applied shear deformation of the ECM is simulated and computed intra-nuclear strain distributions are directly compared to corresponding experimentally measured distributions. Simulations suggest that the nucleus is highly heterogeneous in terms of its mechanical behaviour, with a sigmoidal relationship between experimentally measure greyscale values and corresponding local shear moduli (μn). Three distinct phases are identified within the nucleus: a low stiffness phase (0.17kPa≤μn≤ 0.63kPa) corresponding to mRNA rich interchromatin regions; an intermediate stiffness phase (1.48kPa≤μn≤ 2.7kPa) corresponding to euchromatin; a high stiffness phase (3.58kPa≤μn≤ 4.0kPa) corresponding to heterochromatin. Our simulations indicate that disruption of the nucleus envelope associated with lamin-A/C depletion significantly increases nucleus strain in regions of low DNA concentration. A phenotypic shift of chondrocytes to fibroblast-like cells, a signature for osteoarthritic cartilage, results in a 35% increase in peak nucleus strain compared to control. The findings of this study may have broad implications for the current understanding of the role of nucleus deformation in cell mechanotransduction.
TranSynergy: Mechanism-Driven Interpretable Deep Neural Network for the Synergistic Prediction and Pathway Deconvolution of Drug Combinations
Authors: Liu Qiao , Xie Lei
Published: July 2020

Motivation

Drug combinations have demonstrated great potential in cancer treatments. They alleviate drug resistance and improve therapeutic efficacy. With the fast-growing number of anti-cancer drugs, the experimental investigation of all drug combinations is costly and time-consuming. Computational techniques can improve the efficiency of drug combination screening. Despite recent advances in applying machine learning to synergistic drug combinations prediction, several challenges remain. First, the performance of existing methods is suboptimal. There is still much space for improvement. Second, biological knowledge has not been fully incorporated into the model. Finally, many models are lack of interpretability, limiting their clinical applications.

Results

We develop a knowledge-enabled and self-attention boosted deep learning model, TranSynergy, to improve the performance and interpretability of synergistic drug combinations prediction. TranSynergy is well designed such that cellular effect of drug actions can be explicitly modeled through cell-line gene dependency, gene-gene interaction, and genome-wide drug-target interaction. A novel Shapley Additive Gene Set Enrichment Analysis (SA-GSEA) method is developed to deconvolute biological pathways that contribute to the synergistic drug combination and improve model interpretability. Extensive benchmark studies demonstrate that TranSynergy significantly outperforms the state-of-the-art method, suggesting the potential of mechanism-driven machine learning. Novel pathways that are associated with the synergistic combinations are revealed and supported by experimental evidence. They may provide new insights into identifying biomarkers for precision medicine and discovering new anti-cancer therapies. Several new synergistic drug combinations are predicted with high confidence for ovarian cancer which has few treatment options.

Availability

The code is available athttps://github.com/qiaoliuhub/drug_combination

Contact

lxie@iscb.org
Learning the language of viral evolution and escape
Authors: Hie Brian , Zhong Ellen , Berger Bonnie , Bryson Bryan
Published: July 2020

Viral mutation that escapes from human immunity remains a major obstacle to antiviral and vaccine development. While anticipating escape could aid rational therapeutic design, the complex rules governing viral escape are challenging to model. Here, we demonstrate an unprecedented ability to predict viral escape by using machine learning algorithms originally developed to model the complexity of human natural language. Our key conceptual advance is that predicting escape requires identifying mutations that preserve viral fitness, or “grammaticality,” and also induce high antigenic change, or “semantic change.” We develop viral language models for influenza hemagglutinin, HIV Env, and SARS-CoV-2 Spike that we use to construct antigenically meaningful semantic landscapes, perform completely unsupervised prediction of escape mutants, and learn structural escape patterns from sequence alone. More profoundly, we lay a promising conceptual bridge between natural language and viral evolution.

One sentence summary

Neural language models of semantic change and grammaticality enable unprecedented prediction of viral escape mutations.
Genetic, textual, and archaeological evidence of the historical global spread of cowpea (Vigna unguiculata[L.] Walp)
Authors: Herniter Ira A. , Muñoz-Amatriaín María , Close Timothy J.
Published: July 2020

Cowpea (Vigna unguiculata[L.] Walp.) was originally domesticated in sub-Saharan Africa but is now cultivated on every continent except Antarctica. Utilizing archaeological, textual, and genetic resources, the spread of cultivated cowpea has been reconstructed. Cowpea was domesticated in Africa, likely in both West and East Africa, before 2500 BCE and by 400 BCE was long established in all the modern major production regions of the Old World, including sub-Saharan Africa, the Mediterranean Basin, India, and Southeast Asia. Further spread occurred as part of the Columbian Exchange, which brought African germplasm to the Caribbean, the southeastern United States, and South America, and Mediterranean germplasm to Cuba, the southwestern United States and Northwest Mexico.