bluuebunny/crossref_metadata_2025 huggingface dataset:
Distance Control and Virtual Drilling Improves Anatomical Orientation During Anterior Petrosectomy
Authors: Voormolen Eduard H , Diederen Sander , Cebula Helene , Woerdeman Peter A , Noordmans Herke Jan , Viergever Max A , Robe Pierre A , Froelich Sebastien , Regli Luca , Berkelbach van der Sprenkel Jan Willem
Published: April 2019

BACKGROUND

A combined drill distance control and virtual drilling image guidance feedback method was developed.

OBJECTIVE

To investigate whether first-time usage of the proposed method, during anterior petrosectomy (AP), improves surgical orientation and surgical performance. The accuracy of virtual drilling and the clinical practicability of the method were also investigated.

METHODS

In a simulated surgical setting using human cadavers, a trial was conducted with 5 expert skull base surgeons from 3 different hospitals. They performed 10 AP approaches, using either the feedback method or standard image guidance. Damage to critical structures was assessed. Operating time, drill cavity sizes, and proximity of postoperative drill cavities to the cochlea and the acoustic meatus, were measured. Questionnaires were obtained postoperatively. Errors in the virtual drill cavities as compared with actual postoperative cavities were calculated. In a clinical setup, the method was used during AP.

RESULTS

Surgeons rated their intraoperative orientation significantly better with the feedback method compared with standard image guidance. During the cadaver trial, the cochlea was harmed on 1 occasion in the control group, while surgeons drilled closer to the cochlea and meatus without injuring them in the group using feedback. Virtual drilling under- and overestimation errors were 2.2 ± 0.2 and −3.0 ± 0.6 mm on average. The method functioned properly during the clinical setup.

CONCLUSION

The proposed feedback method improves orientation and surgical performance in an experimental setting. Errors in virtual drilling reflect spatial errors of the image guidance system. The feedback method is clinically practicable during AP.
The Perceptual Present
Authors: Connor Abigail , Smith Joel
Published: April 2019

Phenomenologically speaking, we perceive the present, recall the past, and anticipate the future. We offer an account of the temporal content of the perceptual present that distinguishes it from the recalled past and the anticipated future. We distinguish two views: the Token-Reflexive Account and the Minimal Account. We offer reasons to reject the Token-Reflexive Account, and defend the Minimal Account, according to which the temporal content of the perceptual present is exhausted by its direct reference to the interval of time over which it occurs.
Aiming for impact: Differential effect of motivational drivers on effort and performance in knowledge valorisation
Authors: van de Burgwal Linda H M , Hendrikse Rana , Claassen Eric
Published: April 2019

Societal engagement of scientists critically depends on their intrinsic motivation. Nevertheless, it remains unclear how motivational drivers influence effort and performance in engaging with four distinct stakeholder domains: academic, civil society, state-governmental, and economic. This article tests motivational drivers in a survey among 706 Dutch Life Scientists to study direct and indirect effects on effort and performance and finds that drivers differentially influence effort and performance in the four domains. Analysis supported the identification of a fourth category of drivers: ‘moral’—next to the well-recognised gold, ribbon, and puzzle drivers—and demonstrated their importance for performance in the civil society and state-governmental domains, two domains that have been underserved in previous studies. Pecuniary drivers influenced engagement with academic, as well as economic domains. In line with these findings, spreading responsibilities for engagement with different domains in line with the interests and motivations of individual scientists is recommended.
Subtle Dynamic Flatfoot Deformity: Is It More Than Stage I PTTD?
Authors: Jong Benjamin Y.W. , Femino John E. , Wilken Jason M.
Published: April 2019

Adult acquired flat foot has long been considered synonymous with posterior tibial tendon dysfunction (PTTD), first described by Johnson and Strom in 1989. This is based on the authors’ clinical experience and a small case series described in 1994. However, there is little evidence that PTTD invariably leads to flat foot deformity. We propose a rethinking of stage I PTTD as subtle dynamic flatfoot, wherein adult acquired flat foot is driven largely by gastrocsoleus tightness and progressive hypermobility of the first ray. Clinical assessment should consist of careful evaluation of first ray stability as well as the spring ligament, tibiotalar range of motion, and impingement over the sinus tarsi. We present our preferred treatment strategy. Nonoperatively, patients are managed with a stretching program focused on the hamstrings and gastrocsoleus as well as the use of orthotics and night splint. Operative treatment consists of treatment of any areas of impingement and correcting the biomechanics of the foot and ankle with a Strayer, Cotton Osteotomy, and lateral column lengthening. Resection of the accessory facet of the talus is optional depending on preoperative symptoms.
Perspectives of Patients With Mental Illness on How to Better Teach and Evaluate Diversity Education in the National Health Service
Authors: George Riya Elizabeth , Smith Karl , O'Reilly Michelle , Dogra Nisha
Published: April 2019

Introduction:

Diversity education is a mandatory requirement for all mental-health practitioners and health care professionals in the UK National Health Service. Wide variability exists in the development, delivery, and evaluation of diversity education across health care settings, with limited evidence to suggest the optimal approach for teaching this subject. This study aimed to explore the perspectives of patients with mental illness on how to better teach and evaluate diversity education in the National Health Service.

Methods:

A participatory research approach was used with five mental-health patient organizations. Forty-two patients with mental illness took part in three participatory workshops. Data were analyzed through template analysis.

Results:

The findings indicated that a focus on the nuances and dynamics of clinical relationships would be beneficial. Specifically, the relationship considered most important to examine with respect to diversity education was the “practitioner–self” relationship.

Discussion:

Reconstructing the relationship-centered care model with the addition of the practitioner–self relationship may be better suited to theoretically informing future developments in diversity education. Further research is needed to understand what educational approaches contribute toward a relationship-centered care outlook and how relationship building behaviors, particularly those relevant to the practitioner–self relationship are best developed in diverse settings.
Acral Lentiginous Melanomas Harbour Intratumor Heterogeneity in BRAF Exon 15, With Mutations Distinct From V600E/V600K
Authors: Fernandes Mariana , Barcelos Denise , Comodo Andréia Neves , Guimarães Daiane Pereira , Lopes Carapeto Fernando Cintra , Cardili Leonardo , de Sousa Morães Lais , Cerutti, AP Janete , Landman, AP Gilles
Published: April 2019

The choice of appropriate therapeutic strategies may be influenced by intratumor heterogeneity and makes cancer treatment considerably more challenging. We aimed to evaluate the heterogeneity of BRAF exon 15 mutations in different areas of acral lentiginous melanoma (ALM). The entire exon 15 was sequenced in 4 different areas of paraffin-embedded samples from 26 patients with ALM. A total of 26 of 49 cases of ≥1 mm in depth of ALM identified by clinical, anatomical, and pathological data fulfilled the inclusion and exclusion criteria for this study. Tumors had a mean Breslow depth of 7.2 mm and an average mitotic index of 3 mitosis/mm2. Mutations distinct from the common V600E and V600K were detected in 31%, and intratumor heterogeneity was observed in 31% of samples. Interestingly, 63.5% of all mutations had been previously associated with cancer. Most (62.5%) of the missense BRAF exon 15 mutations found in the ALM samples examined here were deemed “detrimental” for protein function according to at least 2 functional prediction programs, and 3 mutations (37.5%) were predicted to be “neutral,” with no effect on protein function. BRAF exon 15 mutations were detected frequently in ALM and displayed heterogeneity, a finding to be further investigated.
Performance Measures in Dermatologic Surgery: A Review of the Literature and Future Directions
Authors: Chow Conroy , Yuan Joyce T. , Ruiz Emily S. , Soon Seaver L. , Makhzoumi Zaineb , Arron Sarah T.
Published: April 2019

BACKGROUND

In recent years, health care reform initiatives have aimed to assess quality of care through the use of performance measures. Multiple specialties, including dermatology, have implemented registries to track and report health care quality.

OBJECTIVE

The authors review the history and rationale for assessing quality in dermatologic surgery. The authors also discuss the different types of performance measures and the current efforts to develop clinically relevant dermatologic surgery-specific measures.

MATERIALS AND METHODS

An extensive literature review was conducted using OVID, MEDLINE, PubMed, and government and health care-related websites to identify articles related to surgical performance measures.

RESULTS

Few performance measures are established to assess quality in dermatologic surgery. The authors propose specific candidate measures and discuss how clinical registries can capture measures that meet federal reporting requirements.

CONCLUSION

Assessment of health care quality will become increasingly important in health care reform. Physicians need to take an active role in selecting appropriate, clinically relevant performance measures that will help improve patient care while containing health care costs and meeting government-mandated reporting requirements.
Maternal Stress and Mental Health Prior to Their Technology-Dependent Infant's Discharge Home From the NICU
Authors: Toly Valerie Boebel , Blanchette Julia E. , Liu Wei , Sattar Abdus , Musil Carol M. , Bieda Amy , Em Sarah
Published: April 2019

Mothers of infants in the neonatal intensive care unit (NICU) face stressors including turbulent emotions from their pregnancy/unexpected preterm delivery and their infant's unpredictable health status. The study purpose was to examine the psychological state of mothers prior to the discharge of their technology-dependent infants (eg, feeding tubes, supplemental oxygen) from the NICU to home. The study sample consisted of mothers (N = 19) of infants dependent on medical technology being discharged from a large Midwest NICU. A descriptive, correlational design using convenience sampling was employed to recruit mothers to examine associations of infant and maternal factors, resourcefulness, and stress with psychological state (depressive symptoms, posttraumatic stress symptoms). Forty-two percent of mothers were at high risk for clinical depression, with 37% in the clinical range for posttraumatic stress disorder. Increased maternal depressive symptoms were significantly associated with the increased frequency and perceived difficulty of their stress and posttraumatic stress symptoms. Increased posttraumatic stress symptoms were significantly associated solely with elevated depressive symptoms. This study identified factors associated with the mothers' increased psychological distress, providing beginning evidence for future interventions to employ prior to their technology-dependent infant's NICU discharge.
Sclerosing angiomatoid nodular transformation in the spleen
Authors: Cao Peilong , Wang Kai , Wang Chunbao , Wang Hongyan
Published: April 2019

To assess the clinicopathologic features, differential diagnosis, and pathogenesis of sclerosing angiomatoid nodular transformation (SANT) of the spleen.

The clinical characteristics of 7 cases with SANT were retrospectively analyzed. Histochemical and immunohistochemical (EnVision method) examinations were performed. Moreover, quantitative assessment of IgG4 and IgG-positive cells was performed.

The 7 SANT patients included 1 female and 6 males, with ages ranging from 7 to 60 years (mean 33.4 years). They showed no specific clinical manifestations. Macroscopically, the surface of the excised masses was gray-white, and vague nodularity was observed. Mass sizes ranged from 3.0 to 7.0 cm (mean 5.5 cm). Microscopically, all cases were characterized based on multiple angiomatoid nodules of various sizes embedded in a fibrosclerotic stroma. The nodules were round and sometimes convoluted. Moreover, the nodules were composed of slit-like, irregularly-shaped, or slightly dilated vascular spaces lined by plump endothelial cells, and interspersed with a population of spindly or ovoid cells. Immunohistochemical examination showed a heterogeneous staining pattern, with the lining cells of small capillaries expressing CD34 and those of sinusoid-like structures expressing CD8. CD31 was stained in the lining and interspersed cells, thus resulting in a complex meshwork. Additionally, the lining cells were focally positive for CD68. Vimentin and smooth muscle antibody were expressed in all 7 cases, whereas no desmin or CD21 was detected. IgG4-positive cells accounted for 2 to 5 per high-power field (mean 3.7). Furthermore, the IgG-positive cells accounted for 2 to 8 per high-power field (mean 4.2).

SANT is a rare primary benign tumor-like lesion of the spleen, and has characteristic histopathological features and immunohistochemical profiles. SANT should be distinguished from other angiomatoid tumors and tumor-like lesions. Moreover, SANT could be treated by splenectomy, with favorable prognosis. The relationship between SANT and IgG4-related sclerosing lesions remains to be clarified.
Procalcitonin, C-reactive protein, PaCO2, and noninvasive mechanical ventilation failure in chronic obstructive pulmonary disease exacerbation
Authors: Wang Jinrong , Shang Huimian , Yang Xiaoya , Guo Shufen , Cui Zhaobo
Published: April 2019

It is unclear whether procalcitonin (PCT) is correlated with noninvasive ventilation (NIV) failure. This retrospective case–control study aimed to compare PCT levels, C-reactive protein (CRP) levels, and PaCO2 in patients (05/2014–03/2015 at the Harrison International Peace Hospital, China) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and NIV failure/success.

This was a retrospective case–control study of patients with AECOPD who required NIV between May 2014 and March 2015. All consecutive patients with AECOPD admitted at the Department of Critical Care Medicine and transferred from the general ward were included in the study. Hemogram, PCT, erythrocyte sedimentation rate (ESR), arterial blood gas (ABG), and CRP levels were measured ≤1 hour before NIV was used. NIV was considered to have failed if at least one of the following criteria was met: cardiac arrest or severe hemodynamic instability; respiratory arrest or gasping; mask intolerance; difficulty in clearing bronchial secretions; or worsening of ABGs or sensorium level during NIV. The factors associated with NIV failure were determined.

A total of 376 patients were included: 286 with successful NIV and 90 wither NIV failure. The multivariate analysis showed that PCT (OR = 2.0, 95%CI: 1.2–3.2, P = .006), CRP (OR = 1.2, 95%CI: 1.1–1.3, P < .001), and PaCO2 (OR = 1.1, 95%CI: 1.1–1.2, P < .001) ≤1 hour before NIV were independently associated with NIV failure. The optimal cutoff were 0.31 ng/mL for PCT (sensitivity, 83.3%; specificity, 83.7%), 15.0 mg/mL for CRP (sensitivity, 75.6%; specificity, 93.0%), and 73.5 mm Hg for PaCO2 (sensitivity, 71.1%; specificity, 100%). The area under the curve (AUC) was 0.854 for PCT, 0.849 for CRP, and 0.828 for PaCO2. PCT, CRP, and PaCO2 were used to obtain a combined prediction factor, which achieved an AUC of 0.978 (95%CI: 0.961–0.995).

High serum PCT, CRP, and PaCO2 levels predict NIV failure for patients with AECOPD. The combination of these three parameters might enable even more accurate prediction.
Endovascular treatment of multiple tuberculous mycotic aneurysm
Authors: Zhao Shenyu , Wang Zhe , Li Yong , Wang Hong , Zhao Yu
Published: April 2019

Rationale:

We present a rare case of multiple tuberculous mycotic aneurysm. Multiple aneurysms caused by tuberculosis (TB) are difficult to treat. Here, we discuss a treatment modality using a microcore stent graft.

Patient concerns:

A 73-year-old man with pain in the back and on the right side of the chest associated with dry cough, presented with an inability to walk since 1-month.

Diagnoses:

A diagnosis of multiple aneurysms caused by TB was made, based on computed tomography (CT) scan and positive T-spot and Xpert tests.

Interventions:

We administered the empirical anti-TB regimen (pyrazinamide, isoniazid, rifampicin, and ethambutol) and performed endovascular repair using microcore stent graft.

Outcomes:

The post-operative hemodynamic analysis indicated that the patient's aneurysms no longer had a risk of rupture, and blood flow in the major branches of the aorta had been maintained. However, the patient could not survive due to a pulmonary infection acquired during recuperation at a local hospital.

Lessons:

For multiple tuberculous mycotic aneurysms, anti-TB therapy is inadequate and the microcore stent graft is a feasible option that can improve the hemodynamics in the aneurysms.
Femoral artery pseudoaneurysm after carotid artery stenting
Authors: Jeon Seung-Ho , Kang Hyun Goo , Kim Hong-Jin , Seo Man-Wook , Shin Byoung-Soo
Published: April 2019

Rationale:

Pseudoaneurysm, the most common complication of femoral artery catheterization, involves the formation of a space between the lumen and the surrounding fibrous tissue through the damaged arterial wall. In patients treated with antiplatelet and anticoagulant agents, the incidence of vascular complications increases with the increasing use of minimally invasive procedures.

Patient concerns:

We experienced 2 cases of procedure-induced pseudoaneurysms. A 79-year-old man with right hemiparesis visited our hospital. Brain magnetic resonance imaging showed acute left middle cerebral artery territory infarction and severe stenosis of the left proximal carotid artery. The patient was prescribed apixaban and underwent carotid stenting through the right femoral artery. Hematoma and tenderness were observed in the right inguinal region after the procedure. The hemoglobin level decreased from 16.9 g/dL to 9.4 g/dL. Another 78-year-old man with left common carotid artery stenosis was admitted. We performed stent implantation through the right femoral artery and administered aspirin and clopidogrel. After the procedure, hematoma and tenderness of the puncture site were observed. The hemoglobin level decreased from 14.5 g/dL to 10.9 g/dL.

Diagnosis:

Emergency computed tomography confirmed a pseudoaneurysm with a massive hematoma in the right inguinal area. The patients were diagnosed with infection-associated right pseudoaneurysm for which an emergency puncture site repair was performed.

Interventions:

We performed resection of pseudoaneurysm and repaired puncture site.

Outcomes:

The hemoglobin level was stabilized postoperatively and vital sign remained stable.

Lessons:

Pseudoaneurysm is an important complication of femoral artery puncture. The use of a hemostatic device was not superior to manual compression, and the incidence of this complication was significantly higher in patients who received anticoagulant or antiplatelet agents. A pseudoaneurysm may cause a bad prognosis. Therefore, the early detection of pseudoaneurysm and immediate treatment after femoral arterial puncture are needed.
Gastrointestinal stromal tumor presenting as a rectovaginal septal mass
Authors: Cheng Min , Liu Chia-Hao , Horng Huann-Cheng , Chen Yi-Jen , Lo Pei-Fen , Lee Wen-Ling , Wang Peng-Hui
Published: April 2019

Introduction:

Gastrointestinal stromal tumors (GISTs) arising from the gynecological tract are extremely rare. A case of GIST with an unusual presentation as a vaginal mass is presented with comprehensive literature review, aiming to gain a better understanding of the diagnostic and treatment strategy of the disease.

Patient concerns:

A 78-year-old woman presented with persistent vaginal bleeding and difficulty in micturition. Although the tumor mass was diagnosed, the results of preoperative evaluations are uncertain.

Diagnosis:

Preoperative evaluation included the computed tomography examination (a 6.3×5.3 cm cervical mass lesion with rectal and vaginal invasion), colonoscopy (an external compression with an intact mucosa), tumor markers, and biopsy (spindle cell tumor). Postoperative histopathology confirmed the diagnosis of GIST.

Interventions:

Posterior exenteration with complete resection was performed. The patient received postoperative adjuvant imatinib therapy.

Outcomes:

The patient has survived without the disease for more than 3 years.

Conclusion:

It is still a challenge to diagnose GISTs in women with rectovaginal mass preoperatively. Efforts should be made, including a high suspicion and an assistance of immunohistochemistry. A precise diagnosis may offer a better surgical and treatment plan, especially on the preservation of reproductive organs and accessibility of targeted therapy.
Invasive management of symptomatic hepatic hemangioma
Authors: Dong Wenfang , Qiu Bin , Xu Haifeng , He Leren
Published: April 2019

Hepatic hemangioma is common among benign liver tumors and usually grows slowly. About 50–70% of hepatic hemangiomas are asymptomatic, and management is not necessary; however, management should be considered in symptomatic patients. The optimal management of symptomatic hepatic hemangioma depends on multiple factors. Invasive management of symptomatic hepatic hemangioma mainly consists of surgery and interventional radiology, including transarterial embolization, ablation, percutaneous sclerotherapy, and percutaneous argon–helium cryotherapy. Although both surgery and interventional radiology are promising in the management of symptomatic hepatic hemangioma, multiple and/or giant hemangiomas represent a clinical dilemma because the complication rate and recurrence rate are relatively high, and symptom relief is not always achieved. However, a review of recent advances in treatment is lacking. We therefore summarized the current invasive management techniques for symptomatic hepatic hemangioma to potentially facilitate clinical decision-making.
Thirty-Day Hospital Readmissions for Granulomatosis With Polyangiitis in the United States
Authors: Luo Yiming , Jiang Changchuan , Arevalo Molina Ana Belen , Murray Shane , Anez Gustavo Contreras , Salgado Maria , Xu Jiehui
Published: April 2019

Background/Objective

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that often results in frequent hospitalizations. We investigated the characteristics and predictors of 30-day hospital readmissions in GPA.

Methods

We performed a cross-sectional analysis using the 2014 National Readmission Database. We included nonelective admissions with a primary or secondary diagnosis of GPA. We compared characteristics between readmissions and nonreadmissions. Independent predictors for readmissions were studied using mixed-effects multivariable logistic regression.

Results

We evaluated a total of 9749 hospital admissions with GPA, among which there were 2173 readmissions (22.3%) within 30 days of discharge. The top 5 primary reasons for readmissions were GPA, sepsis, pneumonia, acute respiratory failure, and acute kidney injury. Granulomatosis with polyangiitis readmissions were associated with higher length of stay (8.0 vs 7.2 days; p = 0.019) and less discharge home (50% vs 63%, p < 0.001). Independent predictors for readmissions were younger age (odds ratio [OR], 0.99; p = 0.013), no private insurance (OR, 0.50; p < 0.001), higher Charlson Comorbidity Index (OR, 1.12; p = 0.039), congestive heart failure (OR, 1.71; p = 0.001), acute kidney injury (OR, 1.39; p = 0.005), and discharge to home health care (OR, 1.29; p = 0.039).

Conclusions

We found a significant burden of 30-day readmissions among GPA populations. Clinicians should be vigilant regarding patients with high risk of readmissions, including those with younger age, public insurance, higher comorbidity burden, cardiac and renal complications, and unfavorable discharge dispositions.
Aesthetic and Functional Rehabilitation of Postburn Maxillofacial Deformity
Authors: Mohanty Sujata , Bodh Ranjeet , Dabas Jitender , Kumari Saroj , Kohli Sanchaita
Published: April 2019

Postburn maxillofacial deformities, although rare, are a significant cause of morbidity. Since contracture scars have a potential role in deforming the maxillofacial skeleton, the focus of treatment should be on growing patients, where scar contractures can drastically influence growth and morphology of the maxillofacial units. There are certain aspects of severe facial burns and deformities, especially of the jaws, that deserve sincere attention to overcome aesthetic and functional disabilities such as inability to masticate and incompetent lips. The purpose of this article, therefore, is to discuss these injuries, the mechanism of development of deformities of the jaws and associated structures and their management for better aesthetic, functional, and psychological health of patient. An interpretive clinical report is presented.
Palliative Interventional Embolization for Finding of Ectopic Noradrenaline-Secreting Pheochromocytoma in the Nasal Cavity
Authors: Chen Binghong , Wu Hui , Cheng Lilin , Hu Yaomin , Liao Yu , Qiu Yongming , Dai Jiong
Published: April 2019

A 52-year-old male who had chronic hypertension for several years presented with abrupt epistaxis. The CT scan revealed a 40 mm × 40 mm mass in the nasal cavity intended to the maxillary sinus and the base of skull. Nasal endoscope biopsy and serum/urinary catecholamine detection conformed an ectopic noradrenaline-secreting pheochromocytoma. The present research was to discuss the clinical characteristics of the rare pheochromocytoma and the palliative interventional embolization for it.
Case Studies Comparing Learning Profiles and Response to Instruction in Autism Spectrum Disorder and Oral and Written Language Learning Disability at Transition to High School
Authors: Zajic Matthew C. , Dunn Michael , Berninger Virginia W.
Published: April 2019

This study investigated literacy learning in students with specific kinds of language challenges at a specific stage of schooling—transition to high school—when the language requirements of the curriculum can be especially challenging. For this exploratory research, a case study approach was adopted that compared 2 adolescent boys both with language learning problems but with 2 contrasting disabilities—autism spectrum disorder (ASD) versus oral and written language learning disability (OWL LD)—just before entry to ninth grade. Three research aims compared participants on (a) learning profiles assessed via a comprehensive psychoeducational assessment battery, (b) change in their learning profiles based on response to instruction to a computerized intervention, and (c) change in their personal narrative compositions and use of taught translation strategies collected during 6 lessons of the computerized intervention. Results indicated that participants demonstrated variable psychoeducational profiles and response to instruction that highlighted similar yet distinct patterns of strengths and weaknesses. Personal narrative writing samples showed that participants demonstrated distinct challenges, but only the participant with ASD showed no response to instruction and produced predominantly off-topic text. Results are discussed in reference to educational applications and future research design implications to understand the writing challenges experienced by children with ASD in reference to children with OWL LD or other specific learning disabilities.
Altering the size distribution of influenza virion populations
Authors: Burke Amy , Hirst Jack , Hutchinson Edward
Published: April 2019

Harry Smith Vacation Studentship Laboratory-adapted influenza viruses produce predominantly spherical virions. In contrast, clinical and veterinary isolates produce a mixture of virions of different sizes, from 0.1 µm spheres to filaments which can reach tens of microns in length. Filamentous influenza virions were discovered in 1946, but the bulk of influenza research has analysed only spherical forms of the virus and the role of filaments in influenza infections is unclear. Functional studies of filaments require the development of methods to manipulate the ratio of spherical to filamentous virions, and we reasoned that this could be achieved by filtration. To test this, we infected MDCK cells with the filamentous Udorn strain of influenza A virus. We collected virus-containing growth media and passed this through filters with 5 µm, 0.45 µm and 0.2 µm pores. Filtrates and unfiltered virus were compared, using Western blotting to measure their protein composition, plaque assays to measure their infectivity and negative stain transmission electron microscopy to measure individual particle sizes. We found that filtration through a filter with 5 µm pores had little effect on composition, infectivity and the ratio of spherical to filamentous particles. In contrast, sub-micron filters, particularly those with 0.2 µm pores, caused a general depletion of virions but increased the sphere to filament ratio. We therefore concluded that sub-micron pore sizes can be used to preferentially remove filaments from populations of pleomorphic influenza virions, providing a useful tool for subtractive studies of the contribution filaments make to influenza virus infections.
Severe Biallelic Loss-of-function Mutations inNicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2)in Two Fetuses with Fetal Akinesia Deformation Sequence
Authors: Lukacs Marshall , Gilley Jonathan , Zhu Yi , Orsomando Giuseppe , Angeletti Carlo , Liu Jiaqi , Yang Xiuna , Park Joun , Hopkin Robert J. , Coleman Michael P. , Zhai R. Grace , Stottmann Rolf W.
Published: April 2019

The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD+) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins.Nmnat2deficiency in mice, or in its orthologdNmnatinDrosophila, results in axon outgrowth and survival defects. Peripheral nerve axons in NMNAT2-deficient mice fail to extend and innervate targets, and skeletal muscle is severely underdeveloped. In addition, removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal akinesia deformation sequence (FADS), severely reduced skeletal muscle mass and hydrops fetalis. Clinical exome sequencing identified compound heterozygousNMNAT2variant alleles in both cases. Both protein variants are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed.In vitroassays demonstrate altered protein stability and/or defects in NAD+synthesis and chaperone functions. Thus, both patientNMNAT2alleles are null or severely hypo-morphic. These data indicate a previously unknown role forNMNAT2in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder.
A self-administered, artificial intelligence (AI) platform for cognitive assessment in multiple sclerosis (MS)
Authors: Khaligh-Razavi Seyed-Mahdi , Sadeghi Maryam , Khanbagi Mahdiyeh , Kalafatis Chris , Nabavi Seyed Massood
Published: April 2019

Background

Cognitive impairment is common in patients with MS. Accurate and repeatable measures of cognition have the potential to be used as a marker of disease activity. We developed a 5-minute computerized test to measure cognitive dysfunction in patients with MS. The proposed test –named Integrated Cognitive Assessment (ICA)– is self-administered and language-independent.

Objective

To determine ICA’s validity as a digital biomarker for assessing cognitive performance in MS.

Methods

91 MS patients and 83 healthy controls (HC) took part in substudy 1, in which each participant took the ICA test and the Brief International Cognitive Assessment for MS (BICAMS). We assessed ICA’s test-retest reliability, its correlation with BICAMS, its sensitivity to discriminate patients with MS from the HC group, and its accuracy in detecting cognitive dysfunction. In substudy 2, we recruited 48 MS patients, and examined the association between the level of serum neurofilament light (NfL) in these patients and their ICA scores.

Results

ICA demonstrated excellent test-retest reliability (r=0.94), with no learning bias (i.e. no significant practice effect); and had high level of convergent validity with BICAMS. ICA was sensitive in discriminating the MS patients from the HC group, and demonstrated a high accuracy (AUC = 95%) in discriminating cognitively normal from cognitively impaired participants. Additionally, we found a strong association (r=-0.79) between ICA score and the level of NfL in MS patients.

Conclusions

ICA can be used as a digital biomarker for assessment and monitoring of cognitive performance in MS patients. In comparison to standard cognitive tools for MS (e.g. BICAMS), ICA is shorter in duration, does not show a learning bias, is independent of language, and takes advantage of artificial intelligence (AI) to identify cognitive status of patients more accurately. Being a digital test, it further has the potential for easier electronic health record or research database integration.
3,3′-Diindolylmethane Dose-Dependently Prevents Advanced Prostate Cancer
Authors: Li Yufei , Mahloch Nathaniel W. , Starkey Nicholas J.E. , Peña-Luna Mónica , Rottinghaus George E. , Fritsche Kevin L. , Besch-Williford Cynthia , Lubahn Dennis B.
Published: April 2019

3,3′-Diindolylmethane (DIM) is an acid-derived dimer of indole-3-carbinol, found in many cruciferous vegetables, such as broccoli, and has been shown to inhibit prostate cancer (PCa) in several in vitro and in vivo models. We demonstrated that DIM stimulated both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) transcriptional activities and propose that ERβ plays a role in mediating DIM’s inhibition on cancer cell growth. To further study the effects of DIM on inhibiting advanced PCa development, we tested DIM in TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. The control group of mice were fed a high fat diet. Three additional groups of mice were fed the same high fat diet supplemented with 0.04%, 0.2% and 1% DIM. Incidence of advanced PCa, poorly differentiated carcinoma (PDC), in the control group was 60%. 1% DIM dramatically reduced PDC incidence to 24% (p=0.0012), while 0.2% and 0.04% DIM reduced PDC incidence to 38% (p=0.047) and 45% (p=0.14) respectively. Though DIM did affect mice weights, statistical analysis showed a clear negative association between DIM concentration and PDC incidence with p=0.004, while the association between body weight and PDC incidence was not significant (p=0.953). In conclusion, our results show that dietary DIM can inhibit the most aggressive stage of prostate cancer at concentration lower than previously demonstrated, possibly working through an estrogen receptor mediated mechanism.
Machine learning predicts rapid relapse of triple negative breast cancer
Authors: Zhang Yiqing , Nock William , Wyse Meghan , Weber Zachary , Adams Elizabeth , Asad Sarah , Stockard Sinclair , Tallman David , Winer Eric P. , Lin Nancy U. , Cherian Mathew , Lustberg Maryam B. , Ramaswamy Bhuvaneswari , Sardesai Sagar , VanDeusen Jeffrey , Williams Nicole , Wesolowski Robert , Stover Daniel G.
Published: April 2019

Purpose

Metastatic relapse of triple-negative breast cancer (TNBC) within 2 years of diagnosis is associated with particularly aggressive disease and a distinct clinical course relative to TNBCs that relapse beyond 2 years. We hypothesized that rapid relapse TNBCs (rrTNBC; metastatic relapse or death <2 years) reflect unique genomic features relative to late relapse (lrTNBC; >2 years).

Patients and Methods

We identified 453 primary TNBCs from three publicly-available datasets and characterized each as rrTNBc, lrTNBC, or ‘no relapse’ (nrTNBC: no relapse/death with at least 5 years follow-up). We compiled primary tumor clinical and multi-omic data, including transcriptome (n=453), copy number alterations (CNAs; n=317), and mutations in 171 cancer-related genes (n=317), then calculated published gene expression and immune signatures.

Results

Patients with rrTNBC were higher stage at diagnosis (Chi-square p<0.0001) while lrTNBC were more likely to be non-basal PAM50 subtype (Chi-square p=0.03). Among 125 expression signatures, five immune signatures were significantly higher in nrTNBCs while lrTNBC were enriched for eight estrogen/luminal signatures (all FDR p<0.05). There was no significant difference in tumor mutation burden or percent genome altered across the groups. Among mutations, onlyTP53mutations were significantly more frequent in rrTNBC compared to lrTNBC (Fisher exact FDR p=0.009). To develop an optimal classifier, we used 77 significant clinical and ‘omic features to evaluate six modeling approaches encompassing simple, machine learning, and artificial neural network (ANN). Support vector machine outperformed other models with average receiver-operator characteristic area under curve >0.75.

Conclusions

We provide a new approach to define TNBCs based on timing of relapse. We identify distinct clinical and genomic features that can be incorporated into machine learning models to predict rapid relapse of TNBC.
Decoding Complex Sounds Using Broadband Population Recordings from Secondary Auditory Cortex of Macaques
Authors: Heelan Christopher , Lee Jihun , O’Shea Ronan , Brandman David M. , Truccolo Wilson , Nurmikko Arto V.
Published: April 2019

Direct electronic communication with sensory areas of the neocortex is a challenging ambition for brain-computer interfaces. Here, we report the first successful neural decoding of English words with high intelligibility from intracortical spike-based neural population activity recorded from the secondary auditory cortex of macaques. We acquired 96-channel full-broadband population recordings using intracortical microelectrode arrays in the rostral and caudal parabelt regions of the superior temporal gyrus (STG). We leveraged a new neural processing toolkit to investigate the choice of decoding algorithm, neural preprocessing, audio representation, channel count, and array location on neural decoding performance. The results illuminated a view of the auditory cortex as a spatially distributed network and a general purpose processor of complex sounds. The presented spike-based machine learning neural decoding approach may further be useful in informing future encoding strategies to deliver direct auditory percepts to the brain as specific patterns of microstimulation.
Walking kinematics in the polymorphic seed harvester antMessor barbarus:influence of body size and load carriage
Authors: Merienne Hugo , Latil Gérard , Moretto Pierre , Fourcassié Vincent
Published: April 2019

Ants are famous in the animal kingdom for their amazing load carriage performances. Yet, the mechanisms that allow these insects to maintain their stability when carrying heavy loads have been poorly investigated. Here we present a study of the kinematics of loaded locomotion in the polymorphic seed-harvesting antMessor barbarus. In this species big ants have larger heads relative to their size than small ants. Hence, their center of mass is shifted forward, and the more so when they are carrying a load in their mandibles. We tested the hypothesis that this could lead to big ants being less statically stable than small ants, thus explaining their lower load carriage performances. When walking unloaded we found that big ants were indeed less statically stable than small ants but that they were nonetheless able to adjust their stepping pattern to partly compensate for this instability. When ants were walking loaded on the other hand, there was no evidence of different locomotor behaviors in individuals of different sizes. Loaded ants, whatever their size, move too slowly to maintain their balance through dynamic stability. Rather, they seem to do so by clinging to the ground with their hind legs during part of a stride. We show through a straightforward model that allometric relationships have a minor role in explaining the differences in load carriage performances between big ants and small ants and that a simple scale effect is sufficient to explain these differences.
Modulating Fis and IHF binding specificity, crosstalk and regulatory logic through the engineering of complex promoters
Authors: Monteiro Lummy Maria Oliveira , Sanches-Medeiros Ananda , Westmann Cauã Antunes , Silva-Rocha Rafael
Published: April 2019

Bacterial promoters are usually formed by multiplecis-regulatory elements recognized by a plethora of transcriptional factors (TFs). From those, global regulators are key elements since these TFs are responsible for the regulation of hundreds of genes in the bacterial genome. For instance, Fis and IHF are two global regulators which play a major role in gene expression control inEscherichia coliand usually multiplecis-regulatory elements for these proteins co-occur at target promoters. Here, we investigated the relationship between the architecture of thecis-regulatory elements for Fis and IHF inE. coli. For this, we constructed 42 synthetic promoter variants harboring consensuscis-elements for Fis and IHF at different distances from a core −35/−10 region and in different numbers and combinations. We first demonstrated that although Fis preferentially recognizes its consensuscis-element, it can also recognize, to some extent, the consensus binding site for IHF, and the same was true for IHF, which was also able of recognizing Fis binding sites. However, changing the arrangement of thecis-elements (i.e., the position or the number of sites) can completely abolish unspecific binding of both TFs. More remarkably, we demonstrate that combiningcis-elements for both TFs could result in Fis and IHF repressed or activated promoters depending on the final architecture of the promoters in an unpredictable way. Taken together, the data presented here demonstrate how small changes in the architecture of bacterial promoters could result in drastic changes in the final regulatory logic of the system, with important implications for the understanding of natural complex promoters in bacteria and their engineering for novel applications.

Importance

The understanding of the regulatory complex in bacteria is a key issue in modern microbiology. Here, we constructed synthetic bacterial promoters in order to investigate how binding of transcriptional factors to multiple target sites at the promoters can influence gene expression. Our results demonstrate in a systematic way that the arrangement and number of thesecis-regulatory elements are crucial for the final expression dynamics of the target promoters. In particular, we show that TF binding specificity or promiscuity can be modulated using different promoter architectures based on consensuscis-regulatory elements, and that transcriptional repression and activation can also be affected by promoter architecture. These results are relevant both for the understanding of natural systems and for the construction of synthetic circuits for biotechnological applications.
Benchmarking algorithms for genomic prediction of complex traits
Authors: Azodi Christina B. , McCarren Andrew , Roantree Mark , de los Campos Gustavo , Shiu Shin-Han
Published: April 2019

The usefulness of Genomic Prediction (GP) in crop and livestock breeding programs has led to efforts to develop new and improved GP approaches including non-linear algorithm, such as artificial neural networks (ANN) (i.e. deep learning) and gradient tree boosting. However, the performance of these algorithms has not been compared in a systematic manner using a wide range of GP datasets and models. Using data of 18 traits across six plant species with different marker densities and training population sizes, we compared the performance of six linear and five non-linear algorithms, including ANNs. First, we found that hyperparameter selection was critical for all non-linear algorithms and that feature selection prior to model training was necessary for ANNs when the markers greatly outnumbered the number of training lines. Across all species and trait combinations, no one algorithm performed best, however predictions based on a combination of results from multiple GP algorithms (i.e. ensemble predictions) performed consistently well. While linear and non-linear algorithms performed best for a similar number of traits, the performance of non-linear algorithms vary more between traits than that of linear algorithms. Although ANNs did not perform best for any trait, we identified strategies (i.e. feature selection, seeded starting weights) that boosted their performance near the level of other algorithms. These results, together with the fact that even small improvements in GP performance could accumulate into large genetic gains over the course of a breeding program, highlights the importance of algorithm selection for the prediction of trait values.
CyMIRA: The Cytonuclear Molecular Interactions Reference forArabidopsis
Authors: Forsythe Evan S. , Sharbrough Joel , Havird Justin C. , Warren Jessica M. , Sloan Daniel B.
Published: April 2019

The function and evolution of eukaryotic cells depends upon direct molecular interactions between gene products encoded in nuclear and cytoplasmic genomes. Understanding how these cytonuclear interactions drive molecular evolution and generate genetic incompatibilities between isolated populations and species is of central importance to eukaryotic biology. Plants are an outstanding system to investigate such effects because of their two different genomic compartments present in the cytoplasm (mitochondria and plastids) and the extensive resources detailing subcellular targeting of nuclear-encoded proteins. However, the field lacks a consistent classification scheme for mitochondrial- and plastid-targeted proteins based on their molecular interactions with cytoplasmic genomes and gene products, which hinders efforts to standardize and compare results across studies. Here, we take advantage of detailed knowledge about the model angiospermArabidopsis thalianato provide a curated database of plant cytonuclear interactions at the molecular level. CyMIRA (CytonuclearMolecularInteractionsReference forArabidopsis) is available athttp://cymira.colostate.edu/andhttps://github.com/dbsloan/cymiraand will serve as a resource to aid researchers in partitioning evolutionary genomic data into functional gene classes based on organelle targeting and direct molecular interaction with cytoplasmic genomes and gene products. It includes 11 categories (and 27 subcategories) of different cytonuclear complexes and types of molecular interactions, and it reports residue-level information for cytonuclear contact sites. We hope that this framework will make it easier to standardize, interpret and compare studies testing the functional and evolutionary consequences of cytonuclear interactions.