bluuebunny/crossref_metadata_2025 huggingface dataset:
A rare case report of fungal esophagitis combined with giant gastric ulcer in an immunocompetent patient
Authors: Liang Ma , Liwen Zhang , Juan Dai , Yun Zhuang , Yanbo Ding , Jianping Chen
Published: January 2019

Rationale:

Fungal infection of gastrointestinal (GI) tract is usually seen in immunocompromised patients, but can rarely occur in immunocompetent people in whom no permissive factor is present.

Patient concerns:

We describe a 68-year-old male immunocompetent patient presenting with simultaneous fungal esophagitis and giant gastric ulcer.

Diagnoses:

Repeated endoscopic biopsies were taken from the giant gastric ulcer edge and base and histology demonstrated granulation tissue and pseudohyphal fungal forms.

Interventions:

The patient was treated with fluconazole and omeprazole for 8 weeks.

Outcomes:

After antifungal treatment with fluconazole, the patient's clinical symptoms gradually disappeared with the healing of gastric ulcer, which never recurred in this patient until 3 months after follow-up.

Lessons:

Nonhealing gastroesophageal ulcers highlights the importance of repeated endoscopies and biopsies.
Effect of orbital decompression on dysthyroid optic neuropathy
Authors: Liang Qiao-Wen , Yang Huasheng , Luo Wenjing , He Jian-Feng , Du Yi
Published: January 2019

In this study, we try to explore the effect of orbital decompression treatment on severe dysthyroid optic neuropathy.

We retrospectively collected demographic and clinical characteristics of thyroid eye disease patients who performed orbital decompression. Then we analyzed the change of best-corrected visual acuity and exophthalmometry after surgery and the correlations among clinical parameters.

A total of 22 cases (30 eyes) were included in the study. After orbital decompression, visual acuities improved in 16 eyes, declined in 8 eyes, and had no change in 5 eyes. Best-corrected visual acuity was significantly improved (0.1 vs 0.4, P = .039) and exophthalmometry was significantly declined (22.0 mm vs 16.5 mm, P = .001) after orbital decompression. Better postoperative best-corrected visual acuity was significantly correlated with better preoperative best-corrected visual acuity (r = 0.718, P < .05), and with normal optic disc (r = 0.568, P < .05), but not with age, exophthalmometry, keratopathy, and clinical activity score.

These results showed that orbital decompression is a useful approach to manage dysthyroid optic neuropathy. The optimal time for surgery should be chosen based on clinical parameters, such as visual acuity and degree of crowding of orbital apex.
Relapsing granulomatosis with polyangiitis provoked by trauma
Authors: Deng Shan , Xing Yida , Wang Hongjiang , Kong Xiaodan
Published: January 2019

Rationale:

The precise cause of granulomatosis with polyangiitis (GPA) remains unclear. Herein we present a case of refractory GPA occurring after trauma.

Patient concerns:

A 43-year-old man suffered fractures of the left orbital in an accident, and then received surgical repair. At a postoperative follow-up, he developed maxillary sinusitis. Seven months later, he was hospitalized with symptoms of cough, high-grade fever, and loss of weight.

Diagnosis:

He was diagnosed with GPA based on the symptoms of upper and lower respiratory tract involvement, granulomas in a lung biopsy specimen, and presence of PR3-ANCA.

Interventions:

Initially the patient responded well to the treatment of glucocorticoids and cyclophosphamide (CYC). Forty days later, he was hospitalized again with symptoms of fever, cephalgia, and recurrent ulcerated subcutaneous nodules, due to the vasculitic manifestations of GPA. This time he was treated with cyclophosphamide and glucocorticoids with no improvement, and then switched to rituximab.

Outcomes:

After 4 doses of rituximab, the symptom of cephalgia disappeared and subcutaneous ulcerations and conjunctival congestion diminished.

Lessons:

Trauma may act as an inflammatory stimulus to affect the course of disease in GPA. The combination of glucocorticoids and cyclophosphamide is the standard therapy for GPA. Nevertheless, patients who have no response to CYC, especially with predominantly vasculitic manifestations, could resort to rituximab.
Delayed malposition of a double-lumen hemodialysis catheter that caused hemorrhage and hypovolemic shock
Authors: Chen I-Chen , Yang Shih-Chia , Liu Kuan-Ting , Wu Yen-Hung
Published: January 2019

Rationale:

Double-lumen hemodialysis catheters are commonly used as temporary hemodialysis routes. Complications include infection, thrombosis, cardiac arrhythmia, entrapped guide wire, and malposition. We report a rare complication of delayed hemodialysis catheter malposition that caused retroperitoneal hemorrhage and hypovolemic shock during hemodialysis.

Patient concerns:

A 72-year-old female patient who was receiving hemodialysis was referred to our emergency department because of general discomfort and decreased blood pressure (BP) after her regular hemodialysis. She had undergone surgery for a left forearm arteriovenous pseudoaneurysm and received a temporary hemodialysis catheter insertion via the left femoral vein 2 weeks before. The initial blood examination revealed a mildly decreased baseline hemoglobin level (7.2 g/dL) and hyperkalemia (5.9 mmol/L). Her BP recovered after fluid resuscitation. She was administered hemodialysis again, following which her BP reduced and a change in consciousness developed.

Diagnosis:

Chest and abdominal computed tomographies were performed to exclude acute vascular problems and showed a hemodialysis catheter tip protruding from the left iliac vein and hematoma in the left retroperitoneal space and pelvic cavity.

Interventions:

Intubation, fluid resuscitation, vasopressor administration, and blood transfusion were performed. She was admitted to the intensive care unit. The left femoral hemodialysis catheter was removed.

Outcomes:

Follow-up computed tomography revealed resolution of the retroperitoneal space hematoma. She was transferred to the ordinary ward 18 days later with a stable hemodynamic status. Unfortunately, she developed hospital-acquired pneumonia and arteriovenous shunt infection, and died from respiratory failure and sepsis on the 34th day in our hospital.

Lessons:

Femoral double-lumen catheter malposition is rare and potentially fatal. Emergency physicians should be aware of situations wherein a patient's BP declines markedly soon after a hemodialysis initiation.
Ultrasound-guided placement of a midline catheter in a patient with extensive postburn contractures
Authors: Yokota Taisuke , Tokumine Joho , Lefor Alan Kawarai , Hasegawa Ayako , Yorozu Tomoko , Asao Takayuki
Published: January 2019

Rationale:

Obtaining venous access in a patient with extensive postburn scar contractures is a challenge.

Patient concerns:

A 39-year-old woman suffered a burn 2 years previously with a total body surface area burn of 93%, and a burn index of 85. Reconstructive surgery was previously performed 39 times. Split-thickness skin grafting to the neck was planned. She had no accessible peripheral veins.

Diagnosis:

Difficult venous access due to excessive burn scar contractures.

Interventions:

Central venous catheterization was considered impossible even with ultrasound guidance. We placed a midline catheter for intraoperative venous access in a patient with extensive burn scar contractures. The midline catheter is a peripheral venous catheter placed in an arm vein.

Outcomes:

We successfully placed a midline catheter in the right brachial vein. This catheter was used for 24 days without difficulty.

Lessons:

The midline catheter is a viable choice in patients with difficult vascular access due to extensive postburn scar contractures.
Elastography detected solid organ stiffness increased in patients with acromegaly
Authors: Bankir Mehmet , Sumbul Hilmi Erdem , Koc Ayse Selcan , Demirtas Derya , Acibucu Fettah
Published: January 2019

Elastography is a method to examine the increase in solid organs stiffness (SOS), and there is no data in the literature regarding to its use in patients with acromegaly. In this study, we aimed to investigate the change of SOS in patients with acromegaly and to determine the parameters closely related to SOS in same patient groups.

We included 40 subjects with acromegaly and 40 healthy control subjects. In addition to routine renal, liver and thyroid ultrasonography (USG), SOS for 3 solid organs were measured by elastography. The participants of the study were divided into 3 groups as the control (Group-I), acromegaly patients with remission (Group-II), and acromegaly patients without remission (Group-III).

Insulin growth factor-1 (IGF-1) level significantly increased from Group-I to Group-III. Glucose, creatinine, albuminuria, alkaline phosphatase, TSH, and growth factor levels were highest in Group-III and statistically significance was found only between Group-I and Group-III. Liver, kidney and thyroid size and echogenicity were increased from Group-I to Group-III. Liver and renal stiffness and thyroid gland strain ratio significantly increased from Group-I to Group-III and these parameters were statistically different between all groups. In linear regression analysis, IGF-1 levels were independent determinants of SOS.

SOS values of acromegaly patients with active disease were significantly increased compared to both the control group and the acromegaly patients in remission phase. Serum IGF-1 levels were independently associated with SOS in these patients. SOS measurement should be part of a routine USG examination in patients with acromegaly, especially in patients during active disease.
Myeloid Cell Nuclear Differentiation Antigen (MNDA) Positivity in Primary Follicles: Potential Pitfall in the Differential Diagnosis With Marginal Zone Lymphoma
Authors: Manohar Vidhya , Peerani Raheem , Tan Brent , Gratzinger Dita , Natkunam Yasodha
Published: January 2019

Myeloid cell nuclear differentiation antigen (MNDA) is an immunohistochemical marker that is used to distinguish marginal zone lymphomas (MZLs) from other small B-cell lymphomas. An index case that showed MNDA staining in primary follicles prompted the current study to evaluate whether MNDA expression is widespread in primary follicles and to address whether it poses a potential diagnostic pitfall. Of the 15 cases with primary follicles identified by a search of the laboratory information system, 7 had positive MNDA staining. In all cases, there was weak nuclear staining similar to what is typical of MNDA staining in MZLs. All cases showed intense nuclear signal in myeloid lineage cells such as neutrophils, which served as positive internal controls. The histologic and cytologic features of primary follicles and MZLs showed overlapping features, particularly in small biopsies. Our results indicate that weak nuclear MNDA staining can act as a potential pitfall in the evaluation of small B-cell lymphomas. Correlation with other immunohistochemical markers that are useful in the workup of small B-cell lymphomas, as well as those that outline immunoarchitectural features of lymphoid follicles, is suggested when both entities are part of the differential diagnosis. Our results underscore the need for caution in the interpretation of weak nuclear MNDA staining in the evaluation of small B-cell lymphomas.
Physiotherapy Versus Physiotherapy Plus Cognitive Training on Cognition and Quality of Life in Parkinson Disease
Authors: Barboza Natália Mariano , Terra Marcelle Brandão , Bueno Maria Eduarda Brandão , Christofoletti Gustavo , Smaili Suhaila Mahmoud
Published: January 2019

Objective

The aim of the study was to verify the effectiveness of physiotherapy associated with cognitive training to improve cognition and quality of life in individuals with Parkinson disease.

Design

This is a randomized clinical trial involving 58 individuals with mild to moderate Parkinson disease, randomly distributed into two groups: motor group and cognitive-motor group. Both groups were assessed for cognition and quality of life at the beginning of the study, at the end of the intervention protocols, and 3 mos after the end of the intervention. The following instruments were used to assess cognition and quality of life: Mini-Mental State Examination, Montreal Cognitive Assessment, Verbal fluency test, Rey Auditory Verbal Learning Test, Cognitive and perceptual assessment by pictures, Trail Making Test, Clock Drawing Executive Test, and Parkinson Disease Quality of Life Questionnaire. The motor group engaged in motor physiotherapy, whereas the cognitive-motor group underwent combined motor physiotherapy with cognitive training.

Results

The intragroup analysis revealed that both groups presented improved cognition (memory and visuospatial function domains) and quality of life after execution of the protocols, but without statistically significant intergroup differences.

Conclusions

When comparing the intervention moments, the two treatment approaches used were effective for the outcomes: memory, visuospatial function, and quality of life in both groups.
Debunking a Surgical Myth: Do Not Touch the Temporalis
Authors: Bennett Katelyn G. , Ettinger Russell E. , Liang Fan , Beck Peter C.C. , Stoldt Meike K. , McNeely Molly M. , Nabi Syed R. , Vercler Christian J. , Buchman Steven R.
Published: January 2019

Background:

A longstanding dictum exists to avoid surgical manipulation of the temporalis muscle out of concern for an exceedingly high rate of muscle atrophy and recurrent temporal hollowing. The authors challenge this surgical myth, considering such advice to be erroneous. The authors hypothesize that elevation of the temporalis muscle, if performed using standard muscle flap principles, will demonstrate excellent results.

Methods:

To assess temporalis response to surgical manipulation, the authors reviewed patients who underwent calvarial vault remodeling by the senior author for craniosynostosis between 1988 and 2011. Nonsyndromic patients with single-suture synostosis and 5 years of follow-up were eligible for inclusion. The medical record was used to measure rates of reoperation, recurrent temporal hollowing, and persistent temporalis overcorrection.

Results:

Of the cohort reviewed, 196 patients met inclusion criteria. Ten patients (5.1%) exhibited recurrent bitemporal constriction. One patient (0.5%) underwent a revision temporalis turnover flap, and 2 patients (1.0%) underwent soft tissue augmentation. The overall reoperation rate was 1.5%. Temporalis overcorrection, in an attempt to prophylactically rectify the expected atrophy after temporalis manipulation, persisted in 11 patients (5.6%). Three of these patients required treatment with steroid injections, Botox injections, or operative muscle debulking. The overall reoperation rate for temporalis overcorrection was 1.5%.

Conclusions:

The authors’ low reoperation rates for recurrent deformity, in combination with persistent temporalis overcorrection in 5.6% of patients, should dispel the myth that manipulation of the temporalis invariably results in atrophy. The muscle may be surgically manipulated, as long as plastic surgery principles are followed.
Analysis of Surgical Approaches to Skull Base Tumors Involving the Pterygopalatine and Infratemporal Fossa
Authors: Chung Hyo Jin , Moon In Seok , Cho Hyung-Ju , Kim Chang-Hoon , Sharhan Salma Saud Al , Chang Jung Hyun , Yoon Joo-Heon
Published: January 2019

Selecting an appropriate surgical approach for resection of huge skull base tumors involving pterygopalatine and infratemporal fossa is challenging because of their rarity and high possibility of vital anatomical structure injuries. To suggest the guidance of selecting the appropriate approach by analyzing outcomes and satisfactions of known surgical approaches with our previous experience, the authors retrospectively analyzed skull base tumor cases experienced for 24 years, and condensed to 4 well-known surgical approaches: maxillary swing, infratemporal fossa type C, transzygomatic, and a combined transzygomatic–midfacial degloving approach: to review indications, advantages, and limitations of these approaches. Maxillary swing approach was useful in large-sized tumors as it provided wide surgical field; however, inevitable facial scar was the main drawbacks, especially in adolescents. Infratemporal fossa approach type C was helpful in the involvement of vital vascular structures; however, long incision scar with temporal area depression and permanent conductive hearing loss were the factors of patients’ dissatisfaction. Transzygomatic approach could be the good alternative to the infratemporal fossa approach type C; however, en bloc tumor resection was impossible due to its limited operative space. To overcome limitations of these approaches, transzygomatic approach was combined with midfacial degloving approach, and it enabled lateral and anterior access without prominent facial scar and/or deformity while providing wide surgical space. Based on our 24 years of surgical experience in managing huge skull base tumors, the authors recommend the combined transzygomatic–midfacial degloving approach, which enables complete resection with short postoperative healing periods and no disfiguring facial incisions.
Atraumatic Delayed Orbital Hematoma Sixteen Years After Orbital Floor Fracture Repair With Porous Polyethylene Implant
Authors: Slentz Dane Harper , Rajjoub Lamise , Domanski Mark
Published: January 2019

Porous alloplastic materials such as titanium mesh and porous polyethylene allow for the ingrowth of fibrovascular tissues into the implant; stabilizing the implant and reducing the risk of extrusion and extrusion-related complications (such as hematoma formation). The literature contains 2 specific reports of delayed atraumatic orbital hematomas occurring 8 months and 3 years after orbital floor reconstruction with porous polyethylene implants. In this study, an atraumatic orbital hematoma occurring 16 years after orbital floor reconstruction with a porous polyethylene implant was presented. The hematoma was evacuated and the implant was removed without replacement of a secondary implant. The remaining fibrovascular tissue on the underside of the implant provided enough support of the orbital soft tissues to achieve excellent anatomic and physiologic outcomes.
Prevention of heart failure in hypertension – disentangling the role of evolving left ventricular hypertrophy and blood pressure lowering: the ALLHAT study
Authors: Johnson Kyle , Oparil Suzanne , Davis Barry R. , Tereshchenko Larisa G.
Published: January 2019

Background

Hypertension (HTN) is a known risk factor for heart failure (HF), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy (LVH). We studied how much blood pressure (BP) change and evolving LVH contribute to the effect that lisinopril, doxazosin, amlodipine have on HF compared to chlorthalidone.

Methods

We conducted causal mediation analysis of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) data. ALLHAT participants with available serial ECGs and BP measurements were included (n=29,892; mean age 67±4 y; 32% black; 56% men): 11,008 were randomized to chlorthalidone, 5,967 – to doxazosin, 6,593 – to amlodipine, and 6,324 – to lisinopril. Evolving ECG-LVH, and BP-lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator-outcome confounders (demographic and clinical characteristics known to be associated both with both LVH/HTN and HF).

Results

A large majority of participants (96%) had ECG-LVH status unchanged; 4% developed evolving ECG-LVH. On average, BP decreased by 11/7 mmHg. In adjusted Cox regression analyses, progressing ECG-LVH [HR 1.78(1.43-2.22)], resolving ECG-LVH [HR 1.33(1.03-1.70)], and baseline ECG-LVH [1.17(1.04-1.31)] carried risk of incident HF. After full adjustment, evolving ECG-LVH mediated 4% of the effect of doxazosin on HF. Systolic BP-lowering mediated 12% of the effect of doxazosin, and diastolic BP-lowering mediated 10% effect of doxazosin, 7% effect of amlodipine, and borderline 9% effect of lisinopril on HF.

Conclusions

Evolving ECG-LVH and BP change account for 4-13% of the mechanism by which antihypertensive medications prevent HF.
Prevalence and risk factors of postpartum depression within one year after birth in urban slums of Dhaka, Bangladesh
Authors: Azad Rashidul , Fahmi Rukhshan , Shrestha Sadichhya , Joshi Hemraj , Hasan Mehedi , Khan Abdullah Nurus Salam , Chowdhury Mohiuddin Ahsanul Kabir , Arifeen Shams El , Billah Sk Masum
Published: January 2019

Postpartum depression (PPD) is a serious pubic health concern and known to have the adverse effects on mother’s perinatal wellbeing; an d child’s physical and cognitive development. There were limited literatures on PPD in Bangladesh, especially in urban slum context. The aim of this study was to assess the burden and risk factors of PPD among the urban slum women. A cross-sectional study was conducted between November-December 2017 in three urban slums on 376 women within first 12 months of postpartum. A validated Bangla version of Edinburgh Postnatal Depression Scale was used to measure the depression status. Respondent’s socio-economic characteristics and other risk factors were collected with structured validated questionaire by trained interviewers. Unadjusted Prevalence Ratio (PR) and Adjusted Prevalence Ratio (APR) were estimated with Generalized Linear Model(GLM) and Generalized Estimating Equation (GEE) respectively to identify the risk factors of PPD. The prevalence of PPD was 39.4% within first 12 months following the child birth. Job involvement after child delivery (APR=1.9, 95% CI= 1.1, 3.3), job loss due to pregnancy (APR=1.5, 95% CI= 1.0, 2.1), history of miscarriage or still birth or child death (APR=1.4, 95% CI= 1.0, 2.0), unintended pregnancy (APR=1.8, 95% CI= 1.3, 2.5), management of delivery cost by borrowing, selling or mortgaging assets (APR=1.3, 95% CI= 0.9, 1.9), depressive symptom during pregnancy (APR=2.5, 95% CI= 1.7, 3.8) and intimate partner violence (APR=2.0, 95% CI= 1.2, 3.3), were identified as risk factors. PPD was not associated with poverty, mother in law and any child related factors. The burden of postpartum depression was high in the urban slum of Bangladesh. Maternal mental health services should be integrated with existing maternal health services. Research is required for the innovation of effective, low cost and culturally appropriate PPD case management and preventive intervention in urban slum of Bangladesh.
Tracking the popularity and outcomes of all bioRxiv preprints
Authors: Abdill Richard J. , Blekhman Ran
Published: January 2019

Researchers in the life sciences are posting work to preprint servers at an unprecedented and increasing rate, sharing papers online before (or instead of) publication in peer-reviewed journals. Though the increasing acceptance of preprints is driving policy changes for journals and funders, there is little information about their usage. Here, we collected and analyzed data on all 37,648 preprints uploaded to bioRxiv.org, the largest biology-focused preprint server, in its first five years. We find preprints are being downloaded more than ever before (1.1 million tallied in October 2018 alone) and that the rate of preprints being posted has increased to a recent high of 2,100 per month. We also find that two-thirds of preprints posted before 2017 were later published in peer-reviewed journals, and find a relationship between journal impact factor and preprint downloads. Lastly, we developed Rxivist.org, a web application providing multiple ways of interacting with preprint metadata.
BigMPI4py: Python module for parallelization of Big Data objects
Authors: Ascension Alex M. , Araúzo-Bravo Marcos J.
Published: January 2019

Big Data analysis is a discipline with a growing number of areas where huge amounts of data is extracted and analyzed. Parallelization in Python integrates Message Passing Interface via mpi4py module. Since mpi4py does not support parallelization of objects greater than 231bytes, we developed BigMPI4py, a Python module that wraps mpi4py, supporting object sizes beyond this boundary. BigMPI4py automatically determines the optimal object distribution strategy, and also uses vectorized methods, achieving higher parallelization efficiency. BigMPI4py facilitates the implementation of Python for Big Data applications in multicore workstations and HPC systems. We validated BigMPI4py on whole genome bisulfite sequencing (WGBS) DNA methylation ENCODE data of 59 samples from 27 human tissues. We categorized them on the three germ layers and developed a parallel implementation of the Kruskall-Wallis test to find CpGs with differential methylation across germ layers. We observed a differentiation of the germ layers, and a set of hypermethylated genes in ectoderm and mesoderm-related tissues, and another set in endoderm-related tissues. The parallel evaluation of the significance of 55 million CpG achieved a 22x speedup with 25 cores. BigMPI4py is available athttps://gitlab.com/alexmascension/bigmpi4pyand the Jupyter Notebook with WGBS analysis athttps://gitlab.com/alexmascension/wgbs-analysis
Understanding the survival of Zika virus in a vector interconnected sexual contact network
Authors: Ferdousi Tanvir , Cohnstaedt Lee W. , McVey D. S. , Scoglio Caterina M.
Published: January 2019

The recent outbreaks of the insect-vectored Zika virus have demonstrated its potential to be sexually transmitted, which complicates modeling and our understanding of disease dynamics. Autochthonous outbreaks in the US mainland may be a consequence of both modes of transmission, which affect the outbreak size, duration, and virus persistence. We propose a novel individual-based interconnected network model that incorporates both insect-vectored and sexual transmission of this pathogen. This model interconnects a homogeneous mosquito vector population with a heterogeneous human host contact network. The model incorporates the seasonal variation of mosquito abundance and characterizes host dynamics based on age group and gender in order to produce realistic projections. We use a sexual contact network which is generated on the basis of real world sexual behavior data. Our findings suggest that for a high relative transmissibility of asymptomatic hosts, Zika virus shows a high probability of sustaining in the human population for up to 3 months without the presence of mosquito vectors. Zika outbreaks are strongly affected by the large proportion of asymptomatic individuals and their relative transmissibility. The outbreak size is also affected by the time of the year when the pathogen is introduced. Although sexual transmission has a relatively low contribution in determining the epidemic size, it plays a role in sustaining the epidemic and creating potential endemic scenarios.
Determinants of Cancer-specific Quality of Life in Veteran Lung Cancer Survivors Eligible for Long-Term Cure
Authors: Ha Duc , Ries Andrew L. , Swigris Jeffrey J.
Published: January 2019

Rationale/Objective

Quality of life (QoL) is an important issue in lung cancer survivors. We aimed to identify determinants of QoL in lung cancer survivors eligible for long-term cure.

Methods

We performed an exploratory analysis of a cross-sectional study of consecutive lung cancer survivors who completed curative-intent treatment ≥1 month previously. Variables tested included demographic, clinical, physiologic, and symptom-specific patient-reported outcome measures. We defined the primary outcome as a previously-validated cancer-specific QoL measure – the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (C30) summary score. We also verified our findings with the C30 global health status/QoL subscale and a summated score of lung cancer-specific QoL from the EORTC-Lung Cancer Module 13.

Results

In 75 enrolled participants, measures of fatigue, depression, sleep difficulties, and dyspnea were statistically significant determinants of the C30 summary score in multivariable linear regression analyses. Together, these four symptoms accounted for approximately 85% of the variance in cancer-specific QoL (p<0.001). When we verified our findings with global QoL and lung cancer-specific QoL, fatigue and dyspnea were consistent determinants of QoL.

Conclusions

We found four symptoms – dyspnea, fatigue, depression, and sleep difficulties – that are important determinants of and together accounted for almost all of the variance in cancer-specific QoL in lung cancer survivors eligible for long-term cure. These findings have implications to reduce symptom burden and improve function and QoL in these patients.
The genome of cowpea (Vigna unguiculata[L.] Walp.)
Authors: Lonardi Stefano , Muñoz-Amatriaín María , Liang Qihua , Shu Shengqiang , Wanamaker Steve I. , Lo Sassoum , Tanskanen Jaakko , Schulman Alan H. , Zhu Tingting , Luo Ming-Cheng , Alhakami Hind , Ounit Rachid , Hasan Abid Md. , Verdier Jerome , Roberts Philip A. , Santos Jansen R.P. , Ndeve Arsenio , Doležel Jaroslav , Vrána Jan , Hokin Samuel A. , Farmer Andrew D. , Cannon Steven B. , Close Timothy J.
Published: January 2019

Cowpea (Vigna unguiculata[L.] Walp.) is a major crop for worldwide food and nutritional security, especially in sub-Saharan Africa, that is resilient to hot and drought-prone environments. A high-quality assembly of the single-haplotype inbred genome of cowpea IT97K-499-35 was developed by exploiting the synergies between single molecule real-time sequencing, optical and genetic mapping, and a novel assembly reconciliation algorithm. A total of 519 Mb is included in the assembled sequences. Nearly half of the assembled sequence is composed of repetitive elements, which are enriched within recombination-poor pericentromeric regions. A comparative analysis of these elements suggests that genome size differences betweenVignaspecies are mainly attributable to changes in the amount ofGypsyretrotransposons. Conversely, genes are more abundant in more distal, high-recombination regions of the chromosomes; there appears to be more duplication of genes within the NBS-LRR and the SAUR-like auxin superfamilies compared to other warm-season legumes that have been sequenced. A surprising outcome of this study is the identification of a chromosomal inversion of 4.2 Mb among landraces and cultivars, which includes a gene that has been associated in other plants with interactions with the parasitic weedStriga gesnerioides. The genome sequence also facilitated the identification of a putative syntelog for multiple organ gigantism in legumes. A new numbering system has been adopted for cowpea chromosomes based on synteny with common bean (Phaseolus vulgaris).
GRep: Gene Set Representation via Gaussian Embedding
Authors: Wang Sheng , Flynn Emily , Altman Russ B.
Published: January 2019

Molecular interaction networks are our basis for understanding functional interdependencies among genes. Network embedding approaches analyze these complicated networks by representing genes as low-dimensional vectors based on the network topology. These low-dimensional vectors have recently become the building blocks for a larger number of systems biology applications. Despite the success of embedding genes in this way, it remains unclear how to effectively represent gene sets, such as protein complexes and signaling pathways. The direct adaptation of existing gene embedding approaches to gene sets cannot model the diverse functions of genes in a set. Here, we propose GRep, a novel gene set embedding approach, which represents each gene set as a multivariate Gaussian distribution rather than a single point in the low-dimensional space. The diversity of genes in a set, or the uncertainty of their contribution to a particular function, is modeled by the covariance matrix of the multivariate Gaussian distribution. By doing so, GRep produces a highly informative and compact gene set representation. Using our representation, we analyze two major pharmacogenomics studies and observe substantial improvement in drug target identification from expression-derived gene sets. Overall, the GRep framework provides a novel representation of gene sets that can be used as input features to off-the-shelf machine learning classifiers for gene set analysis.
Motion direction representation in multivariate electroencephalography activity for smooth pursuit eye movements
Authors: Lee Joonyeol , Jeong Woojae , Kim Seolmin , Kim Yee-Joon
Published: January 2019

Visually-guided smooth pursuit eye movements are composed of initial open-loop and later steady-state periods. Feedforward sensory information dominates the motor behavior during the open-loop pursuit, and a more complex feedback loop regulates the steady-state pursuit. To understand the neural representations of motion direction during open-loop and steady-state smooth pursuits, we recorded electroencephalography (EEG) responses from human observers while they tracked random dot kinematograms as pursuit targets. We estimated population direction tuning curves from multivariate EEG activity using an inverted encoding model. We found significant direction tuning curves as early as 20 ms from motion onset. Direction tuning responses were generalized to later times during the open-loop smooth pursuit, but they became more dynamic during the later steady-state pursuit. The encoding quality of retinal motion direction information estimated from the early direction tuning curves was predictive of trial-by-trial variation in initial pursuit directions. These results suggest that the movement directions of open-loop smooth pursuit are guided by the representation of the retinal motion present in the multivariate EEG activity.
Targeting tumor-intrinsic metabolic node sensitizes pancreatic cancer to anti-PD1 therapy
Authors: Sharma Nikita S , Gupta Vineet K , Garrido Vanessa T , Hadad Roey , Durden Brittany C , Kesh Kousik , Giri Bhuwan , Ferrantella Anthony , Dudeja Vikas , Saluja Ashok , Banerjee Sulagna
Published: January 2019

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA-4, PD-1, PD-L1) has not been very successful against PDAC.

The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize UDP-GlcNAc.

In the current manuscript, we target this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-L-norleucine or DON). Our results show that DON decreases the self-renewal potential and metastatic ability of tumor cell. Further, treatment with DON results in a decrease in hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM. this in turn, increases CD8+ cytotoxic T-cells infiltration, and makes the tumors tumors more amenable and sensitive to anti-PD1 therapy.
The Imprinted Igf2-Igf2r Axis is Critical for Matching Placental Microvasculature Expansion to Fetal Growth
Authors: Sandovici Ionel , Georgopoulou Aikaterini , Pérez-García Vicente , Hufnagel Antonia , López-Tello Jorge , Lam Brian Y.H. , Schiefer Samira N. , Gaudreau Chelsea , Santos Fátima , Hoelle Katharina , Yeo Giles S.H. , Burling Keith , Reiterer Moritz , Fowden Abigail L. , Burton Graham J. , Branco Cristina M. , Sferruzzi-Perri Amanda N. , Constância Miguel
Published: January 2019

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here we demonstrate, through fetal, endothelial, hematopoietic and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signalling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.
Causal evidence supporting the proposal that dopamine transients function as a temporal difference prediction error
Authors: Maes Etienne JP , Sharpe Melissa J , Gardner Matthew P.H. , Chang Chun Yun , Schoenbaum Geoffrey , Iordanova Mihaela D.
Published: January 2019

Reward-evoked dopamine is well-established as a prediction error. However the central tenet of temporal difference accounts – that similar transients evoked by reward-predictive cues also function as errors – remains untested. To address this, we used two phenomena, second-order conditioning and blocking, in order to examine the role of dopamine in prediction error versus reward prediction. We show that optogenetically-shunting dopamine activity at the start of a reward-predicting cue prevents second-order conditioning without affecting blocking. These results support temporal difference accounts by providing causal evidence that cue-evoked dopamine transients function as prediction errors.
Using digital organisms to investigate the effect of whole genome duplication in (artificial) evolution
Authors: Yao Yao , Carretero-Paulet Lorenzo , Van de Peer Yves
Published: January 2019

The potential role of whole genome duplication (WGD) in evolution is controversial. Whereas some view WGD mainly as detrimental and an evolutionary ‘dead end’, there is growing evidence that the long-term establishment of polyploidy might be linked to environmental change, stressful conditions, or periods of extinction. However, despite much research, the mechanistic underpinnings of why and how polyploids might be able to outcompete non-polyploids at times of environmental upheaval remain indefinable. Here, we improved our recently developed bio-inspired framework, combining an artificial genome with an agent-based system, to form a population of so-called Digital Organisms (DOs), to examine the impact of WGD on evolution under different environmental scenarios mimicking extinction events of varying strength and frequency. We found that, under stable environments, DOs with non-duplicated genomes formed the majority, if not all, of the population, whereas the numbers of DOs with duplicated genomes increased under dramatically challenging environments. After tracking the evolutionary trajectories of individual artificial genomes in terms of sequence and encoded gene regulatory networks (GRNs), we propose that increased complexity, modularity, and redundancy of duplicated GRNs might provide DOs with increased adaptive potential under extinction events, while ensuring mutational robustness of the whole GRN. Our results confirm the usefulness of our computational simulation in studying the role of WGD in evolution and adaptation, helping to overcome the traditional limitations of evolution experiments with model organisms, and provide some additional insights into how genome duplication might help organisms to compete for novel niches and survive ecological turmoil.
Complete genome screening of clinical MRSA isolates identifies lineage diversity and provides full resolution of transmission and outbreak events
Authors: Sullivan Mitchell J , Altman Deena R , Chacko Kieran I , Ciferri Brianne , Webster Elizabeth , Pak Theodore R. , Deikus Gintaras , Lewis-Sandari Martha , Khan Zenab , Beckford Colleen , Rendo Angela , Samaroo Flora , Sebra Robert , Karam-Howlin Ramona , Dingle Tanis , Hamula Camille , Bashir Ali , Schadt Eric , Patel Gopi , Wallach Frances , Kasarskis Andrew , Gibbs Kathleen , van Bakel Harm
Published: January 2019

Whole-genome sequencing (WGS) of Staphylococcus aureus is increasingly used as part of infection prevention practices, but most applications are focused on conserved core genomic regions due to limitations of short-read technologies. In this study we established a long-read technology-based WGS screening program of all first-episode MRSA blood infections at a major urban hospital. A survey of 132 MRSA genomes assembled from long reads revealed widespread gain/loss of accessory mobile genetic elements among established hospital- and community-associated lineages impacting >10% of each genome, and frequent megabase-scale inversions between endogenous prophages. We also characterized an outbreak of a CC5/ST105/USA100 clone among 3 adults and 18 infants in a neonatal intensive care unit (NICU) lasting 7 months. The pattern of changes among complete outbreak genomes provided full spatiotemporal resolution of its origins and progression, which was characterized by multiple sub-transmissions and likely precipitated by equipment sharing. Compared to other hospital strains, the outbreak strain carried distinct mutations and accessory genetic elements that impacted genes with roles in metabolism, resistance and persistence. This included a DNA-recognition domain recombination in the hsdS gene of a Type-I restriction-modification system that altered DNA methylation. RNA-Seq profiling showed that the (epi)genetic changes in the outbreak clone attenuated agr gene expression and upregulated genes involved in stress response and biofilm formation. Overall our findings demonstrate that long-read sequencing substantially improves our ability to characterize accessory genomic elements that impact MRSA virulence and persistence, and provides valuable information for infection control efforts.
Attention Promotes the Neural Encoding of Prediction Errors
Authors: Smout Cooper A. , Tang Matthew F. , Garrido Marta I. , Mattingley Jason B.
Published: January 2019

The human brain is thought to optimise the encoding of incoming sensory information through two principal mechanisms: prediction uses stored information to guide the interpretation of forthcoming sensory events, and attention prioritizes these events according to their behavioural relevance. Despite the ubiquitous contributions of attention and prediction to various aspects of perception and cognition, it remains unknown how they interact to modulate information processing in the brain. A recent extension of predictive coding theory suggests that attention optimises the expected precision of predictions by modulating the synaptic gain of prediction error units. Since prediction errors code for the difference between predictions and sensory signals, this model would suggest that attention increases the selectivity for mismatch information in the neural response to a surprising stimulus. Alternative predictive coding models proposes that attention increases the activity of prediction (or ‘representation’) neurons, and would therefore suggest that attention and prediction synergistically modulate selectivity for feature information in the brain. Here we applied multivariate forward encoding techniques to neural activity recorded via electroencephalography (EEG) as human observers performed a simple visual task, to test for the effect of attention on both mismatch and feature information in the neural response to surprising stimuli. Participants attended or ignored a periodic stream of gratings, the orientations of which could be either predictable, surprising, or unpredictable. We found that surprising stimuli evoked neural responses that were encoded according to the difference between predicted and observed stimulus features, and that attention facilitated the encoding of this type of information in the brain. These findings advance our understanding of how attention and prediction modulate information processing in the brain, and support the theory that attention optimises precision expectations during hierarchical inference by increasing the gain of prediction errors.
Rcs phosphorelay activation in cardiolipin-deficient Escherichia coli reduces biofilm formation
Authors: Nepper Julia F. , Lin Yin C. , Weibel Douglas B.
Published: January 2019

Biofilm formation is a complex process that requires a number of transcriptional, proteomic, and physiological changes to enable bacterial survival. The lipid membrane presents a barrier to communication between the machinery within bacteria and the physical and chemical features of their extracellular environment, and yet little is known about how the membrane influences biofilm development. We found that depleting the anionic phospholipid cardiolipin reduces biofilm formation in Escherichia coli cells by as much as 50%. The absence of cardiolipin activates the Rcs envelope stress response, which represses production of flagella, disrupts initial biofilm attachment, and reduces biofilm growth. We demonstrate that a reduction in the concentration of cardiolipin impairs translocation of proteins across the inner membrane, which we hypothesize activates the Rcs pathway through the outer membrane lipoprotein RcsF. Our study demonstrates a molecular connection between the composition of membrane phospholipids and biofilm formation in E. coli and suggests that altering lipid biosynthesis may be a viable approach for altering biofilm formation and possibly other multicellular phenotypes related to bacterial adaptation and survival.

Importance

There is a growing interest in the role of lipid membrane composition in the physiology and adaptation of bacteria. We demonstrate that a reduction in the anionic phospholipid cardiolipin impairs biofilm formation in Escherichia coli cells. Depleting cardiolipin reduced protein translocation across the inner membrane and activated the Rcs envelope stress response. Consequently, cardiolipin depletion produced cells lacking assembled flagella, which impacted their ability to attach to surfaces and seed the earliest stage in biofilm formation. This study provides empirical evidence for the role of anionic phospholipid homeostasis in protein translocation and its effect on biofilm development, and highlights modulation of the membrane composition as a potential method of altering bacterial phenotypes related to adaptation and survival.
CryoAPEX - an electron tomography tool for subcellular localization of membrane proteins
Authors: Sengupta Ranjan , Poderycki Michael J. , Mattoo Seema
Published: January 2019

We describe a method, termed cryoAPEX, that couples chemical fixation and high pressure freezing of cells with peroxidase-tagging (APEX) to allow precise localization of membrane proteins in the context of a well-preserved subcellular membrane architecture. Further, cryoAPEX is compatible with electron tomography. As an example, we apply cryoAPEX to obtain a high-resolution three-dimensional contextual map of the human Fic (filamentation induced by cAMP) protein, HYPE/FicD. HYPE is a single pass membrane protein that localizes to the endoplasmic reticulum (ER) lumen and regulates the unfolded protein response. Alternate cellular locations for HYPE have been suggested. CryoAPEX analysis shows that, under normal/resting conditions, HYPE localizes robustly within the subdomains of the ER and is not detected in the secretory pathway or other organelles. CryoAPEX is broadly applicable for assessing both lumenal and cytosol-facing membrane proteins.

Summary statement

CryoAPEX couples localization of peroxidase-tagged membrane proteins at high-resolution with 3D structural analysis, within an optimally preserved cellular context.