bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Neural Tube Defects (NTDs) After Exposure to Raltegravir During Pregnancy
Authors: Shamsuddin Hala , Raudenbush Casey L. , Sciba Brittany L. , Zhou Yun-Ping , Mast T. Christopher , Greaves Wayne L. , Hanna George J. , Leong Ronald , Straus Walter
Published: March 2019

Objective:

To evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy.

Methods:

Exposures to raltegravir during pregnancy reported cumulatively through May 31, 2018, to the company safety database were reviewed to identify cases of NTDs. This database includes all reports of pregnancy from Merck-sponsored clinical trials, spontaneous postmarketing reports, and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (before knowledge of pregnancy outcome) or retrospective (after knowledge of pregnancy outcome). We also reviewed data from 2 ongoing pregnancy cohorts.

Results:

A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, 3 NTD cases per APR criteria were identified (anencephaly, and 2 meningomyelocele), of which only one (meningomyelocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate.

Conclusions:

Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. The current data support the updated DHHS and EACS treatment guidelines for use of raltegravir as a preferred integrase inhibitor in all stages of pregnancy.
Volume Replacement Fluid Demarks Benign Insulinoma With 68Ga-DOTA-Exendin-4 PET/CT
Authors: Antwi Kwadwo , Nicolas Guillaume , Fani Melpomeni , Christ Emanuel , Wild Damian
Published: March 2019

Insulinomas are often difficult to localize. We present a 47-year-old woman who had recurrent neuroglycopenic symptoms and positive Whipple triad for 28 months. The 14 hours of fasting test confirmed the diagnosis of endogenous hyperinsulinemic hypoglycemia which is highly suspicious for the presence of an insulinoma. Previously performed MRI, endoscopic ultrasound, 111In-pentetreotide SPECT/CT, and 68Ga-DOTA-exendin-4 PET/CT did not show any evidence of an insulinoma. Subsequently, 68Ga-DOTA-exendin-4 PET/CT was repeated with the previous infusion of a colloidal volume replacement fluid (Gelofusine), known to reduce 68Ga-DOTA-exendin-4 accumulation in the kidneys. Consequently, the insulinoma was unmasked from the left kidney, allowing curative surgery.
Correlation of 99mTc-TRODAT-1 SPECT Imaging Findings and Clinical Staging of Parkinson Disease
Authors: Gupta Vanshika , Ranjan Rajeev , Verma Ritu , Belho Ethel S. , Malik Dharmender , Mahajan Harsh
Published: March 2019

Purpose

The aims of this study were to evaluate 99mTc-TRODAT-1 SPECT imaging patterns and to assess their correlation with disease severity in clinically diagnosed patients of Parkinson disease (PD).

Methods

The study included 241 patients with clinically diagnosed idiopathic Parkinson disease who underwent 99mTc-TRODAT-1 SPECT/CT scan. Binding ratios were calculated for each striatum, caudate, and putamen individually, by drawing region of interest. Occipital cortex region of interest was taken for background correction. Correlation of binding ratio with increasing clinical stage was derived, as described by modified Hoehn and Yahr scale.

Results

Median binding ratio was least in the contralateral putamen for all stages of modified Hoehn and Yahr. A statistically significant negative correlation was found between increasing disease severity and binding ratio in all subregions of striatum. Patients were clinically categorized into postural instability and gait disorder group and tremor-dominant PD group. No significant asymmetry was found between the left and right striatum in patients belonging to postural instability and gait disorder group and in those with bilateral tremors without lateralization.

Conclusions

99mTc-TRODAT-1 SPECT is useful in early detection and in assessing disease severity of PD. A significant asymmetry with the contralateral side being affected more than the ipsilateral side can be attributed to tremor-dominant patients. The binding ratio of the ipsilateral striatum may serve useful as a marker of remaining functional dopaminergic neuronal reserve in the striatum.
Quality and Safety in Healthcare, Part LII
Authors: Harolds Jay A.
Published: March 2019

The study of positive psychology has brought to light multiple ways to improve one's ability to bounce back from setbacks and deal better with stress. The individual should focus on his/her accomplishments, not dwell on mistakes, work to improve relationships with others, find meaning in work, and spend the time required to have happiness. Being able to recognize when situations are too stressful and understand the need to take breaks from them, especially by acquiring new knowledge, is important and effective. It is often quite helpful to utilize coaching based on positive psychology to improve one's resiliency and recover from burnout.
Diffuse-Type Tenosynovial Giant Cell Tumor of the Thoracic Spine
Authors: Shen Guohua , Ma Huan , Pan Lili , Su Minggang , Kuang Anren
Published: March 2019

D-TGCT (diffuse-type tenosynovial giant cell tumor) is a benign proliferative disorder of the synovial membranes that usually occurs in the appendicular skeleton, especially large joints such as the knee, hip, and elbow. It rarely involves the spine. In this report, we describe a rare case of D-TGCT in the thoracic spine, which showed a lytic lesion with high FDG uptake. It can mimic metastases or neurogenic tumors and should be included in the differential diagnosis of spinal tumors.
Postoperative Pain Management Following Craniosynostosis Repair: Current Practices and Future Directions
Authors: Brown Stav , Yao Amy , Sanati-Mehrizy Paymon , Zackai Sheemon P. , Taub Peter J.
Published: March 2019

Background:

Postoperative analgesia following craniosynostosis repair is a clinical challenge for plastic and reconstructive surgeons. There is a paucity of published data on the postoperative pain associated with craniosynostosis repair procedures and the prescribed analgesia varies with different unit protocols. The authors sought to summarize the current knowledge of the postoperative analgesia following craniosynostosis repair by reviewing the literature for existing regimens, clinical outcomes, and recommendations.

Methods:

Two independent investigators conducted a literature search of the Pubmed, Cochrane, and Google Scholar databases for relevant clinical studies. Studies were abstracted for procedure type, postoperative pain management protocol, pain scores, side effects, complications, and clinical recommendations.

Results:

Ten studies describing the use of analgesic agents in open craniosynostosis surgery from 2000 to 2018 were fully reviewed, comprising a total of 431 patients undergoing surgical procedures using a combination regimen of narcotic and nonnarcotic agents (n = 315) and nonnarcotic agents alone (n = 116).

Conclusion:

Multimodal analgesia is the primary regimen used following open craniosynostosis repair procedures. Opioids are a critical component in pain management regimens, relieving patient discomfort. However, due to the deleterious effects that come with their prolonged use, intravenous acetaminophen is currently used as an alternative in many centers. The preferred mode of pain medication administration in the pediatric population is increasingly via the intravenous route which ensures that a full dose of pain medication is given. The authors suggest the use of dexmedetomidine, both an adjunct to intravenous acetaminophen and as a substitute for morphine due to its superior safety and efficacy profile.
Prediction of Minimally Conscious State With Brain Stem Reflexes in Unconscious Patients After Traumatic Brain Injury
Authors: Bao Yun , Mao Jian , Mei Fen , Liu Fan , Qi Songtao , Qiu Binghui
Published: March 2019

Objective:

To evaluate the predictive power of the brain stem reflexes (BSRs) for minimally conscious state in unconscious patients after traumatic brain injury.

Materials and Methods:

A total of 120 patients with duration of unconsciousness were enrolled in this study. BSRs were recorded 14 days after Traumatic brain injury, and classified into 3 grades. Predictors including BSRs, age, sex, Glasgow Coma Scale (GCS), and cause of injury were also analyzed, respectively. The outcome was divided into 2 groups including unconscious group and minimally conscious state (MCS) group.

Results:

Seventy-two of 120 were minimally conscious and 48 of 120 were unconscious at 6 months from the onset of injury. The BSRs outmatched the predictive accuracy of the GCS for outcome (AUROC, 0.853; 95% confidence interval, 0.753–0.953; and AUROC, 0.655; 95% confidence interval, 0.512–0.799, respectively). BSRs grade (P < 0.001) and GCS (P < 0.05) were significantly associated with the outcome. The accuracy of the whole regression model for predicting unconscious and MCS was 91.7% and 79.2%, respectively.

Conclusion:

The BSRs grade shows a significantly higher accuracy for prediction of MCS compared with the GCS. BSRs grade is a simple, yet reliable and stratification tool for early decision making.
Less Is More in Congenital and Pediatric Nasal Lesions
Authors: Wolfswinkel Erik M. , Fahradyan Artur , Tsuha Michaela , Goel Pedram , Starnes-Roubaud Margaret , Howell Lori K. , Hammoudeh Jeffrey A. , Urata Mark M. , Magee William
Published: March 2019

Congenital and pediatric nasal lesion resection and their reconstructive outcomes are not well studied. A surgeon must consider the site, size, depth, etiology, age, and effect on future function (including growth). As such, it is important to contrast the differences between the adult's and child's nose. The authors propose that more conservative resection and reconstructive methods may better serve congenital and pediatric nasal lesions. An Internal Review Board approved study of congenital and pediatric nasal lesions using a defect only approach from 2005 to 2017 was performed. Lesions, type of surgeries, complications, aesthetic outcome, and additional interventions were reviewed. One hundred twenty-seven patients met the study criteria with a median age at surgery of 5.4 years with follow-up of 1.4 years (1 week–11.3 years). The most common diagnosis was congenital melanocytic nevus (47, 37%). The lesions were located on more than 1 subunit in 34 (27%) patients with an average surface area of 3.7 (0.04–32) cm2. The most common primary procedure was excision and primary closure with adjacent tissue undermining/rearrangement (73, 57.4%) followed by full-thickness skin graft (23, 18.1%). The aesthetic outcome was considered acceptable in a high number of patients 117 (92%), while 10 (8%) patients had unacceptable aesthetic outcomes, mostly due to scarring. The authors’ data supports the concept of minimal healthy tissue excision or lesion only excision when treating pediatric and congenital nasal lesions.
Eagle Syndrome: A Wide Spectrum of Clinical and Neuroradiological Findings From Cervico-Facial Pain to Cerebral Ischemia
Authors: Galletta Karol , Siniscalchi Enrico Nastro , Cicciù Marco , Velo Mariano , Granata Francesca
Published: March 2019

Eagle syndrome (ES) is a rare symptomatic condition generally caused by abnormal elongation of the styloid process or calcification of stylo-hyoid ligament.

Patients with ES typically present a variety of symptoms, which range from mild discomfort to acute neurologic and referred pain in head-and-neck region.

Eagle syndrome could be identified through physical examination but often goes undetected in the absence of imaging studies.

Although uncommon, it should be considered in the differential diagnosis in patients with cervico-facial pain.

The authors report 3 cases with clinical evidence of ES, including both neurologic and vascular patterns, with a clinical and radiological diagnosis.

The authors also propose a brief review of its main clinical presentations, diagnostic studies, and part of treatment options of the syndrome.
The Second Division of Trigeminal Nerve for Corneal Neurotization: A Novel One-Stage Technique in Combination With Facial Reanimation
Authors: Gennaro Paolo , Gabriele Guido , Aboh Ikenna Valentine , Cascino Flavia , Menicacci Cristina , Mazzotta Cosimo , Bagaglia Simone
Published: March 2019

Corneal neurotization represents an effective surgical strategy to restore corneal sensibility in patients affected by neurotrophic keratopathy.

Corneal sensibility is essential in preserving structure and function of the eye. Loss of corneal sensibility can lead to a degenerative condition of the cornea known as neurotrophic keratopathy.

Moreover, patients suffering from facial palsy show failure of full eyelid closure resulting in chronic corneal exposure and subsequent progressive damage.

Reports have shown that the use of the contralateral ophthalmic division of the trigeminal nerve can be effective in restoring corneal sensibility. In the present study the authors expose a new technique by means of which direct neurotization of the anesthetic cornea was achieved using the homolateral second division of the trigeminal nerve. Effectiveness of the technique was evaluated using in vivo confocal microscopy.

To the best of authors’ knowledge, this is the first report of this technique in literature.
Use of Neutrophil, Eosinophil, Basophil, and Platelet to Lymphocyte Ratio to Predict Patient Satisfaction After Septoplasty Plus Inferior Turbinate Reduction
Authors: Kökoğlu Kerem , Şahin Mehmet Ilhan
Published: March 2019

Aim:

Investigation of the predictive value of neutrophil, platelet, eosinophil, and basophil to lymphocyte ratio (NLR, PLR, ELR, and BLR) in evaluation of patients’ satisfaction of septoplasty + inferior turbinate reduction operations.

Patients and Methods:

Seventy-six patients who were operated because of nasal obstruction were enrolled in the study. They were invited to the hospital and asked to answer a modified nasal obstruction symptom evaluation (NOSE) survey to determine their degree of satisfaction. Patients were divided into 2 groups according to their modified NOSE survey results, dissatisfied and satisfied groups. The 2 groups were compared in terms of demographic data, surgery, and hematological values. In addition, correlation analysis was performed between NLR, PLR, ELR, BLR, and modified NOSE scores.

Results:

There were 29 patients in the dissatisfied group and 47 patients in the satisfied group. Both groups were similar in terms of mean age, gender, surgery type, septal deviation type, smoking, hemoglobin, neutrophil, and white blood count (P > 0.05). There were significant differences between the 2 groups in terms of ELR and BLR (P < 0.05). In addition, there were negative and statistically significant correlations between modified NOSE scores and ELR and BLR. As ELR and BLR values increased, the satisfaction rate decreased.

Conclusion:

Eosinophil to lymphocyte ratio and BLR could be used to predict patient satisfaction after septoplasty and inferior turbinate reduction and for selection of patients.
Intrathecal therapy for pain in cancer patients
Authors: Dupoiron Denis
Published: March 2019

Purpose of review

Intrathecal drug delivery systems (IDDS) for cancer pain remain little employed despite a high level of efficiency even though the technique is widely recommended. This review aims to summarize recent advances in IDDS for cancer patients.

Recent findings

The respective roles of catheter positioning, volume and flow rate in diffusion of intrathecal treatments, as well as the individual roles of blood pressure, heart rate, and amplitude of the respiratory movements in cerebrospinal fluid (CSF) treatment dispersion, are now well established. Models are available using MRI data. Morphine has long been the gold standard in first line treatment, but recent publications conclude that ziconotide has largely proven its efficiency and that adverse effects are controllable. Four recent publications have evaluated cohorts of cancer patients treated by IDDS in 315 patients. All found a great efficiency of intrathecal treatment for cancer pain. Technical innovations include new catheters and anchorage devices for easier placement and a lower rate of complication. Three-dimensional (3D) CT scan appears to be a noninvasive technique for the diagnosis of catheter complications. Ultrasound should be used to locate pump septum for refill.

All recent recommendations highlight the efficiency of IDDS and propose to use it sooner.
Augmentation of T-cell activation by oscillatory forces and engineered antigen-presenting cells
Authors: Majedi Fatemeh S. , Hasani-Sadrabadi Mohammad Mahdi , Thauland Timothy J. , Li Song , Bouchard Louis-S. , Butte Manish J.
Published: March 2019

Activation of T cells by antigen presenting cells allows them to proliferate, produce cytokines, and kill infected or cancerous cells. We and others have shown that T cell receptors receive and in fact require mechanical forces from their own movements and the movements of antigen presenting cells. Emulation of T cell activation in vitro allows for the massive expansion of T cells necessary for clinical applications. In this paper, we studied the impact of augmenting novel artificial antigen presenting cells of various sizes and antigenic signal strength with mechanical, oscillatory movement. We showed that dynamic culture roughly doubles signal strength as compared to conventional, static culture. We demonstrated that tuning the strength of signal to a “sweet spot” allows for robust expansion of induced regulatory T cells, which is impeded by approaches that simply maximize activation.
Diversity and relative abundance of Collembola in a wheat (Triticum aestivum) field at Aligarh
Authors: Abbas Mohammad Jalaluddin , Parwez Hina
Published: March 2019

Collembolans are novel indicators of soil quality as they are enormously diversified in agricultural soils. However, their abundance is ever dynamic due to the dynamic climatic conditions. In order to ascertain the diversity and relative abundance of Collembola associated with wheat field, soil samples were taken at weekly intervals from selected field of Quarsi village located at Aligarh district of Uttar Pradesh (India). Total 20 samples were taken for the site study during the investigation period and soil microarthropods extracted by using modified Tullgren funnel apparatus. The results of our study showed that, the species diversity of Collembolans mainly consists of individuals belonging to family Entomobryoidae, Isotomidae, Hypogastruridae and Sminthuridae. Among these, Hypogastrurides were dominant (56.84 %) in entire community of Collembola. Soil temperature was negatively correlated (r = −0.932, P<0.05) with reference to Collembolans population, whereas soil moisture (r = 0.502, P>0.05) as well as available nitrogen (r = 0.656, P>0.05) both were positively correlated. The highest population of Collembolans was recorded at neutral pH level. In terms of numbers of soil microarthropods, Collembolans apparently constituted a better population than the other diverse group of soil microarthropods such as Acari(mites). The present study has shown profound diversity of Collembolans and highlights the significance of the variety of chemical and edaphic factors which regulate the fluctuation and diversity of microarthropods in a varied manner.
Do questionnaires reflect their purported cognitive functions?
Authors: Clark Ian A. , Maguire Eleanor A.
Published: March 2019

Questionnaires are used widely across psychology and permit valuable insights into a person’s thoughts and beliefs, which are difficult to derive from task performance measures alone. Given their importance and widespread use, it is vital that questionnaires map onto the cognitive functions they purport to reflect. However, where performance on naturalistic tasks such as imagination, autobiographical memory, future thinking and navigation is concerned, there is a dearth of knowledge about the relationships between task performance and questionnaire measures. Questionnaires are also typically designed to probe a specific aspect of cognition, when instead researchers sometimes want to obtain a broad profile of a participant. To the best of our knowledge, no questionnaire exists that asks simple single questions about a wide range of cognitive functions. To address these gaps in the literature, we recruited a large sample of participants (n = 217), all of whom completed a battery of widely used questionnaires and performed naturalistic tasks involving imagination, autobiographical memory, future thinking and navigation. We also devised a questionnaire that comprised simple single questions about the cognitive functions of interest. There were four main findings. First, imagination and navigation questionnaires reflected performance on their related tasks. Second, memory questionnaires were associated with autobiographical memory vividness and not internal (episodic) details. Third, imagery questionnaires were more associated with autobiographical memory vividness and future thinking than the questionnaires purporting to reflect these functions. Finally, initial exploratory analyses suggested that a broad profile of information can be obtained efficiently using a small number of simple single questions, and these modelled task performance comparably to established questionnaires in young, healthy adults. Overall, while some questionnaires can act as proxies for behaviour, the relationships between memory and future thinking tasks and questionnaires are more complex and require further elucidation.
Human lateral Frontal Pole contributes to control over social-emotional action
Authors: Bramson Bob , Folloni Davide , Verhagen Lennart , Hartogsveld Bart , Mars Rogier B. , Toni Ivan , Roelofs Karin
Published: March 2019

Regulation of emotional behavior is essential for human social interactions. Recent work has exposed its cognitive complexity, as well as its unexpected reliance on portions of the anterior prefrontal cortex (aPFC) also involved in exploration, relational reasoning, and counterfactual choice, rather than on dorsolateral and medial prefrontal areas involved in several forms of cognitive control. This study anatomically qualifies the contribution of aPFC territories to the regulation of social-emotional actions, and explores a possible structural pathway through which emotional regulation might be implemented.

We provide converging evidence from task-based fMRI, diffusion-weighted imaging, and functional connectivity fingerprints for a novel neural element in emotional regulation. Task-based fMRI in human male participants (N = 40) performing a social-emotional approach-avoidance task identified aPFC territories involved in the regulation of social-emotional actions. Connectivity fingerprints, based on diffusion-weighted imaging and resting-state connectivity, localized those task-defined frontal regions to the lateral frontal pole (FPl), an anatomically-defined portion of the aPFC that lacks a homologous counterpart in macaque brains. Probabilistic tractography indicated that 10-20% of inter-individual variation in social-emotional regulation abilities is accounted for by the strength of structural connectivity between FPl and amygdala. Evidence from an independent replication sample (N = 50; 10 females) further substantiated this result. These findings provide novel neuroanatomical evidence for incorporating FPl in models of control over human social-emotional behavior.

Significance statement

Successful regulation of emotional behaviors is a prerequisite for successful participation in human society, as is evidenced by the social isolation and loss of occupational opportunities often encountered by people suffering from emotion-regulation disorders such as social-anxiety disorder and psychopathy. Knowledge about the precise cortical regions and connections supporting this control is crucial for understanding both the nature of computations needed to successfully traverse the space of possible actions in social situations, and the potential interventions that might result in efficient treatment of social-emotional disorders. This study provides evidence for a precise cortical region (FPl) and a structural pathway (the ventral amygdalofugal bundle) through which a cognitively complex form of emotional action regulation might be implemented in the human brain.
Anatomo-functional correlates of auditory development in infancy
Authors: Adibpour Parvaneh , Lebenberg Jessica , Kabdebon Claire , Dehaene-Lambertz Ghislaine , Dubois Jessica
Published: March 2019

Brain development incorporates several intermingled mechanisms throughout infancy leading to intense and asynchronous maturation across cerebral networks and functional modalities. Combining electroencephalography (EEG) and diffusion magnetic resonance imaging (MRI), previous studies in the visual modality showed that the functional maturation of the event-related potentials (ERP) during the first postnatal semester relates to structural changes in the corresponding white matter pathways. Here we aimed to investigate similar issues in the auditory modality. We measured ERPs to syllables in 1-to 6-month-old infants and analyzed them in relation with the maturational properties of underlying neural substrates measured with diffusion tensor imaging (DTI). We first observed a decrease in the latency of the auditory P2, and a decrease of diffusivities in the auditory tracts and perisylvian regions with age. Secondly, we highlighted some of the early functional and structural substrates of lateralization. Contralateral responses to monoaural syllables were stronger and faster than ipsilateral responses, particularly in the left hemisphere. Besides, the acoustic radiations, arcuate fasciculus, middle temporal and angular gyri showed DTI asymmetries with a more complex and advanced microstructure in the left hemisphere, whereas the reverse was observed for the inferior frontal and superior temporal gyri. Finally, after accounting for the age-related variance, we correlated the inter-individual variability in P2 responses and in the microstructural properties of callosal fibers and inferior frontal regions. This study combining dedicated EEG and MRI approaches in infants highlights the complex relation between the functional responses to auditory stimuli and the maturational properties of the corresponding neural network.
Genome-wide association study of Parkinson’s disease progression biomarkers in 12 longitudinal patients’ cohorts
Authors: Iwaki Hirotaka , Blauwendraat Cornelis , Leonard Hampton L. , Kim Jonggeol J. , Liu Ganqiang , Maple-Grødem Jodi , Corvol Jean-Christophe , Pihlstrøm Lasse , van Nimwegen Marlies , Hutten Samantha J. , Khanh-Dung H. Nguyen , Rick Jacqueline , Eberly Shirley , Faghri Faraz , Auinger Peggy , Scott Kirsten M. , Wijeyekoon Ruwani , Van Deerlin Vivianna M. , Hernandez Dena G. , Gibbs J. Raphael , Chitrala Kumaraswamy Naidu , Day-Williams Aaron G. , Brice Alexis , Alves Guido , Noyce Alastair J. , Tysnes Ole-Bjørn , Evans Jonathan R. , Breen David P. , Estrada Karol , Wegel Claire E. , Danjou Fabrice , Simon David K. , Andreassen Ole , Ravina Bernard , Toft Mathias , Heutink Peter , Bloem Bastiaan R. , Weintraub Daniel , Barker Roger A. , Williams-Gray Caroline H. , van de Warrenburg Bart P. , Van Hilten Jacobus J. , Scherzer Clemens R. , Singleton Andrew B. , Nalls Mike A.
Published: March 2019

Background

Several reports have identified different patterns of Parkinson’s disease progression in individuals carrying missense variants in theGBAorLRRK2genes. The overall contribution of genetic factors to the severity and progression of Parkinson’s disease, however, has not been well studied.

Objectives

To test the association between genetic variants and the clinical features and progression of Parkinson’s disease on a genome-wide scale.

Methods

We accumulated individual data from 12 longitudinal cohorts in a total of 4,093 patients with 25,254 observations over a median of 3.81 years. Genome-wide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently-identified disease risk variants, were also investigated for the associations with these phenotypes.

Results

Two variants were genome-wide significant. Rs382940(T>A), within the intron ofSLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (HR 2.04 [1.58, 2.62], P-value = 3.46E-8). Rs61863020(G>A), an intergenic variant and eQTL forADRA2A, was associated with a lower prevalence of insomnia at baseline (OR 0.63 [0,52, 0.75], P-value = 4.74E-8). In the targeted analysis, we found nine associations between known Parkinson’s risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports ofGBAcoding variants (rs2230288: p.E365K, rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, andAPOEE4 tagging variant (rs429358) being associated with greater cognitive deficits in patients.

Conclusions

We identified novel genetic factors associated with heterogeneity of progression in Parkinson’s disease. The results provide new insights into the pathogenesis of Parkinson’s disease as well as patient stratification for clinical trials.
Genetic structure of prey populations underlies the geographic mosaic of arms race coevolution
Authors: Hague Michael T.J. , Stokes Amber N. , Feldman Chris R. , Brodie Edmund D. , Brodie Edmund D.
Published: March 2019

Reciprocal adaptation is the hallmark of arms race coevolution, but the symmetry of evolutionary change between interacting species is often untested, even in the best-studied battles of natural enemies. We tested whether prey and predator exhibit symmetrical local co-adaptation in the example of a geographic mosaic of coevolution between toxic newts (Taricha granulosa) and resistant garter snakes (Thamnophis sirtalis). Prior work showing a tight correlation between levels of newt toxin and snake resistance is regarded as textbook evidence of the intense arms race between natural enemies. Here, we similarly found that toxin and resistance are functionally matched in prey and predator populations, further suggesting that mosaic variation in the armaments of both species results from the local pressures of reciprocal selection. Contrary to conventional wisdom, however, we found that local variation in newt toxin is best predicted by neutral population divergence rather than the resistance of co-occurring predators. Snake resistance, on the other hand, is clearly explained by local levels of prey toxin. Prey populations seem to structure variation in defensive toxin levels across the geographic mosaic, which in turn determines selection on predator resistance. Exaggerated armaments suggest that coevolution occurs in certain hotspots, but our results imply that neutral processes like gene flow—rather than reciprocal adaptation—structure the greatest source of variation across the landscape. This pattern supports the predicted role of “trait remixing” in the geographic mosaic of coevolution, the process by which non-adaptive forces dictate spatial variation in the interactions among species.

SIGNIFICANCE STATEMENT

When the weapons of natural enemies like prey toxins and predator resistance are matched across the geographic landscape, they are usually presumed to result from arms race coevolution. In the textbook example of an arms race, matched levels of newt toxin and garter snake resistance have long been regarded as evidence of such local co-adaptation. To the contrary, we found that local variation in newt toxicity is best explained by the neutral geographic structure of newt populations. This spatial variation of prey in turn dictates local selection on garter snakes, structuring the geographic pattern of predator resistance. These results demonstrate how landscape patterns of phenotypic variation are determined by a mixture of natural selection, historical biogeography, and gene flow that comprise the geographic mosaic of coevolution.
A multi-omic cohort as a reference point for promoting a healthy human gut microbiome
Authors: Jie Zhuye , Liang Suisha , Ding Qiuxia , Li Fei , Tang Shanmei , Wang Dan , Lin Yuxiang , Chen Peishan , Cai Kaiye , Qiu Xuemei , Li Qiang , Liao Yunli , Zhou Dongsheng , Lian Heng , Zuo Yong , Chen Xiaomin , Rao Weiqiao , Ren Yan , Wang Yuan , Zi Jin , Wang Rong , Zhou Hongcheng , Lu Haorong , Wang Xiaohan , Zhang Wei , Zhang Tao , Xiao Liang , Zong Yang , Liu Weibin , Yang Huanming , Wang Jian , Hou Yong , Liu Xiao , Kristiansen Karsten , Zhong Huanzi , Jia Huijue , Xu Xun
Published: March 2019

More than a decade of gut microbiome studies have a common goal for human health. As most of the disease studies sample the elderly or the middle-aged, a reference cohort for young individuals has been lacking. It is also not clear what other omics data need to be measured to better understand the gut microbiome. Here we present high-depth metagenomic shotgun sequencing data for the fecal microbiome together with other omics data in a cohort of 2,183 adults, and observe a number of vitamins, hormones, amino acids and trace elements to correlate with the gut microbiome and cluster with T cell receptors. Associations with physical fitness, sleeping habits and dairy consumption are identified in this large multi-omic cohort. Many of the associations are validated in an additional cohort of 1,404 individuals. Our comprehensive data are poised to advise future study designs to better understand and manage our gut microbiome both in population and in mechanistic investigations.
Germline features associated with immune infiltration in solid tumors
Authors: Shahamatdar Sahar , He Meng Xiao , Reyna Matthew , Gusev Alexander , AlDubayan Saud H. , Van Allen Eliezer M. , Ramachandran Sohini
Published: March 2019

Given the clinical success of immune checkpoint blockade (ICB) across a diverse set of solid tumors, and the emerging role for different immune infiltrates in contributing to response to ICB, a comprehensive assessment of the properties that dictate immune infiltrations may reveal new biological insights and inform the development of new effective therapies. Multiple studies have examined somatic and functional immune properties associated with different tumor infiltrates; however, germline features that associate with specific immune infiltrates in cancers have been incompletely characterized. Here, we analyzed over 7 million autosomal germline variants in the TCGA cohort (5788 European-ancestry samples across 30 cancer types) and tested for pan-cancer association with established immune-related phenotypes that describe the tumor immune microenvironment. We identified: one SNP associated with the fraction of follicular helper T cells in bulk tumor; 77 unique candidate genes, some of which are involved in cytokine-mediated signaling (e.g. CNTF and TRIM34) and cancer pathogenesis (e.g. ATR and AKAP9); and subnetworks with genes that are part of DNA repair (RAD51 and XPC) and transcription elongation (CCNT2) pathways. We found a positive association between polygenic risk for rheumatoid arthritis and absolute fraction of infiltrating CD8 T cells. Overall, we identified multiple germline genetic features associated with specific tumor-immune phenotypes across cancer, and developed a framework for probing inherited features that contribute to variation in immune infiltration.
Bacterial biodiversity drives the evolution of CRISPR-based phage resistance in Pseudomonas aeruginosa
Authors: Alseth Ellinor O , Pursey Elizabeth , Luján Adela M , McLeod Isobel , Rollie Clare , Westra Edze R
Published: March 2019

Approximately half of all bacterial species encode CRISPR-Cas adaptive immune systems1, which provide immunological memory by inserting short DNA sequences from phage and other parasitic DNA elements into CRISPR loci on the host genome2. Whereas CRISPR loci evolve rapidly in natural environments3, bacterial species typically evolve phage resistance by the mutation or loss of phage receptors under laboratory conditions4,5. Here, we report how this discrepancy may in part be explained by differences in the biotic complexity of in vitro and natural environments6,7. Specifically, using the opportunistic pathogen Pseudomonas aeruginosa and its phage DMS3vir, we show that coexistence with other human pathogens amplifies the fitness trade-offs associated with phage receptor mutation, and therefore tips the balance in favour of CRISPR-based resistance evolution. We also demonstrate that this has important knock-on effects for P. aeruginosa virulence, which became attenuated only if the bacteria evolved surface-based resistance. Our data reveal that the biotic complexity of microbial communities in natural environments is an important driver of the evolution of CRISPR-Cas adaptive immunity, with key implications for bacterial fitness and virulence.
Formalizing metabolic-regulatory networks by hybrid automata
Authors: Liu Lin , Bockmayr Alexander
Published: March 2019

Computational approaches in systems biology have become a powerful tool for understanding the fundamental mechanisms of cellular metabolism and regulation. However, the interplay between the regulatory and the metabolic system is still poorly understood. In particular, there is a need for formal mathematical frameworks that allow analyzing metabolism together with dynamic enzyme resources and regulatory events. Here, we introduce a metabolic-regulatory network model (MRN) that allows integrating metabolism with transcriptional regulation, macromolecule production and enzyme resources. Using this model, we show that the dynamic interplay between these different cellular processes can be formalized by a hybrid automaton, combining continuous dynamics and discrete control.
Morphological variation inBlommersiapelvic shape coincides with muscular architecture and parallels genus phylogenetic evolution
Authors: Santos-Santos Javier H. , Guinovart-Castán Mireia , Vieites David R.
Published: March 2019

“This manuscript has been withdrawn by the authors as it was submitted without appropriate permission. If you have any questions, please contact the corresponding author.”
Genetic dissection of the redundant and divergent functions of histone chaperone paralogs in yeast
Authors: Savic Neda , Shortill Shawn P. , Bilenky Misha , Dilworth David , Hirst Martin , Nelson Christopher J.
Published: March 2019

Gene duplications increase organismal robustness by providing freedom for gene divergence or by increasing gene dosage. The yeast histone chaperones Fpr3 and Fpr4 are paralogs that can assemble nucleosomesin vitro, however the genomic locations they target and their functional relationship is poorly understood. We refined the yeast synthetic genetic array (SGA) approach to enable the functional dissection of gene paralogs. Applying this method to Fpr3 and Fpr4 uncovered their redundant and divergent functions: while Fpr3 is uniquely involved in chromosome segregation, Fpr3 and Fpr4 co-operate on some genes and are redundant on others where they impact gene expression and transcriptional processivity. We find that the TRAMP5 RNA exosome is essential inΔfpr3Δfpr4yeast and leverage this information to identify Fpr3/4 target loci. Amongst these are the non-transcribed spacers of ribosomal DNA where either paralog is sufficient to establish chromatin that is both transcriptionally silent and refractory to recombination. These data provide evidence that Fpr3 and Fpr4 have shared chromatin-centric functions, especially at nucleolar rDNA. However, their distinct genetic interaction profiles show they also have evolved separate functions outside of the nucleolus.
Estimating Diversity Through Time using Molecular Phylogenies: Old and Species-Poor Frog Families are the Remnants of a Diverse Past
Authors: Billaud O. , Moen D. S. , Parsons T. L. , Morion H.
Published: March 2019

Estimating how the number of species in a given group varied in the deep past is of key interest to evolutionary biologists. However, current phylogenetic approaches for obtaining such estimates have limitations, such as providing unrealistic diversity estimates at the origin of the group. Here we develop a robust probabilistic approach for estimating Diversity-Through-Time (DTT) curves and uncertainty around these estimates from phylogenetic data. We show with simulations that under various realistic scenarios of diversification, this approach performs better than previously proposed approaches. We also characterize the effect of tree size and undersampling on the performance of the approach. We apply our method to understand patterns of species diversity in anurans (frogs and toads). We find that Archaeobatrachia – a species-poor group of old frog clades often found in temperate regions – formerly had much higher diversity and net diversification rate, but the group declined in diversity as younger, nested clades diversified. This diversity decline seems to be linked to a decline in speciation rate rather than an increase in extinction rate. Our approach, implemented in the R package RPANDA, should be useful for evolutionary biologists interested in understanding how past diversity dynamics have shaped present-day diversity. It could also be useful in other contexts, such as for analyzing clade-clade competitive effects or the effect of species richness on phenotypic divergence. [phylogenetic comparative methods; birth-death models; diversity curves; diversification; extinction; anurans]
The mechanisms of dynamin-actin interaction
Authors: Zhang Ruihui , Gerassimov Nathalie , Lee Donghoon M. , Jimah John R. , Kim Sangjoon , Luvsanjav Delgermaa , Winkelman Jonathan , Mettlen Marcel , Abrams Michael E. , Kalia Raghav , Keene Peter , Pandey Pratima , Ravaux Benjamin , Kim Ji Hoon , Ditlev Jonathon A. , Zhang Guofeng , Rosen Michael K. , Frost Adam , Alto Neal M. , Gardel Margaret , Schmid Sandra L. , Hinshaw Jenny E. , Chen Elizabeth H.
Published: March 2019

Cell-cell fusion is an indispensable process in the conception, development and physiology of multicellular organisms. Here we demonstrate a direct and noncanonical role for dynamin, best known as a fission GTPase in endocytosis, in cell-cell fusion. Our genetic and cell biological analyses show that dynamin colocalizes within the F-actin-enriched podosome-like structures at the fusogenic synapse, which is required for generating invasive membrane protrusions and myoblast fusion in vivo, in an endocytosis-independent manner. Biochemical, negative stain EM and cryo-electron tomography (cryo-ET) analyses revealed that dynamin forms helices that directly bundles actin filaments by capturing multiple actin filaments at their outer rim via interactions with dynamin’s proline-rich domain. GTP hydrolysis by dynamin triggers disassembly of the dynamin helix, exposes the sides of the actin filaments, promotes dynamic Arp2/3-mediated branched actin polymerization, and generates a mechanically stiff actin network. Thus, dynamin functions as a unique actin-bundling protein that enhances mechanical force generation by the F-actin network in a GTPase-dependent manner. Our findings have universal implications for understanding dynamin-actin interactions in various cellular processes beyond cell-cell fusion.
FcγRIIB I232T polymorphic change allosterically suppresses ligand binding
Authors: Hu Wei , Zhang Yong , Sun Xiaolin , Xu Liling , Xie Hengyi , Li Zhanguo , Liu Wanli , Lou Jizhong , Chen Wei
Published: March 2019

FcγRIIB bindings to its ligand suppress immune cell activation. A single-nucleotide polymorphic (SNP) change, I232T, in the transmembrane (TM) domain of FcγRIIB loses its suppression function, which clinically associates with systemic lupus erythematosus (SLE). Previously, we reported that I232T tilts FcγRIIB’s TM domain. In this study, combining with molecular dynamics simulations and single-cell FRET assay, we further revealed that such tilting by I232T unexpectedly bends the FcγRIIB’s ectodomain towards plasma membrane to allosterically impede FcγRIIB’s ligand association. We then used single-cell biomechanical assay to further find out that I232T also reduces two-dimensional in-situ binding affinities and association rates of FcγRIIB interacting with its ligands by three-folds. This allosteric regulation by a SNP provides an intrinsic molecular mechanism for functional loss of FcγRIIB-I232T in SLE patients.
Automated reconstruction of all gene histories in large bacterial pangenome datasets and search for co-evolved gene modules with Pantagruel
Authors: Lassalle Florent , Veber Philippe , Jauneikaite Elita , Didelot Xavier
Published: March 2019

The availability of bacterial pangenome data grows exponentially, requiring efficient new methods of analysis. Currently popular approaches for the fast comparison of genomes have the drawback of not being based on explicit evolutionary models of diversification. Making sense of bacterial genome evolution, and notably in the accessory genome, requires however to take into account the complex processes by which the genomes evolve. Here we present the Pantagruel bioinformatic software pipeline, which enables the construction of a complete bacterial pangenome database geared towards the inference of gene evolution scenarios using gene tree/species tree reconciliation. Pantagruel is a modular pipeline that combines state-of-the-art external software with unique new methods. It can be executed with no supervision to perform a standard pangenome analysis, or be configured by advanced users to integrate methods of choice. A relational database underlies its data structure, allowing efficient retrieval of the large-scale data generated by integrative analyses of pangenome evolutionary history. From the reconstructed gene evolution scenarios, two main outputs are derived: firstly the gene tree-aware assignation of orthology, allowing the fine analysis of gene gain and loss history over the species phylogeny, and secondly a network of gene-to-gene association based on correlated events in scenarios of gene evolution, leading to the definition of co-evolved gene modules. Pantagruel is available as an open source software package at https://github.com/flass/pantagruel.