bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life outcomes after endoscopic approaches to intracranial tumors
Authors: Schaberg Madeleine R.
Published: November 2017

Purpose of review

To review the literature on quality of life (QOL) in endoscopic approaches to anterior and central intracranial skull-base disease. As endoscopic surgical techniques have gained widespread acceptance and complications and morbidity remain low and comparable with microscopic and open approaches, a shift to focusing on patients’ perception of their own well being as an important outcome parameter has been made. In addition to the traditional measurements of surgical outcomes (extent of resection, recurrence rate, morbidity, survival, and complication rate), the success of a surgery can now be assessed using QOL measures.

Recent findings

The main tools for assessing QOL in endoscopic skull-base surgery (anterior skull-base questionnaire and 22-item sinonasal outcome test) were not specifically designed for endoscopic skull-base approaches, and recently, a new tool was introduced and validated, the skull-base inventory, adding to our armamentarium, but it has not yet been widely employed. Endoscopic skull-base surgery leads to improved or sustained long-term QOL overall but it is significantly influenced by tumor disease. Specific endoscopic surgical technique (such as nasoseptal flap closure) appears to have less impact on QOL.

It is becoming critical to assess therapeutic interventions in terms of impact on a patient's QOL. QOL can be useful in comparing efficacy of surgical interventions, and in the future, it will likely become a reportable indicator of surgical outcome and guide our surgical technique recommendations. Large-scale prospective multicenter trials would be beneficial.
Safety of Appetite Manipulation in Children with Feeding Disorders Admitted to an Inpatient Feeding Program
Authors: Pollow Alyssa S. , Karls Catherine A. , Witzlib Mary , Noel Richard J. , Goday Praveen S. , Silverman Alan H.
Published: November 2017

Objective:

Appetite manipulation can be effective in weaning children off gastrostomy tube feeding dependence but can cause dehydration, hypoglycaemia, and ketone body production, which is anorexigenic. As the safety of this approach has not been described, our aim was to describe adverse events observed when weaning children from G‐tube dependence using our appetite manipulation protocol.

Methods:

This was a retrospective study of prospectively collected data of patients who completed our inpatient tube‐weaning protocol. Daily safety parameters included twice‐daily urine specific gravities and urine ketones and fasting capillary blood glucose. Graded clinical interventions to manage adverse events were collected.

Results:

A total of 143 children with a mean age of 4.8 ± 2.4 years were seen in the inpatient feeding program of which 74 (51.7%) were male. The children were hospitalized 10.1 ± 2.5 days with the vast majority being discharged between days 11 and 14. Overall, 78.2% of patients experienced at least 1 adverse event: urine specific gravity >1.020 was seen in 60.5%, ketonuria in 48.9%, and hypoglycemia (⩽60 mg/dL) in 13.4%. Only 2 children had blood glucose levels <40 mg/dL and these were corrected with oral supplementation. Graded clinical interventions to manage adverse events included oral rehydration in 89.9% of children and supplemental tube feeding in 25.2%.

Conclusions:

Adverse effects are common when appetite manipulation is used to wean children off G‐tube dependence. Anticipating, monitoring, and having a clear intervention plan in a closely monitored setting are necessary to safely use this method.
The Role of Combination Therapy in Pediatric Inflammatory Bowel Disease
Authors: Day Andrew S. , Gulati Ajay S. , Patel Nishaben , Boyle Brendan , Park K.T. , Saeed Shehzad A.
Published: November 2017

The treatment goal for children suffering from inflammatory bowel disease has been evolving with biologic therapies like anti‐tumor necrosis factor agents assuming a more central role in treatment of more aggressive and extensive phenotype. Earlier introduction of anti‐tumor necrosis factor agents have shown to be more effective and may even alter the natural history of inflammatory bowel disease. Development of anti‐drug antibodies, however, limits long‐term usage and leads to dose adjustment in almost half of patients treated with these medications. One of the strategies to minimize the development of anti‐drug antibodies has been concomitant use of immunomodulator medications, resulting in fewer infusion reactions and sustained trough levels, potentially lowering the need for dose adjustments. Balanced with these benefits of optimized dosing and likely more sustained response, however, is the concern about increased risk of complications, such as infections and malignancies. The current manuscript reviews the available pediatric literature regarding efficacy, safety, and side effect profile of combination (immunomodulator and biologics) therapy in pediatric Crohn disease and ulcerative colitis, with particular emphasis on cost constraints, and recommendations for selection of patients who would benefit most from combination therapy.
Recurrent Acute Chest Syndrome in Pediatric Sickle Cell Disease: Clinical Features and Risk Factors
Authors: Patterson Gaylen D. , Mashegu Hafsat , Rutherford Jordan , Seals Samantha , Josey David , Karlson Cynthia , McNaull Melissa , May Warren , Carroll Clinton , Barr Frederick E. , Majumdar Suvankar
Published: December 2017

Acute chest syndrome (ACS) is a common and serious lung complication in sickle cell disease. A retrospective medical chart review was performed over a 6-year period in all pediatric ACS patients to investigate whether factors during the initial hospitalization were associated with recurrent ACS episodes. There were 386 episodes of ACS: 149 had only 1 episode of ACS, and 76 had >1 episode of ACS; 172 (76.4%) had hemoglobin SS, and 39 (17.3%) had hemoglobin SC. The most common presenting features were fever (83%), pain (70%), and cough (61%), which changed with the number of ACS episodes. Children <4 years old were at greatest risk of recurrent ACS (P=0.018). In addition, history of asthma (adjusted incident rate ratio [IRR]=1.52; 95% confidence interval [CI], 1.22-1.98; P<0.0001), shortness of breath (IRR, 1.29; 95% CI, 1.02-1.62; P=0.033), and length of hospital stay (IRR, 1.04; 95% CI, 1.01-1.08; P=0.017) were significantly associated with prospective ACS events. Multiple episodes of ACS are common in sickle cell disease, and certain risk factors during the initial hospitalization are associated with recurrent ACS.
Creativity and Innovation in Health Care
Authors: Zuber Christi Dining , Moody Louise
Published: December 2017

There is an increasing drive in health care for creativity and innovation to tackle key health challenges, improve quality and access, and reduce harm and costs. Human-centered design (HCD) is a potential approach to achieving organizational innovation. However, research suggests the nursing workforce feels unsupported to take the risks needed for innovation, and leaders may not understand the conditions required to fully support them. The aim of this study was to identify enabling conditions that support frontline nurses in their attempts to behave as champions of innovation and change. An HCD workshop was undertaken with 125 nurses employed in clinical practice at Kaiser Permanente. The workshop included empathy mapping and semistructured questions that probed participant experiences with innovation and change. The data were collated and thematic analysis undertaken through a Grounded Theory approach. The data were analyzed to identify key enabling conditions. Seven enablers emerged: personal need for a solution; challenges that have meaningful purpose; clarity of goal and control of resources; active experimentation; experiences indicating progress; positive encouragement and confidence; and provision of psychological safety. These enablers were then translated into pragmatic guidelines for leaders on how the tools of HCD may be leveraged for innovation and change in health care.
Allergic Colitis With Pneumatosis Intestinalis in an Infant
Authors: Liu Helena , Turner Troy W.S.
Published: November 2017

Inflammatory causes of bloody diarrhea during infancy include necrotizing enterocolitis and allergic colitis, often due to cow’s milk protein. We report this case of cow’s milk protein allergy, managed successfully with elimination of dietary antigen, to highlight the unusual finding of pneumatosis intestinalis on abdominal x-ray, a radiographic hallmark associated with necrotizing enterocolitis. Detailed patient’s history, clinical presentation, and physical examinations are discussed for cow’s milk protein allergy and necrotizing enterocolitis.
Effects of Platelet-Rich Plasma on Pain and Muscle Strength in Patients With Knee Osteoarthritis
Authors: Wu Yung-Tsan , Hsu Kao-Chih , Li Tsung-Ying , Chang Cheng-Kuang , Chen Liang-Cheng
Published: November 2017

Objective

No studies comparing the effects of platelet-rich plasma (PRP) injection and placebo injection in bilateral knee osteoarthritis in the same patient, or discussing muscle strength after PRP injection, have been published.

Design

Twenty patients with bilateral knee osteoarthritis were eligible, and 40 knees were randomized into two groups: PRP (knees [right or left by a coin toss] receiving a single intra-articular PRP injection) and saline group (the contralateral knee of the same patient, into which single 4-mL intra-articular injection of normal saline was administered). The primary outcome measure was Western Ontario and McMaster's Universities Osteoarthritis Index and the secondary included isokinetic test results. The evaluation was at baseline and at 2 wks, 1, 3, and 6 mos after injection.

Results

The PRP group showed a significant reduction in the Western Ontario and McMaster's Universities Osteoarthritis Index pain and total scores compared with normal saline group (P < 0.05). Although a significantly greater percentage of knee strength (extensor > flexor) was found in the PRP group during a longer follow-up period, PRP treatment resulted in insignificant differences in muscle strength compared with normal saline.

Conclusions

Platelet-rich plasma treatment significantly improves pain, stiffness, and disability in patients with knee osteoarthritis compared with normal saline treatment. Additional strength training is recommended to enhance muscle strength recovery.
Prescription Opioid Use among Opioid-Naive Women Undergoing Immediate Breast Reconstruction
Authors: Marcusa Daniel P. , Mann Rachel A. , Cron David C. , Fillinger Brooklyn R. , Rzepecki Alexandra K. , Kozlow Jeffrey H. , Momoh Adeyiza , Englesbe Michael , Brummett Chad , Waljee Jennifer F.
Published: November 2017

Background:

Cancer patients may be particularly vulnerable to the deleterious effects of prolonged opioid use. The authors explored the factors that influence postoperative opioid prescription fills among women following postmastectomy reconstruction.

Methods:

Using the Truven Health MarketScan Research Databases, the authors identified a cohort of 4113 opioid-naive patients undergoing mastectomy and immediate breast reconstruction between January of 2010 and August of 2014. Outcomes included average daily oral morphine equivalents and the incidence of prolonged opioid fills (between 90 and 120 days after surgery). Using multivariable regression, the authors examined the effect of patient demographic characteristics, reconstructive technique, comorbid medical and psychiatric conditions, and postoperative complications on outcome variables.

Results:

In this cohort, 90 percent of patients filled opioid prescriptions perioperatively, and 10 percent continued to fill prescriptions beyond 3 months after surgery. Patients with depression were more likely to fill prescriptions of higher average daily oral morphine equivalents (74.2 mg versus 58.3 mg; p < 0.01), and patients with anxiety were more likely to fill opioids for prolonged periods (13.4 percent versus 9.1 percent; p < 0.01). Patients undergoing autologous free flap reconstruction were less likely to fill prescriptions for a prolonged period following surgery (5.9 percent versus 10.2 percent; p < 0.001).

Conclusions:

Prescription opioid fills are common following breast reconstruction, and 10 percent of all patients continue to fill opioid prescriptions beyond 3 months after surgery. Prolonged fills are influenced by both patient factors and surgical procedure, and attention should be directed toward identifying opioid alternatives when possible.

CLINCAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Evidence-Based Performance Measures: Quality Metrics for the Care of Patients Undergoing Breast Reconstruction
Authors: Manahan Michele A. , Wooden William A. , Becker Stephen M. , Cacioppo Jason R. , Edge Stephen B. , Grandinetti Amanda C. , Gray Diedra D. , Holley Susan O. , Karp Nolan S. , Kocak Ergun , Rao Roshni , Rosson Gedge D. , Schwartz Jaime S. , Sitzman Thomas J. , Soltanian Hooman T. , TerKonda Sarvam P. , Wallace Anne M.
Published: November 2017

The American Society of Plastic Surgeons commissioned the Breast Reconstruction Performance Measure Development Work Group to identify and draft quality measures for the care of patients undergoing breast reconstruction surgery. Two outcome measures were identified. The first desired outcome was to reduce the number of returns to the operating room following reconstruction within 60 days of the initial reconstructive procedure. The second desired outcome was to reduce flap loss within 30 days of the initial reconstructive procedure. All measures in this report were approved by the American Society of Plastic Surgeons Breast Reconstruction Performance Measures Work Group and the American Society of Plastic Surgeons Executive Committee. The Work Group recommends the use of these measures for quality initiatives, Continuing Medical Education, Maintenance of Certification, American Society of Plastic Surgeons’ Qualified Clinical Data Registry reporting, and national quality reporting programs.
Medication Adherence in a Nationwide Cohort of Veterans Initiating Pre-exposure Prophylaxis (PrEP) to Prevent HIV Infection
Authors: van Epps Puja , Maier Marissa , Lund Brian , Howren Matthew Bryant , Beck Brice , Beste Lauren , Skolnik Avy , Vaughan-Sarrazin Mary , Ohl Michael E.
Published: November 2017

Background:

Current guidelines for pre-exposure prophylaxis (PrEP) to prevent HIV infection call for long-term, daily use of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). Little is known about long-term adherence with TDF/FTC prescribed for PrEP in routine clinical practice.

Setting:

Veterans Health Administration (VHA) clinics.

Methods:

We used VHA data to create a nationwide cohort of Veterans initiating PrEP between July 1, 2012, and June 30, 2016. We examined pharmacy refill data to estimate adherence based on the proportion of days covered (PDC) by TDF/FTC in the first year and used logistic regression to identify patient characteristics associated with high adherence (ie, PDC >0.8). We also quantified how often Veterans discontinued PrEP in the first year, based on a gap of 120 days or more in medication possession.

Results:

Among 1086 individuals initiating PrEP, the median PDC for TDF/FTC in the first year was 0.74 (interquartile range 0.40–0.92). In multivariable analysis, high adherence was associated with older age (odds ratio 1.97; 1.41–2.74 for age 50–64 compared with <35), white compared with black race (odds ratio 2.12; 1.53–2.93), and male sex (odds ratio 3.39; 1.37–8.42). Forty-four percent discontinued PrEP in the first year.

Conclusions:

First-year adherence with TDF/FTC was overall high in a nationwide cohort of PrEP users. Differences in adherence by age, race, and sex suggest potential for disparities in PrEP effectiveness in routine clinical practice.
High Acceptability and Increased HIV-Testing Frequency After Introduction of HIV Self-Testing and Network Distribution Among South African MSM
Authors: Lippman Sheri A. , Lane Tim , Rabede Oscar , Gilmore Hailey , Chen Yea-Hung , Mlotshwa Nkuli , Maleke Kabelo , Marr Alexander , McIntyre James A.
Published: November 2017

Background:

South African men who have sex with men (MSM) have a high burden of undiagnosed HIV infection and HIV-testing rates incommensurate with their risk. HIV self-testing (HIVST) may increase testing uptake, frequency, and earlier HIV detection and treatment.

Setting:

Gert Sibande and Ehlanzeni districts, Mpumalanga Province, South Africa.

Methods:

We conducted a longitudinal HIVST study among MSM between June 2015 and May 2017. Overall 127 HIV-negative MSM were provided with up to 9 test kits of their choice—oral fluid or blood fingerstick—to use themselves and distribute to their networks. Surveys conducted 3- and 6-month post–enrollment elicited information on HIVST experiences, preferences, acceptability, utilization, and distribution. We used generalized estimating equations to assess changes in testing frequency.

Results:

Ninety-one percent of participants self-tested. All participants who self-tested reported being likely to self-test again, with over 80% preferring HIVST to clinic-based testing. Fingerstick was preferred to oral fluid tests by approximately 2:1. Returning participants distributed 728 tests to sexual partners (18.5% of kits), friends (51.6%), and family (29.8%). Six participants seroconverted during the study, and 40 new diagnoses were reported among test recipients. Frequent (semi-annual) testing increased from 37.8% before the study to 84.5% at follow-up (P < 0.001), and participants reported anticipated frequent testing of 100% if HIVST were available compared with 84% if only clinic-testing were available in the coming year (P < 0.01).

Conclusions:

HIVST use and network distribution is acceptable and feasible for MSM in South Africa and can increase testing uptake and frequency, potentially improving early detection among MSM and their networks.
Increased Delay Between Gadolinium Chelate Administration and T1-Weighted Magnetic Resonance Imaging Acquisition Increases Contrast-Enhancing Tumor Volumes and T1 Intensities in Brain Tumor Patients
Authors: Piechotta Paula L. , Bonekamp David , Sill Martin , Wick Antje , Wick Wolfgang , Bendszus Martin , Kickingereder Philipp
Published: November 2017

Objectives

The aim of this study was to evaluate the impact of delayed T1-weighted (T1-w) MRI acquisition after gadolinium chelate administration on brain tumor volumes and T1-w intensities.

Materials and Methods

Fifty-five patients with histologically confirmed, contrast-enhancing intra-axial brain tumors were analyzed in this prospective test-retest study. Patients underwent 2 consecutive 3 T MRI scans (separated by a 1-minute break) during routine follow-up with contrast-enhanced T1 (ceT1-w), T2, and FLAIR acquisition. Macrocyclic gadolinium chelate–based contrast agent was only administered before the first ceT1-w acquisition; median latency to ceT1-w acquisition was 6.72 minutes (IQR, 6.53–6.92) in the first and 16.27 minutes (IQR, 15.49–17.26) in the second scan. Changes in tumor volumes and relative ceT1-w intensities between the 2 acquisitions were quantitatively assessed following semiautomated tumor segmentation (separately for contrast-enhancement [CE], necrosis [NEC], and nonenhancing [NE] tumor).

Results

Semiautomatically segmented CE tumor volumes were significantly larger in the second acquisition (median +32% [1.2 cm3]; IQR, 16%–62%; P < 0.01), which corresponded to a 10% increase in CE tumor diameter (+0.3 cm). Contrarily, NEC and NE tumor volumes were significantly smaller (median −24% [IQR, −36% to −54%], P < 0.01 for NEC and −2% [IQR, −1% to −3%], P = 0.02 for NE tumor). Bland-Altman plots confirmed a proportional bias toward higher CE and lower NEC volumes for the second ceT1-w acquisition. Relative ceT1-w intensities for both early- (regions already enhancing in the first scan) and late-enhancing (newly enhancing regions in the second scan) tumor were significantly increased in the second acquisition (by 5.8% and 27.3% [P < 0.01, respectively]). Linear-mixed effects modeling confirmed that the increase in CE volumes and CE intensities is a function of the interval between contrast agent injection and ceT1-w acquisition (P < 0.01 each).

Conclusions

Our study indicates that the maximum extent of CE tumor volumes and intensities may increase beyond the time frame of 4 to 8 minutes after contrast agent injection and potentially affects the diagnosis of progressive or recurrent disease because late-enhancing recurrent disease might not be unequivocally detected on standard follow-up MRI.
Optic Disc Edema in Glial Fibrillary Acidic Protein Autoantibody–Positive Meningoencephalitis
Authors: Chen John J. , Aksamit Allen J. , McKeon Andrew , Pittock Sean J. , Weinshenker Brian G. , Leavitt Jacqueline A. , Morris Padraig P. , Flanagan Eoin P.
Published: November 2017

Background:

Glial fibrillary acidic protein (GFAP) autoantibody–positive meningoencephalitis is a newly described entity characterized by a corticosteroid-responsive meningoencephalomyelitis. Some patients with GFAP autoantibody–positive meningoencephalitis have been found to have optic disc edema, which has previously not been well characterized.

Methods:

We performed a retrospective, observational case series of Mayo Clinic patients found to have GFAP-IgG and optic disc edema from January 1, 2000, to December 31, 2016. We identified 40 patients with GFAP-IgG seropositivity by tissue-based immunofluorescence and cell-based assay. Patients were screened for the following inclusion criteria: 1) serum, cerebrospinal fluid, or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining with confirmation of IgG reactive with specific GFAPα isoform by cell-based assay; 2) meningoencephalitis or encephalitis; and 3) optic disc edema. We excluded those with coexisting aquaporin-4-IgG or insufficient clinical information.

Results:

Ten patients had optic disc edema and met inclusion criteria. The median age was 39.5 years and 60% were men. Visual acuity was unaffected and disc edema was bilateral in all cases. Mild vitreous cell was noted in 3 patients. The optic disc edema resolved with corticosteroid treatment but resulted in mild optic atrophy in 2 patients. The median lumbar puncture opening pressure was 144 mm H2O (range, 84–298 mm H2O). Brain MRI revealed radial perivascular enhancement in all except 1 patient. Fluorescein angiography was available for 1 patient with optic disc edema, which showed leakage from the venules.

Conclusions:

Patients with GFAP autoantibody–positive meningoencephalitis can have optic disc edema that can mimic papilledema. The cause of the optic disc edema remains uncertain, but most patients did not have raised intracranial pressure.
Comparison of Heart Rate Variability Parameters to the Autonomic Reflex Screen in Postural Orthostatic Tachycardia Syndrome and Neurogenic Orthostatic Hypotension
Authors: Baker Jacquie , Racosta Juan M. , Kimpinski Kurt
Published: November 2017

Purpose:

The clinical significance of heart rate variability (HRV) in the context of autonomic dysfunction continues to be a matter of debate. Therefore, the purpose of the current study was to investigate the clinical relevance of HRV in the context of autonomic dysfunction.

Methods:

Heart rate variability data from 225 volunteers consisting of controls (n = 166) and patients with mild (n = 25) and severe (n = 34) autonomic dysfunction were retrospectively analyzed. Time and frequency parameters were correlated against baseline and standardized tests of autonomic function.

Results:

During baseline, resting HR was negatively correlated with time (SD of all normal RR interval, r = −0.511; RMSSD, r = −0.585; pNN50, r = −0.545) and frequency (low-frequency, r = −0.362; high-frequency, r = −0.421) parameters (P < 0.01). Resting systolic blood pressure demonstrated similar significant correlations (P < 0.01). During head-up tilt, SD of all normal RR intervals was positively correlated with ∆HR and change in systolic blood pressure (r = 0.340; r = 0.538, respectively; P < 0.01). Similarly, low-frequency, high-frequency, and low-frequency/high-frequency ratios were correlated with ∆HR (r = 0.422, r = 0.176, r = 0.470) and change in systolic blood pressure (r = 0.451, r = 0.407, and r = 0.185) (P < 0.01). Time parameters (SD of all normal RR intervals, RMSSD, and pNN50) were all significantly correlated with deep breathing (r = 0.600; r = 0.556; r = 0.516; P < 0.01, respectively). Low-frequency and high-frequency power were also correlated (r = 0.596; r = 0.580, respectively) (P < 0.01).

Conclusions:

Time and frequency parameters showed significant negative correlations with baseline hemodynamics. During a test of sympathetic activation and parasympathetic withdrawal, this relationship shifted to reveal significant positive correlations between HRV parameters and hemodynamics. Last, during a test of parasympathetic activation, there were significant positive correlations with cardiovagally mediated HRV parameters. Overall, these results suggest broader clinical relevance for HRV parameters within the spectrum of autonomic functioning.
Extended "Constant Field" equations: an electrodiffusion model of NMDA receptors
Authors: Moradi Keivan , Moradi Kamran , Bakouie Fatemeh , Gharibzadeh Shahriar
Published: November 2017

Ion channels are experimentally divided into Ohmic and non-Ohmic channels. Similarly, a theoretical dichotomy exists in the flux equations of these channels. The "constant field" or "Goldman-Hodgkin and Katz" current equation is a commonly accepted analytic model of electrodiffusion in channels. This equation, however, seems to have some shortcomings, such as the inability to explain the nonlinear relation between the single channel current and the membrane potential in non-Ohmic channels. In this study, we introduce the "general" and "extended" versions of this equation that are applicable to both Ohmic and non-Ohmic channels. Our results showed the ability of these equations to simulate the NMDA receptor current, as a non-Ohmic channel, not only in the symmetric "uni-ionic" solutions but also in the asymmetric "bi-ionic" solutions of sodium and calcium ions. Our equations reveal for the first time that sodium ions like calcium ions are able to block the NMDA receptors current. It seems that the previously identified cation binding-sites have a prominent role in changing the diffusion coefficient inside the channel. We also propose the concentration-dependent change in the asymmetry of diffusion coefficient as a remarkably effective mechanism for shaping the channel's I-V curve.
Equine strongyle communities are constrained by horse sex and species dipersal-fecundity trade-off
Authors: Guillaume Sallé , Sławomir Kornaś , Marta Basiaga
Published: November 2017

Equine strongyles are a major health issue. Large strongyles can cause death of horses while cyathostomins (small strongyles) have shown increased resistance to anthelmintics worldwide. Description of strongyle communities have accumulated but little is known about the diversity of these communities and underpinning environmental factors.

This study analysed the diversity of strongyle communities in 48 horses from Poland. Strongyle species fell into two groups, contrasted by their prevalence and relative abundance. Seven horses were necessary to sample at least 90% of strongyle community diversity, providing a minimal cut-off to implement sampling trial in the field. Strongyle communities entertained a network of mostly positive interactions and species co-occurrence was found more often than expected by chance. In addition, species fecundity and prevalence were negatively correlated r=-0.78), suggesting functional trade-offs between species dispersal abilities and fecundity. This functional trade-off may underpin species coexistence. Horse sex was also a significant constraint shaping strongyle communities. Indeed, mares generally displayed more similar strongyle communities than stallions (p=0.004) and Cylicostephanus calicatus was more abundant in stallions suggesting sex-specific interactions (p=0.02). While niche partitioning is likely to explain some of the positive interactions between equine strongyle species, coexistence may also result from a functional trade-off between dispersal ability and fecundity. There is significant evidence that horse sex drives strongylid community structure, which may require differential control strategies between mares and stallions.
Estimating the prevalence of missing experiments in a neuroimaging meta-analysis
Authors: Samartsidis Pantelis , Montagna Silvia , Laird Angela R. , Fox Peter T. , Johnson Timothy D. , Nichols Thomas E.
Published: November 2017

Coordinate-based meta-analyses (CBMA) allow researchers to combine the results from multiple fMRI experiments with the goal of obtaining results that are more likely to generalise. However, the interpretation of CBMA findings can be impaired by the file drawer problem, a type of publications bias that refers to experiments that are carried out but are not published. Using foci per contrast count data from the BrainMap database, we propose a zero-truncated modelling approach that allows us to estimate the prevalence of non-significant experiments. We validate our method with simulations and real coordinate data generated from the Human Connectome Project. Application of our method to the data from BrainMap provides evidence for the existence of a file drawer effect, with the rate of missing experiments estimated as at least 6 per 100 reported.
Anterior cingulate cortex connectivity is associated with suppression of behavior in a rat model of chronic pain
Authors: Morris Laurel S. , Sprenger Christian , Koda Ken , de la Mora Daniela M. , Yamada Tomomi , Mano Hiroaki , Kashiwagi Yuto , Yoshioka Yoshichika , Morioka Yasuhide , Seymour Ben
Published: November 2017

A cardinal feature of persistent pain that follows injury is a general suppression of behavior, in which motivation is inhibited in a way that promotes energy conservation and recuperation. Across species, the anterior cingulate cortex (ACC) is associated with the motivational aspects of phasic pain, but whether it mediates motivational functions in persistent pain is less clear. Using burrowing behavior as an marker of non-specific motivated behavior in rodents, we studied the suppression of burrowing following painful CFA or control injection into the right knee-joint of 37 rats (18 with pain), and examined associated neural connectivity with ultra-high-field resting state functional MRI. We found that connectivity between ACC and the subcortex correlated with the reduction in burrowing behavior observed following the pain manipulation. In a full replication study we confirmed these findings in a group of 44 rats (23 with pain). Across both datasets, reduced burrowing was assosciated with increased connectivity between ACC and subcortical structures including hypothalamic/preoptic nuclei and the bed nucleus of the stria terminalis. Together, the findings implicate ACC connectivity as a robust correlate of the motivational aspect of persistent pain in rodents.
Diabetic Retinopathy detection through integration of Deep Learning classification framework
Authors: Rakhlin Alexander
Published: November 2017

This document represents a brief account of ongoing project for Diabetic Retinopathy Detection (DRD) through integration of state-of the art Deep Learning methods. We make use of deep Convolutional Neural Networks (CNNs), which have proven revolutionary in multiple fields of computer vision including medical imaging, and we bring their power to the diagnosis of eye fundus images. For training our models we used publicly available Kaggle data set. For testing we used portion of Kaggle data withheld from training and Messidor-2 reference standard. Neither withheld Kaggle images, nor Messidor-2 were used for training. For Messidor-2 we achieved sensitivity 99%, specificity 71%, and AUC 0.97. These results close to recent state-of-the-art models trained on much larger data sets and surpass average results of diabetic retinopathy screening when performed by trained optometrists. With continuous development of our Deep Learning models we expect to further increase the accuracy of the method and expand it to cataract and glaucoma diagnostics.
Linking drug target and pathway activation for effective therapy using multi-task learning
Authors: Yang Mi , Simm Jaak , Lam Chi Chung , Zakeri Pooya , van Westen Gerard J.P. , Moreau Yves , Saez-Rodriguez Julio
Published: November 2017

Despite the abundance of large-scale molecular and drug-response data, the insights gained about the mechanisms underlying treatment efficacy in cancer has been in general limited. Machine learning algorithms applied to those datasets most often are used to provide predictions without interpretation, or reveal single drug-gene association and fail to derive robust insights. We propose to use Macau, a bayesian multitask multi-relational algorithm to generalize from individual drugs and genes and explore the interactions between the drug targets and signaling pathways’ activation. A typical insight would be: “Activation of pathway Y will confer sensitivity to any drug targeting protein X”. We applied our methodology to the Genomics of Drug Sensitivity in Cancer (GDSC) screening, using gene expression of 990 cancer cell lines, activity scores of 11 signaling pathways derived from the tool PROGENy as cell line input and 228 nominal targets for 265 drugs as drug input. These interactions can guide a tissue-specific combination treatment strategy, for example suggesting to modulate a certain pathway to maximize the drug response for a given tissue. We confirmed in literature drug combination strategies derived from our result for brain, skin and stomach tissues. Such an analysis of interactions across tissues might help target discovery, drug repurposing and patient stratification strategies.
Reconstructing phylogeny from reduced-representation genome sequencing data without assembly or alignment
Authors: Fan Huan , Ives Anthony R. , Surget-Groba Yann
Published: November 2017

Although genome sequencing is becoming cheaper and faster, reducing the quantity of data by only sequencing part of the genome lowers both sequencing costs and computational burdens. One popular genome-reduction approach is restriction site associated DNA sequencing, or RADseq. RADseq was initially designed for studying genetic variation across genomes usually at the population level, and it has also proved to be suitable for interspecific phylogeny reconstruction. RADseq data pose challenges for standard phylogenomic methods, however, due to incomplete coverage of the genome and large amounts of missing data. Alignment-free methods are both efficient and accurate for phylogenetic reconstructions with whole genomes and are especially practical for non-model organisms; nonetheless, alignment-free methods have only been applied with whole genome sequences. Here, we test a full-genome assembly and alignment-free method, AAF, in application to RADseq data and propose two procedures for reads selection to remove missing data. We validate these methods using both simulations and a real dataset. Reads selection improved the accuracy of phylogenetic construction in every simulated scenario and the real dataset, making AAF comparable to or better than alignment-based method with much lower computation burdens. We also investigated the sources of missing data in RADseq and their effects on phylogeny reconstruction using AAF. The AAF pipeline modified for RADseq data, phyloRAD, is available on github (https://github.com/fanhuan/phyloRAD).
Drug repurposing for yellow fever using high content screening
Authors: Pilger Denise R. B. , Moraes Carolina B. , Gil Laura H. V. , Freitas-Junior Lucio H.
Published: November 2017

Background

Yellow fever is an acute febrile illness caused by a mosquito-borne flavivirus. The discovery that mosquitos were responsible for transmission and that the disease was preventable by vector control, as well as the development of an efficacious vaccine (in the 1930s) have reduced its public health impact. However, underutilization of vaccination and discontinuation of vector control measures have led to yellow fever outbreaks, affecting thousands of people in Africa and South America, and is a continued threat to people who travel to endemic regions without vaccination. An additional concern is that the vaccine has important contraindications, and the currently available doses are insufficient to immunize the populations under risk of contracting yellow fever. Specific antiviral chemotherapy would be an alternative to vaccination, however there is none yet available. Drug repurposing is one strategy that can speed up drug discovery and development and has been underexplored for yellow fever.

Methods

A high content screening assay for the discovery of anti-yellow fever compounds was developed and used to screen a library of pharmacologically compounds, which includes approved drugs and covers most signalling pathways and all major drug target classes. The same library was screened against cells infected with a serotype 2 of the dengue virus.

Results and conclusion

From 1280 compounds screened, 88 compounds (6,9% of the library) were found to reduce yellow fever virus (YFV) infection in 50% or more. Interestingly, the number of compounds that presented similar activity against dengue (DENV) infection was considerably lower (18 compounds, 1,4%). Among these, 12 compounds were active against both viruses, highlighting the potential of finding compounds with broad antiviral activity in diversity libraries. The top 27 anti-YFV compounds were selected for further activity determination in dose-response. Five compounds (Gant61, benztropine mesylate, brequinar sodium salt hydrate, PF-429242 dihydrochloride and U-73343) presented selective activity against YFV infection in a human cell line, but only two of them, brequinar and U-73343, were also active against DENV. These compounds, which represent a broad spectrum of pharmacological functions, have not been previously described as having anti-YFV activity, thus offering a valuable opportunity for the development of specific antiviral chemotherapy for yellow fever.
Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience
Authors: Neuner Sarah M. , Hohman Timothy J. , Richholt Ryan , Bennett David A. , Schneider Julie A. , De Jager Philip L. , Huentelman Matthew J. , O’Connell Kristen M. S. , Kaczorowski Catherine C.
Published: November 2017

Identifying genes that modify symptoms of Alzheimer’s disease (AD) will provide novel therapeutic strategies to prevent, cure or delay AD. To discover genetic modifiers of AD, we combined a mouse model of AD with a genetically diverse reference panel to generate F1 mice harboring identical ‘high-risk’ human AD mutations but which differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of causal human AD mutations and validate this panel as an AD model by demonstrating a high degree of phenotypic, transcriptomic, and genetic overlap with human AD. Genetic mapping was used to identify candidate modifiers of cognitive deficits and amyloid pathology, and viral-mediated knockdown was used to functionally validate Trpc3 as a modifier of AD. Overall, work here introduces a ‘humanized’ mouse population as an innovative and reproducible resource for the study of AD and identifies Trpc3 as a novel therapeutic target.

Highlights

New transgenic mouse population enables mapping of AD risk and resilience factors

Transcriptomic and phenotypic profiles in diverse AD mice parallel those in humans

Apoe genotype and expression correlate with cognitive symptoms in mice

Trpc3 is a novel target to reduce amyloid load and cognitive symptoms in AD
The effects of host species and sexual dimorphism differ among root, leaf and flower microbiomes of wild strawberriesin situ
Authors: Wei Na , Ashman Tia-Lynn
Published: November 2017

Plant-associated microbiomes profoundly influence host interactions with below- and aboveground environments. Characterizing plant-associated microbiomes in experimental settings have revealed important drivers of microbiota assemblies within host species. However, it remains unclear how important these individual drivers (e.g., organ type, host species, host sexual phenotype) are in structuring the patterns of plant–microbiota association in the wild.

Using 16s rRNA sequencing, we characterized root, leaf and flower microbiomes in three closely related, sexually polymorphicFragariaspecies, in the broadly sympatric portion of their native ranges in Oregon, USA. Taking into account the potential influence of broad-scale abiotic environments, we quantified the relative effects of organ type, host species and sex on the α- and β-diversity of bacterial communities in these wild populations. Our statistical models showed that organ type explained the largest variation of compositional and phylogenetic α- and β-diversity of plant microbiomes, and its overall effect exceeded that of host plant species. Yet, the influence of host species increased from root to leaf to flower microbiomes. We found strong sexual dimorphism in flower and leaf microbiomes, especially in host species with the most complete separation of sexes. Our results provide the first demonstration of enhanced effects of host species and sexual dimorphism from root to flower microbiomes. While these findings await manipulative experiments to disentangle contributions of micro-environment and the residing microbiota from host genetic effects, we anticipate that such phenotypic patterns of host species–microbiota association may be broadly applicable to other plants in the wild.
The Plateau Method for Forensic DNA SNP Mixture Deconvolution
Authors: Ricke Darrell O. , Isaacson Joe , Watkins James , Fremont-Smith Philip , Boettcher Tara , Petrovick Martha , Wack Edward , Schwoebel Eric
Published: November 2017

Identification of individuals in complex DNA mixtures remains a challenge for forensic analysts. Recent advances in high throughput sequencing (HTS) are enabling analysis of DNA mixtures with expanded panels of Short Tandem Repeats (STRs) and/or Single Nucleotide Polymorphisms (SNPs). We present the plateau method for direct SNP DNA mixture deconvolution into sub-profiles based on differences in contributors’ DNA concentrations in the mixtures in the absence of matching reference profiles. The Plateau method can detect profiles of individuals whose contribution is as low as 1/200 in a DNA mixture (patent pending)1.
Differential temporal dynamics during visual imagery and perception
Authors: Dijkstra Nadine , Mostert Pim , de Lange Floris P. , Bosch Sander , van Gerven Marcel A. J.
Published: December 2017

Visual perception and imagery rely on similar representations in the visual cortex. During perception, visual activity is characterized by distinct processing stages, but the temporal dynamics underlying imagery remain unclear. Here, we investigated the dynamics of visual imagery in human participants using magnetoencephalography. We show that, contrary to perception, the onset of imagery is characterized by broad temporal generalization. Furthermore, there is consistent overlap between imagery and perceptual processing around 150 ms and from 300 ms after stimulus onset, presumably reflecting completion of the feedforward sweep and perceptual stabilization respectively. These results indicate that during imagery either the complete representation is activated at once and does not include low-level visual areas, or the order in which visual features are activated is less fixed and more flexible than during perception. These findings have important implications for our understanding of the neural mechanisms of visual imagery.
An Essential Role forArgonaute 2in EGFR-KRAS Signaling in Pancreatic Cancer Development
Authors: Shankar Sunita , Tien Jean Ching-Yi , Siebenaler Ronald F. , Chugh Seema , Dommeti Vijaya L. , Zelenka-Wang Sylvia , Waninger Jessica , Juckette Kristin M. , Xu Alice , Wang Xiao-Ming , Mody Malay , Eyunni Sanjana , Goodrum Andrew , Tsaloff Grace , Zhang Yuping , Apel Ingrid J. , Wang Lisha , Siddiqui Javed , Smith Richard D. , Carlson Heather A. , Tesmer John J. , Cao Xuhong , Shi Jiaqi , Kumar-Sinha Chandan , Crawford Howard C. , Chinnaiyan Arul M.
Published: December 2017

KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss ofAGO2inKRASG12D-driven pancreatic cancer. Genetic ablation ofAGO2does not interfere with development of the normal pancreas orKRASG12D-driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however,AGO2is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis.AGO2ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss ofTrp53(p53) in this model obviates the requirement ofAGO2for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2Y393by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRASG12C-AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: anAGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and anAGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.
In vivo multiphoton fluorescence imaging with polymer dots
Authors: Hassan Ahmed M. , Wu Xu , Jarrett Jeremy W. , Xu Shihan , Miller David R. , Yu Jiangbo , Perillo Evan P. , Liu Yen-Liang , Chiu Daniel T. , Yeh Hsin-Chih , Dunn Andrew K.
Published: December 2017

Deep in vivo imaging of vasculature requires small, bright, and photostable fluorophores suitable for multiphoton microscopy (MPM). Although semiconducting polymer dots (pdots) are an emerging class of highly fluorescent contrast agents with favorable advantages for the next generation of in vivo imaging, their use for deep multiphoton imaging has never before been demonstrated. Here we characterize the multiphoton properties of three pdot variants (CNPPV, PFBT, and PFPV) and demonstrate deep imaging of cortical microvasculature in C57 mice. Specifically, we measure the two-versus three-photon power dependence of these pdots and observe a clear three-photon excitation signature at wavelengths longer than 1300 nm, and a transition from two-photon to three-photon excitation within a 1060 – 1300 nm excitation range. Furthermore, we show that pdots enable in vivo two-photon imaging of cerebrovascular architecture in mice up to 850 μm beneath the pial surface using 800 nm excitation. In contrast with traditional multiphoton probes, we also demonstrate that the broad multiphoton absorption spectrum of pdots permits imaging at longer wavelengths (λex = 1,060 and 1225 nm). These wavelengths approach an ideal biological imaging wavelength near 1,300 nm and confer compatibility with a high-power ytterbium-fiber laser and a high pulse energy optical parametric amplifier, resulting in substantial improvements in signal-to-background ratio (>3.5-fold) and greater cortical imaging depths of 900 μm and 1300 μm. Ultimately, pdots are a versatile tool for MPM due to their extraordinary brightness and broad absorption, which will undoubtedly unlock the ability to interrogate deep structures in vivo.