bluuebunny/crossref_metadata_2025 huggingface dataset:
Using local ecological knowledge to inform fisheries assessment: measuring agreement among Polish fishermen about the abundance and condition of Baltic cod (Gadus morhua)
Authors: Figus Elizabeth , Carothers Courtney , Beaudreau Anne H
Published: March 2017

Although fisheries managers often attempt to incorporate stakeholders’ views into development of policy options, integration of fishermen’s local ecological knowledge into biological assessments remains uncommon. Using the case of the eastern Baltic cod (Gadus morhua) resource, this article documented local ecological knowledge about a managed fishery stock. In 2012 and 2013, local media reported that fishermen were observing increased occurrences of cod with poor body condition (“skinny” cod) in their catches from waters off Poland. Polish cod fishermen were interviewed (n = 31) to quantify the strength of their agreement about the abundance and body condition of cod. Agreement among fishermen was assessed about trends in abundance and occurrence of “skinny” cod, as well as the mechanisms explaining those patterns. Cultural consensus analysis showed strong agreement among Polish fishermen that “skinny” cod may be attributed to overfishing on sprat, a key prey species. Fishermen and scientists observed similar declines in the abundance and condition of cod along the Polish coastline; however, they may perceive causes of those changes differently. Generalized additive models were used to show that trends in fishermen’s observations of abundance and “skinny” cod occurrence may be partially explained by variation in temperature, salinity, and sprat abundance.
Baptism by fire: the pivotal role of ancient conflagrations in evolution of the Earth's flora
Authors: He Tianhua , Lamont Byron B
Published: March 2017

Fire became a defining feature of the Earth's processes as soon as land plants evolved 420 million years ago and has played a major role in shaping the composition and physiognomy of many ecosystems ever since. However, there remains a general lack of appreciation of the place of fire in the origin, evolution, ecology and conservation of the Earth's biodiversity. We review the literature on the presence of fire throughout the Earth's history following the evolution of land plants and examine the evidence for the origin and evolution of adaptive functional traits, biomes and major plant groups in relation to fire. We show that: (1) fire activities have fluctuated throughout geological time due to variations in climate, and more importantly in atmospheric oxygen, as these affected fuel levels and flammability; (2) fire promoted the early evolution and spread of major terrestrial plant groups; (3) fire has shaped the floristics, structure and function of major global biomes; and (4) fire has initiated and maintained the evolution of a wide array of fire-adapted functional traits since the evolution of land plants. We conclude that fire has been a fundamental agent of natural selection on terrestrial plants throughout the history of life on the Earth's land surface. We suggest that a paradigm shift is required to reassess ecological and evolutionary theories that exclude a role for fire, and also there is a need to review fire-suppression policies on ecosystem management and biodiversity conservation in global fire-prone regions.
Recognition and management of Clostridium difficile in older adults
Authors: Sams Anna Wentz , Kennedy-Malone Laurie
Published: March 2017

Clostridium difficile infection (CDI) is increasing in the outpatient setting, and older adults are at a higher risk for contracting CDI and experiencing poor outcomes. NPs may see this infection in the primary care setting. This article focuses on the presentation, treatment, and clinical practice implications for CDI in community-dwelling older adults.
Age-Based Normative Measurements of the Pediatric Pelvis
Authors: Oetgen Matthew E. , Andelman Steven , Martin Benjamin D.
Published: March 2017

Objectives:

Pediatric pelvic trauma is associated with high rates of morbidity and mortality. Current classifications do not take into account age-dependent quantitative differences of the pediatric pelvis making accurate diagnosis of pathologic diastasis of the pubic symphysis, sacroiliac (SI) joints, and triradiate cartilage difficult. The purpose of this study was to establish age-based normative values for the width of the pubic symphysis, SI joints, and the triradiate cartilage of the pediatric pelvis.

Methods:

All computed tomographic (CT) scans of the abdomen and pelvis from patients between the ages 2 and 16 years over a 3-year period at a single institution were evaluated. Patients were excluded if the CT was performed as part of a trauma evaluation or for a history of neuromuscular disease or spinopelvic instrumentation. A total of 821 CT were included. The width of pubic symphysis, right and left SI joints, and each limb of the triradiate cartilages was measured using the PACS digital measurement tool. Left and right measurements of the SI joints and triradiate cartilage were combined and reported together.

Results:

From age 2 to 16 years, the average widths of the SI joint and pubic symphysis decreased from 3.11 to 1.80 mm and 5.55 to 3.69 mm, respectively. The average widths of the 3 limbs of the triradiate cartilage also slightly decreased from age 2 until closure: ilioischial, iliopubic, and ischiopubic cartilages decreasing from 3.72 to 2.74 mm, 4.42 to 3.52 mm, and 3.08 to 2.97 mm, respectively.

Conclusions:

This study demonstrates an age-dependent decrease in width of the pubic symphysis and left and right SI joints. By contrast, the widths of the triradiate cartilage remain relatively stable until closure. We believe that these age-based normative values will aid in future diagnosis of pathologic diastasis of these areas of the pediatric pelvis.
Proximal Femoral Shortening After Cephalomedullary Nail Insertion for Intertrochanteric Fractures
Authors: Gilat Ron , Lubovsky Omri , Atoun Ehud , Debi Ronen , Cohen Ornit , Weil Yoram A.
Published: March 2017

Objective:

To assess the incidence of proximal femoral shortening (PFS) and its effect on the patient outcomes when intertrochanteric fractures were treated with a cephalomedullary nail (CMN).

Design:

Retrospective cohort study.

Settings:

Level II trauma center.

Patients:

Forty-eight consecutive patients with OTA/AO 31-A intertrochanteric fractures.

Intervention:

All patients were treated with a Gamma3 CMN (Stryker, Kalamazoo, MI).

Methods:

PFS was assessed for abductor lever arm (x vector), femoral height (y vector), and overall shortening (z vector) on anteroposterior radiographs. Fixation success and retained ambulatory capacity were noted.

Results:

Shortening of >5 mm of the x, y, and z vectors was evident in 18, 20, and 29 patients, respectively. Shortening of >10 mm of the x, y, and z vectors was measured in 5, 6, and 8 patients, respectively. Mean shortening of the x, y, and z vectors was 4.5, 5.5, and 7 mm, respectively. Greater PFS was found to be associated with fixation failure and inability to retain ambulatory capacity, independently (P ≤ 0.05 and P ≤ 0.025, respectively). Of note, an unstable fracture pattern was not found to be associated with greater PFS.

Conclusions:

PFS is a common phenomenon after CMN of intertrochanteric fractures with a Gamma CMN. In addition, greater PFS seems to be associated with fixation failure and inability to retain ambulatory capacity postoperatively.

Level of Evidence:

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Clinical and Functional Results of 119 Patients With Knee Dislocations
Authors: Scarcella Nicholas R. , Weinberg Douglas S. , Bowen Stephen , Vallier Heather A.
Published: March 2017

Objectives:

To describe clinical results and functional outcomes of knee dislocations treated with a consistent strategy within our institution.

Design:

Retrospective case series.

Setting:

Level 1 trauma center.

Patients:

One hundred nineteen patients were treated at one institution between 2000 and 2014 for knee dislocation.

Main Outcome Measurements:

Knee range of motion, functional instability, and complications were recorded. Musculoskeletal Function Assessment (MFA) and Lysholm scores were obtained after minimum of 1 year.

Results:

Sixty-three early complications were noted in 36 patients (32%), with an overall amputation rate of 9.2% (8 early and 3 late amputations). Of the patients who retained their limb, 4.5% reported instability. Open knee dislocations were associated with amputation (26% vs. 1.3%, P < 0.001). Popliteal arterial injuries were associated with more amputation (31% vs. 3.2%, P = 0 < 0.001), infection (37% vs. 8%, P = 0.002), and deep venous thrombosis (32% vs. 8.8%, P = 0.014). Patients with wound infection were more likely to develop heterotopic ossification (36% vs. 9.4%, P = 0.017) and less knee motion (77.5 vs. 117 degrees P = 0.049). Knee motion improved over time for all patients with a mean arc of 86 degrees at 3 months, 109 degrees at 6 months, and 115 degrees at 12 months. An Injury Severity Score of ≥20 was associated with less knee motion (97 vs. 121 degrees P = 0.029). Mean Lysholm score was 86.7, and mean MFA score was 35.7 after mean follow-up of 90 months and 82 months, respectively.

Conclusions:

Few patients (4.5%) experienced functional instability. However, early complications occurred frequently (32%) as expected, particularly in patients with open injuries and/or arterial injury. Limitations in knee motion were associated with high Injury Severity Score, infection, and heterotopic ossification. Mean knee scores were good, consistent with reasonable knee function, although MFA scores suggest a lower level of generalized function.

Level of Evidence:

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
A Retrospective Case-Matched Cost Comparison of Surgical Treatment of Melanoma and Nonmelanoma Skin Cancer in the Outpatient Versus Operating Room Setting
Authors: Johnson Ryan P. , Butala Niraj , Alam Murad , Lawrence Naomi
Published: March 2017

BACKGROUND

To date, no study has used authentic billing data in a case–control matched fashion to examine the cost of treating skin cancer in different settings.

OBJECTIVE

To compare the cost of surgical treatment of skin cancer in the outpatient versus operating room setting using matched cases based on patient and skin cancer characteristics.

METHODS

ICD-9 diagnosis codes for skin cancers were used to find patients who had a malignant excision current procedural terminology code in the operating room setting during 2010 to 2014. Patient and skin cancer characteristics were used to match cases to those treated as an outpatient. A total of 36 cases (18 operating room and 18 outpatient) had the required information and characteristics to be matched and analyzed for cost. Health status was determined using the American Society of Anesthesiologists anesthesia grading scale.

RESULTS

No statistically significant differences were found in the age (p > 0.9) or American Society of Anesthesiologists scores (p > 0.6) of the outpatient and operating room cases. The median cost for outpatient cases was $1,745. For operating room cases, the median cost was $11,323. This was a statistically significant difference (p < 0.001).

CONCLUSION

The outpatient setting remains a cost-effective location to treat skin cancer compared with the operating room.
Population Pharmacokinetics of Gemcitabine and dFdU in Pancreatic Cancer Patients Using an Optimal Design, Sparse Sampling Approach
Authors: Serdjebi Cindy , Gattacceca Florence , Seitz Jean-François , Fein Francine , Gagnière Johan , François Eric , Abakar-Mahamat Abakar , Deplanque Gael , Rachid Madani , Lacarelle Bruno , Ciccolini Joseph , Dahan Laetitia
Published: March 2017

Background:

Gemcitabine remains a pillar in pancreatic cancer treatment. However, toxicities are frequently observed. Dose adjustment based on therapeutic drug monitoring might help decrease the occurrence of toxicities. In this context, this work aims at describing the pharmacokinetics (PK) of gemcitabine and its metabolite dFdU in pancreatic cancer patients and at identifying the main sources of their PK variability using a population PK approach, despite a sparse sampled-population and heterogeneous administration and sampling protocols.

Methods:

Data from 38 patients were included in the analysis. The 3 optimal sampling times were determined using KineticPro and the population PK analysis was performed on Monolix. Available patient characteristics, including cytidine deaminase (CDA) status, were tested as covariates. Correlation between PK parameters and occurrence of severe hematological toxicities was also investigated.

Results:

A two-compartment model best fitted the gemcitabine and dFdU PK data (volume of distribution and clearance for gemcitabine: V1 = 45 L and CL1 = 4.03 L/min; for dFdU: V2 = 36 L and CL2 = 0.226 L/min). Renal function was found to influence gemcitabine clearance, and body surface area to impact the volume of distribution of dFdU. However, neither CDA status nor the occurrence of toxicities was correlated to PK parameters.

Conclusions:

Despite sparse sampling and heterogeneous administration and sampling protocols, population and individual PK parameters of gemcitabine and dFdU were successfully estimated using Monolix population PK software. The estimated parameters were consistent with previously published results. Surprisingly, CDA activity did not influence gemcitabine PK, which was explained by the absence of CDA-deficient patients enrolled in the study. This work suggests that even sparse data are valuable to estimate population and individual PK parameters in patients, which will be usable to individualize the dose for an optimized benefit to risk ratio.
Comparison of Noncontact Specular and Confocal Microscopy for Evaluation of Corneal Endothelium
Authors: Huang Jianyan , Maram Jyotsna , Tepelus Tudor C. , Sadda Srinivas R. , Chopra Vikas , Lee Olivia L.
Published: March 2017

Purpose:

To compare endothelial cell analysis obtained by noncontact specular and confocal microscopy, using the Konan NSP-9900 and Nidek ConfoScan4 systems, respectively.

Methods:

Three groups including 70 healthy eyes, 49 eyes with Fuchs endothelial corneal dystrophy (FECD), and 78 eyes with glaucoma were examined with both the Konan NSP-9900 specular microscope and the Nidek ConfocScan4 confocal microscope. Certified graders at the Doheny Image Reading Center compared corneal endothelial images from both instruments side by side to assess image quality. Endothelial cell density (ECD) measurements were calculated and compared using three different modalities: (1) each instrument's fully automated analysis; (2) each instrument's semiautomatic analysis with grader input; and (3) manual grading methods by certified grader.

Results:

All normal eyes yielded gradable endothelial images, and most but not all glaucomatous eyes yielded images with high enough image quality to allow grading. In addition, in corneas with severe FECD, poor image quality precluded ECD grading by specular microscopy in 20 eyes (40.8%) but in only 4 (8.2%) confocal images from the same eyes. For the gradable images, the ECD values obtained using the manual grading method from either device were comparable with no statistically significant difference (P>0.05) between specular and confocal devices. Machine-generated ECD values were significantly different from manual results, measuring greater in all cases with specular microscopy. Machine-generated ECD values from confocal microscopy also differed significantly from manual determinations, but not in a consistent direction. Semiautomatic methods for both instruments obtained clinically acceptable ECD values.

Conclusions:

Automatic machine-generated ECD measurements differed significantly from manual assessments of corneal endothelium by both specular and confocal microscopy, suggesting that automated results should be used with caution. But ECD values derived manually were comparable between the two devices in both normal and glaucomatous eyes, suggesting that manually graded images from the two instruments can be used interchangeably for reliable ECD measurements. Because of a higher proportion of gradable images, confocal microscopy may be superior to specular microscopy for ECD measurements in FECD.
Effects of Myopic Orthokeratology on Visual Performance and Optical Quality
Authors: Liu Guihua , Chen Zhi , Xue Feng , Li Jing , Tian Mi , Zhou Xingtao , Wei Ruihua
Published: March 2017

Objectives:

To analyze the changes in visual performance and optical quality after orthokeratology (ortho-k) treatment and its correlation with the magnitude of lens decentration and the diameter of treatment zone (TxZ).

Methods:

A prospective study was conducted in 27 eyes of 27 patients wearing ortho-k contact lens. Area under log contrast sensitivity function (AULCSF), modulation transfer function cutoff values (MTFcutoff), Strehl ratio (SR), and objective scattering index (OSI) were measured and compared before and 1 month after ortho-k lens treatment. Refractive sphere, astigmatism, and diameter and decentration of TxZ were tested against the change in AULCSF, MTFcutoff, SR, and OSI after ortho-k treatment in stepwise multiple linear regression models.

Results:

Objective scattering index significantly increased and AULCSF, MTFcutoff, and SR significantly decreased after ortho-k lens wear (all P<0.001). The mean TxZ diameter was 3.61±0.26 mm, and the mean magnitude of TxZ decentration was 0.60±0.16 mm. The amount of lens decentration significantly correlated with the change in AULCSF and MTFcutoff (P=0.027 and P=0.005, respectively). The diameter of TxZ significantly correlated with the change in MTFcutoff and SR (P=0.005 and P=0.024, respectively).

Conclusions:

Visual and optical quality decreases after ortho-k treatment, which can be alleviated by a larger TxZ diameter and a smaller lens decentration.
Minimally Invasive Aortic Valve Replacement via Right Anterior Minithoracotomy and Central Aortic Cannulation
Authors: Bethencourt Daniel M. , Le Jennifer , Rodriguez Gabriela , Kalayjian Robert W. , Thomas Gregory S.
Published: March 2017

Objective

This study reports the evolution of a minimally invasive aortic valve replacement (mini-AVR) technique that uses a right anterior minithoracotomy approach with central cannulation, for a 13-year period. This technique has become our standard approach for isolated primary AVR in nearly all patients.

Methods

This observational study evaluated perioperative clinical outcomes of patients 18 years or older who underwent mini-AVR from November 2003 to June 2015.

Results

The mini-AVR technique was used in 202 patients during two periods of 2003 to 2009 (n = 65, “early”) and 2010 to 2015 (n = 137, “late”). The mean ± SD age was 72.5 ± 12.9 years and 60% were male. Demographic parameters were statistically similar between the study periods, except for increased body weight in the later period (75.3 ± 14.7 vs 80.9 ± 20.8 kg, P = 0.03). The mean cardiopulmonary bypass and aortic cross-clamp times were significantly different by each year and Bonferroni adjustment, with significant decreases in cardiopulmonary bypass and aortic cross-clamp times beginning 2006. Compared with the early study period, late study period patients were more often extubated intraoperatively (52% vs 12%, P < 0.001), had less frequent prolonged ventilator use postoperatively (6% vs 16%, P = 0.018), required fewer blood transfusions (mean, 2.0 ± 2.3 U vs 3.6 ± 3.0 U; P = 0.011), and had shorter postoperative stay (6.3 ± 4.5 days vs 8.0 ± 5.9 days, P = 0.026). Numerically, fewer postoperative strokes (1% vs 6%, P = 0.09) and fewer reoperations for bleeding (3% vs 6%, P = 0.3) occurred in the late period. In-hospital mortality did not differ (1/65 early vs 3/137 late).

Conclusions

Overall mini-AVR intraoperative and postoperative clinical outcomes improved for this 13-year experience.
Using a Mixed Methods Approach to Examine Practice Characteristics Associated With Implementation of an Adult Immunization Intervention Using the 4 Pillars Practice Transformation Program
Authors: Hawk Mary , Nowalk Mary Patricia , Moehling Krissy K. , Pavlik Valory , Raviotta Jonathan M. , Brown Anthony E. , Zimmerman Richard K. , Ricci Edmund M.
Published: March 2017

Adult immunization rates are consistently suboptimal, exacting significant human and financial burden of preventable disease. Practice-level interventions to improve immunization rates have produced mixed results. The context of change critically affects implementation of evidence-based interventions. We conducted a randomized controlled cluster trial of the 4 Pillars Practice Transformation Program to increase adult vaccination rates in primary care practices and used qualitative methods to test intervention effects and understand practice characteristics associated with implementation success. We conducted qualitative interviews with staff from 14 practices to assess implementation experiences. Thematic analysis of data pointed to the importance of quality improvement history, communication and practice leadership, Immunization Champion leadership effectiveness, and organizational flexibility. Practices were scored on these characteristics and grouped into four types: Low Implementers, Medium Implementers, High Implementers, and Public/University Practices. Intervention uptake and immunization rate changes were compared, and a significant increase in influenza vaccination rates (3.9 percentage points [PPs]; p = .038) was observed for High Implementers only. Significant increases in Tdap vaccination rates were observed for High Implementers (9.3 PP; p = 0.006) and the Public/University groups (6.5 PP; p = 0.012), but not other groups. Practice characteristics may be critical factors in predicting intervention success.
Using Technology to Enhance Discharge Teaching and Improve Coping for Patients After Stroke
Authors: Schneider Melissa A. , Howard Katrina A.
Published: March 2017

Background: A diagnosis of stroke is a life-changing event. Effective discharge teaching after a stroke is crucial for recovery, but the overload of information can be overwhelming for patients and caregivers. Purpose: The purpose of this study was to examine differences in discharge readiness and postdischarge coping in patients admitted for stroke after the use of individualized postdischarge information/education provided via a technology package (including patient online portal access, e-mail/secure messaging) compared with current standard discharge teaching methods (verbal/written instructions). Methods: This study used a descriptive comparative design to evaluate the difference between the nonintervention group A and the intervention group B. Patients in group B received additional discharge information via secured e-mail messaging at postdischarge days 2, 6, and 10. Two validated tools, Readiness for Hospital Discharge Form and Post-Discharge Coping Difficulty Scale, were used. Results: One hundred patients were recruited for the study, but the final number of complete data sets collected was 86—42 in group A and 44 in group B. There was no statistically significant difference between the groups in discharge readiness. There was a significant difference in coping scores between the 2 groups, with the technology group exhibiting higher coping. Conclusions: New technology affords new options to improve discharge readiness and contribute to positive patient coping after stroke. The researchers hope that this study will contribute to the growing body of evidence showing success using aspects of technology to enhance discharge teaching and follow-up after discharge.
Endoscopic Ear Surgery for External Auditory Canal Cholesteatoma
Authors: Dähn Jörg , Anschuetz Lukas , Konishi Masaya , Sayles Mark , Caversaccio Marco , Dubach Patrick
Published: March 2017

Background:

Treatment of external auditory canal cholesteatoma (EACC) has been a question of debate. To our knowledge and according to a systematic review of endoscopic ear surgery (EES) in 2015, this study describes for the first time the technique and outcome by solely transcanal EES for EACC.

Study Method:

Retrospective case series, level of evidence IV.

Methods:

Between October 2014 and December 2016, nine patients with unilateral EACC have been treated by EES. Using a bimanual technique, canaloplasty has been performed using tragal perichondrium, cartilage, or artificial bone. Symptoms, signs, and reconstruction technique have been assessed and the primary endpoint: healing time was compared with benchmark values in the literature.

Results:

During the 26 months study period all of our nine Naim stage III EACCs were successfully treated by EES with median healing time of 23.8 days. EACC limited to the external auditory canal (Naim stage III) represented an ideal target for EES minimizing tissue damage and thus median healing time compared with retroauricular (42–56 d) or endaural (59 d) surgical techniques.

Discussion:

Shorter healing time helped to reduce skepticism toward a surgical treatment of EACC from the patient's perspective. Moreover, EES relied on reduced bulky equipment, dressing time, and complex maintenance compared with microscopic techniques.

Conclusion:

Transcanal endoscopic surgery is a valid treatment option for EACC up to Naim stage III. Moreover, the described procedure fosters in our eyes the teaching of our residence to get familiar with the basic steps of EES.
Diagnosis and Treatment of Vestibular Neuritis/Neuronitis or Peripheral Vestibulopathy (PVP)? Open Questions and Possible Answers
Authors: Hegemann Stefan C. A. , Wenzel Angela
Published: March 2017

The acute vestibular syndrome is a clinically defined entity consisting of vertigo or dizziness that develops acutely over minutes to hours and is accompanied by nausea/vomiting, gait instability, head motion intolerance, and nystagmus, while persisting over a day or more. When it is caused by a peripheral vestibular lesion and is not associated with clinically manifest auditory deficits, it is mostly labeled vestibular neuritis/neuronitis/neuropathy or sometimes peripheral vestibulopathy. Here, we propose hypotheses and discuss current research advances on viral or vascular factors in the pathogenesis, the recurrence, the site of lesion, old and new treatment options, contraindicated measures, the differential diagnosis, and the prognosis of vestibular neuritis/neuronitis/neuropathy or vestibulopathy. Possibly, other structures than the vestibular nerve are also involved in the pathogenetic process and the label peripheral vestibulopathy would be more apt.
Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome
Authors: Antonescu Cristina R. , Owosho Adepitan A. , Zhang Lei , Chen Sonja , Deniz Kemal , Huryn Joseph M. , Kao Yu-Chien , Huang Shih-Chiang , Singer Samuel , Tap William , Schaefer Inga-Marie , Fletcher Christopher D.
Published: March 2017

CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.
Effect of Combination Antiretroviral Therapy on HIV-1-specific Antibody-Dependent Cellular Cytotoxicity Responses in Subtype B- and Subtype C-Infected Cohorts
Authors: Madhavi Vijaya , Kulkarni Archana , Shete Ashwini , Lee Wen S. , Mclean Milla R. , Kristensen Anne B. , Ghate Manisha , Wines Bruce D. , Hogarth Phillip M. , Parsons Matthew S. , Kelleher Anthony , Cooper David A. , Amin Janaki , Emery Sean ,   ENCORE1 Study Group, Thakar Madhuri , Kent Stephen J.
Published: March 2017

Background:

There is growing interest in immune therapies to clear the latent HIV-1 after combination antiretroviral therapy (cART). There is limited information on the effect of cART on antibody-dependent cellular cytotoxicity (ADCC), and no studies have directly compared ADCC in HIV-1 subtype B- and subtype C-infected subjects. The effect of improving immunocompetence on ADCC to influenza also remains unexplored.

Methods:

The effect of cART on HIV-1- and influenza-specific ADCC was analyzed in 2 cohorts (39 subtype B- and 47 subtype C-infected subjects) before and after 2 years of cART. ADCC analyses included an enzyme-linked immunosorbent assay–based dimeric recombinant soluble (rs) FcγRIIIa-binding assay, antibody-dependent natural killer cell activation assay, and ADCC-mediated killing assays.

Results:

HIV-1 subtype B and C Env-specific antibody binding to dimeric rsFcγRIIIa were reduced in subtypes B- and C-infected cohorts after 2 years of cART (both P < 0.05). Reduced ADCC-mediated killing of target cells expressing subtype B Env in the subtype B-infected cohort (P = 0.003) was observed after 96 weeks of cART, but not of subtype C Env in the subtype C-infected cohort. A greater reduction in ADCC was detected in subjects with baseline CD4 counts >300 cells/μL (P < 0.05). The resolving immunodeficiency after 96 weeks of cART resulted in improved HA-specific ADCC to 6 strains of influenza (all P < 0.01).

Conclusions:

cART results in HIV-1 antigen loss and reductions in HIV-1 Env-specific antibodies with Fc functionality in both subtype B- and C-infected subjects, particularly in immunocompetent subjects. Simultaneously, cART improves ADCC to diverse strains of influenza, suggesting reduction in influenza disease after cART.
The CSF Immune Response in HIV-1–Associated Cryptococcal Meningitis: Macrophage Activation, Correlates of Disease Severity, and Effect of Antiretroviral Therapy
Authors: Scriven James E. , Graham Lisa M. , Schutz Charlotte , Scriba Thomas J. , Wilkinson Katalin A. , Wilkinson Robert J. , Boulware David R. , Urban Britta C. , Meintjes Graeme , Lalloo David G.
Published: March 2017

Background:

Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART).

Methodology:

We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks).

Findings:

CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14+and 35% CD14−monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4+, CD8+,and CD4−CD8−T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and largerCryptococcusorganisms. Mortality was associated with reduced interferon-gamma concentrations and CD4−CD8−T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206.

Conclusions:

Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.
Ethoscopes: an open platform for high-throughputethomics
Authors: Geissmann Quentin , Rodriguez Luis Garcia , Beckwith Esteban J. , French Alice S. , Jamasb Arian R. , Gilestro Giorgio F.
Published: March 2017

We present ethoscopes, machines for high-throughput analysis of behaviour inDrosophilaand other animals. Ethoscopes provide a software and hardware solution that is reproducible and easily scalable; they perform, in real-time, tracking and profiling of behaviour using a supervised machine learning algorithm; they can deliver behaviourally-triggered stimuli to flies in a feedback-loop mode; and they are highly customisable and open source. Ethoscopes can be built easily using 3D printing technology and rely on Raspberry Pi microcomputers and Arduino boards to provide affordable and flexible hardware. All software and construction specifications are available athttp://lab.gilest.ro/ethoscope.
Breathlessness and the body: Neuroimaging evidence for the inferential leap
Authors: Faull Olivia K , Hayen Anja , Pattinson Kyle T S
Published: March 2017

Breathlessness debilitates millions of people with chronic illness. Mismatch between breathlessness severity and objective disease markers is common and poorly understood. Traditionally, sensory perception was conceptualised as a stimulus-response relationship, although this cannot explain how conditioned symptoms may occur in the absence of physiological signals from the lungs or airways. A Bayesian model is now proposed in which the brain generates sensations based on expectations learned from past experiences (priors), which are then checked against incoming afferent signals. In this model, psychological factors may act as moderators. They may either alter priors, or change the relative attention towards incoming sensory information, leading to more variable interpretation of an equivalent afferent input.

In the present study we conducted a preliminary test of this model in a supplementary analysis of previously published data (Hayen 2017). We hypothesised that individual differences in psychological traits (anxiety, depression, anxiety sensitivity) would correlate with the variability of subjective evaluation of equivalent breathlessness challenges. To better understand the resulting inferential leap in the brain, we explored whether these behavioural measures correlated with activity in areas governing either prior generation or sensory afferent input.

Behaviorally, anxiety sensitivity was found to positively correlate with each subject’s variability of intensity and unpleasantness during mild breathlessness, and with unpleasantness during strong breathlessness. In the brain, anxiety sensitivity was found to positively correlate with activity in the anterior insula during mild breathlessness, and negatively correlate with parietal sensorimotor areas during strong breathlessness.

Our findings suggest that anxiety sensitivity may reduce the robustness of this Bayesian sensory perception system, increasing the variability of breathlessness perception and possibly susceptibility to symptom misinterpretation. These preliminary findings in healthy individuals demonstrate how differences in psychological function influence the way we experience bodily sensations, which might direct us towards better understanding of symptom mismatch in clinical populations.
Generation of a double binary transgenic zebrafish model to study myeloid gene regulation in response to melanocyte transformation
Authors: Kenyon Amy , Gavriouchkina Daria , Napolitani Giorgio , Cerundolo Vincenzo , Sauka-Spengler Tatjana
Published: March 2017

A complex network of inflammation succeeds somatic cell transformation and malignant disease. Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells as they establish themselves as the precursors of a tumour. By the time a patient has a detectable solid tumour, cancer cells have escaped the initial immune response mechanisms. To date, no model exists for studying the underlying mechanisms that govern the initial phase of the immune response when transformed cells become precursors of cancer. Here we describe the development of a double binary zebrafish model designed for exploring regulatory programming of the myeloid cells as they respond to oncogenic transformed melanocytes. A hormone-inducible binary system allows for temporal control of different Ras-oncogenes (NRasK61Q, HRasG12V, KRasG12V) expression in melanocytes, enabling analysis of melanocyte transformation and melanoma initiation. This model was coupled to binary cell-specific biotagging models allowingin vivobiotinylation and subsequent isolation of macrophage or neutrophil nuclei for regulatory profiling of their active transcriptomes. Nuclear transcriptional profiling of neutrophils, performed for the first time as they respond to the earliest precursors of melanomain vivo, revealed an intricate landscape of regulatory factors that may promote progression to melanoma including fgf1, fgf6, cathepsin H, cathepsin L, galectin 1 and galectin 3. The model presented here provides a powerful platform to study the myeloid response to the earliest precursors of melanoma.

Summary Statement

We present an innovative double binary zebrafish model for exploring the underlying regulatory mechanisms that govern the myeloid response mechanisms at the onset of melanoma.
External introductions helped drive and sustain the high incidence of HIV-1 in rural KwaZulu-Natal, South Africa
Authors: Rasmussen David A. , Wilkinson Eduan , Vandormael Alain , Tanser Frank , Pillay Deenan , Stadler Tanja , de Oliveira Tulio
Published: March 2017

Despite increasing access to antiretroviral therapy, HIV incidence in rural KwaZulu-Natal communities remains among the highest ever reported in Africa. While many epidemiological factors have been invoked to explain this high incidence, widespread human mobility and movement of viral lineages between geographic locations have implicated high rates of transmission across communities. High rates of crosscommunity transmission call into question how effective increasing local coverage of antiretroviral therapy will be at preventing new infections, especially if many new cases arise from external introductions. To help address this question, we use a new phylodynamic modeling approach to estimate both changes in epidemic dynamics through time and the relative contribution of local transmission versus external introductions to overall incidence from HIV-1 subtype C phylogenies. Our phylodynamic estimates of HIV prevalence and incidence are remarkably consistent with population-based surveillance data. Our analysis also reveals that early epidemic dynamics in this population were largely driven by a wave of external introductions. More recently, we estimate that anywhere between 20-60% of all new infections arise from external introductions from outside the local community. These results highlight the power of using phylodynamic methods to study generalized HIV epidemics and the growing need to consider larger-scale regional transmission dynamics above the level of local communities when designing and testing prevention strategies.
Type 1 diabetes genome-wide association analysis with imputation identifies five new risk regions
Authors: Cooper Nicholas J. , Wallace Chris , Burren Oliver , Cutler Antony , Walker Neil , Todd John A.
Published: March 2017

Type 1 diabetes genotype datasets have undergone several well powered genome wide analysis studies (GWAS), identifying 57 associated regions at the time of analysis. There are still many regions of smaller effect size or low frequency left to discover, and better exploitation of existing type 1 diabetes cohorts with meta analysis and imputation can precede the acquisition of new or larger cohorts. An existing dataset of 5,913 case and 8,828 control samples was analysed using genome-wide microarrays (Affymetrix GeneChip 500KandIllumina Infinium 550K) with imputation viaIMPUTE2with the 1000 Genomes Project (phase 3) reference panel. Genotyping coverage was doubled in known association regions, and increased by four fold in other regions compared to previous studies. Our analysis resulted in new index variants for 17/57 regions, an expanded set of plausible candidate SNPs for 17 regions, and five novel type 1 diabetes association regions at 1p31.3, 1q24.3, 1q31.2, 2q11.2 and 11q12.2. Candidate genes for the new loci includedITGB3BP, FASLG, RGS1, AFF3andCD5/CD6. Further prioritisation of causal genes and causal variants will require detailed RNA and protein expression studies, in conjunction with genome annotation studies including analysis of physical promoter-enhancer interactions.
Diverse genome organization following 13 independent mesopolyploid events in Brassicaceae contrasts with convergent patterns of gene retention
Authors: Mandáková Terezie , Li Zheng , Barker Michael S. , Lysak Martin A.
Published: March 2017

Hybridization and polyploidy followed by genome-wide diploidization significantly impacted the diversification of land plants. The ancient At-αwhole-genome duplication (WGD) preceded the diversification of crucifers (Brassicaceae). Some genera and tribes also experienced younger, mesopolyploid WGDs concealed by subsequent genome diploidization. Here we tested if multiple base chromosome numbers originated due to genome diploidization after independent mesopolyploid WGDs and how diploidization impacted post-polyploid gene retention. Sixteen species representing ten Brassicaceae tribes were analyzed by comparative chromosome painting and/or whole-transcriptome analysis of gene age distributions and phylogenetic analyses of gene duplications. Overall, we found evidence for at least 13 independent mesopolyploidies followed by different degrees of diploidization across the Brassicaceae. New mesotetraploid events were uncovered for tribes Anastaticeae, Iberideae and Schizopetaleae, and mesohexaploid WGDs for Cochlearieae and Physarieae. In contrast, we found convergent patterns of gene retention and loss among these independent WGDs. Our combined analyses of Brassicaceae genomic data indicate that the extant chromosome number variation in many plant groups, and especially polybasic but monophyletic taxa, can result from clade-specific genome duplications followed by diploidization. Our observation of parallel gene retention and loss across multiple independent WGDs provides one of the first multi-species tests that post-polyploid genome evolution is predictable.

Significance statement

Our data show that multiple base chromosome numbers in some Brassicaceae clades originated due to genome diploidization following multiple independent whole-genome duplications (WGD). The parallel gene retention/loss across independent WGDs and diploidizations provides one of the first tests that post-polyploid genome evolution is predictable.
Fragmentation modes and the evolution of life cycles
Authors: Pichugin Yuriy , Peña Jorge , Rainey Paul B. , Traulsen Arne
Published: March 2017

Reproduction is a defining feature of living systems. To reproduce, aggregates of biological units (e.g., multicellular organisms or colonial bacteria) must fragment into smaller parts. Fragmentation modes in nature range from binary fission in bacteria to collective-level fragmentation and the production of unicellular propagules in multicellular organisms. Despite this apparent ubiquity, the adaptive significance of fragmentation modes has received little attention. Here, we develop a model in which groups arise from the division of single cells that do not separate but stay together until the moment of group fragmentation. We allow for all possible fragmentation patterns and calculate the population growth rate of each associated life cycle. Fragmentation modes that maximise growth rate comprise a restrictive set of patterns that include production of unicellular propagules and division into two similar size groups. Life cycles marked by single-cell bottlenecks maximise population growth rate under a wide range of conditions. This surprising result offers a new evolutionary explanation for the widespread occurrence of this mode of reproduction. All in all, our model provides a framework for exploring the adaptive significance of fragmentation modes and their associated life cycles.

Author Summary

Mode of reproduction is a defining trait of all organisms, including colonial bacteria and multicellular organisms. To produce offspring, aggregates must fragment by splitting into two or more groups. The particular way that a given group fragments defines the life cycle of the organism. For instance, insect colonies can reproduce by splitting or by producing individuals that found new colonies. Similarly, some colonial bacteria propagate by fission or by releasing single cells, while others split in highly sophisticated ways; in multicellular organisms reproduction typically proceeds via a single cell bottleneck phase. The space of possibilities for fragmentation is so vast that an exhaustive analysis seems daunting. Focusing on fragmentation modes of a simple kind we parametrise all possible modes of group fragmentation and identify those modes leading to the fastest population growth rate. Two kinds of life cycle dominate: one involving division into two equal size groups, and the other involving production of a unicellular propagule. The prevalence of these life cycles in nature is consistent with our null model and suggests that benefits accruing from population growth rate alone may have shaped the evolution of fragmentation mode.