bluuebunny/crossref_metadata_2025 huggingface dataset:
LONG-TERM VISUAL OUTCOMES AND CLINICAL FEATURES AFTER ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTION–RELATED ENDOPHTHALMITIS
Authors: Rayess Nadim , Obeid Anthony , Storey Philip P. , Juliano Joseph , Rahimy Ehsan , Moshfeghi Andrew A. , Garg Sunir , Hsu Jason
Published: August 2018

Purpose:

To determine long-term visual outcomes in patients who developed endophthalmitis after intravitreal anti–vascular endothelial growth factor injections and to correlate visual outcomes with clinical features.

Methods:

This is a retrospective, multicenter, consecutive case series of patients diagnosed with anti–vascular endothelial growth factor injection–related endophthalmitis who were treated at Mid Atlantic Retina, the Retina Service of Wills Eye Hospital, Philadelphia, PA, and the University of Southern California Roski Eye Institute, Los Angeles, CA. Patients were included if they had at least 1 year of follow-up. Primary outcome was to evaluate long-term visual outcomes up to 5 years of follow-up. The secondary outcome was to determine clinical features (e.g., culture results) that may predict long-term visual acuity outcomes.

Results:

A total of 56 cases of endophthalmitis from 168,247 anti–vascular endothelial growth factor injections were identified (0.033%, 1/3,004 injections), from which 51 eyes met inclusion criteria. Mean follow-up period was 3.3 years (median 4 years; range 1–5 years). A total of 24 patients (47%) reached a maximum final follow-up of 5 years. Mean Snellen visual acuity at the causative injection visit was 20/102 and decreased to counting fingers at diagnosis (P < 0.001). At 6-month follow-up, mean visual acuity improved to 20/644 (P < 0.001) and remained stable up to 5 years (20/480, P = 0.003) follow-up compared with diagnosis. At the final follow-up, 20 eyes had visual acuity that returned to within one line of baseline visual acuity (visual recovery group), whereas 31 patients' visual acuity was at least one line worse than initial visual acuity (visual deterioration group). The cultures for the visual recovery group were more likely to grow coagulase-negative Staphylococcus, whereas the visual deterioration group primarily grew Streptococcus species, Staphylococcus aureus, and Enterococcus faecalis (P = 0.002, comparing organisms isolated in the visual recovery and deterioration group).

Conclusion:

Visual outcomes after anti–vascular endothelial growth factor injection–related endophthalmitis seem to reach peak improvement by 6 months and remain stable up to a median of 4-year follow-up. Patients who develop culture-negative endophthalmitis or endophthalmitis secondary to coagulase-negative Staphylococcus are more likely to regain baseline visual acuity compared with cases secondary to Streptococcus species.
LATE-ONSET OCULAR HYPERTENSION AFTER VITRECTOMY
Authors: Reibaldi Michele , Avitabile Teresio , Russo Andrea , Bonfiglio Vincenza , Mariotti Cesare , Romano Mario R. , Boscia Francesco , Cennamo Gilda , Fallico Matteo , Parisi Guglielmo , Castellino Niccolò , Bucolo Claudio , Li Volti Giovanni , Longo Antonio
Published: August 2018

Purpose:

To determine the incidence and risk factors for late-onset ocular hypertension (LOH) after vitrectomy.

Methods:

From the electronic medical records of consecutive patients who underwent primary vitrectomy, from January 2010 to December 2015, at 5 tertiary vitreoretinal centers in Italy, patient demographics, systemic, ophthalmic, operative, and postoperative data were drawn. Main outcome measure was the presence of LOH, defined as intraocular pressure >21 mmHg detected more than 2 months after vitrectomy on at least 2 consecutive visits.

Results:

Among 6,048 patients, LOH was found in 294 (4.9%) vitrectomized eyes and in 87 (1.4%) fellow eyes, (chi square; P < 0.001). Multivariable logistic regression showed that significant risk factors for developing LOH included intraoperative triamcinolone use (odds ratio [OR], 7.62; P < 0.001), longer axial length (OR, 1.55; P = 3.023), preoperative higher intraocular pressure (OR, 1.81; P = 0.003), and postvitrectomy pseudophakic/aphakic status (OR, 2.04; P < 0.001). Decision-tree analysis showed that the stronger predictor of LOH was intraoperative triamcinolone use (P < 0.001). Secondary predictors were a preoperative intraocular pressure more than 15 mmHg (P < 0.001) in eyes that use triamcinolone, and postvitrectomy pseudophakic/aphakic status (P = 0.007) in eyes that did not use triamcinolone.

Conclusion:

Late-onset ocular hypertension occurred in 4.9% of vitrectomized eyes. The main risk factors were intraoperative use of triamcinolone and postvitrectomy pseudophakic/aphakic status.
Clinical Outcomes of Descemet Membrane Endothelial Keratoplasty in Eyes With Previous Radial Keratotomy
Authors: Parker Jack S. , Parker John S. , Melles Gerrit R. J.
Published: August 2018

Purpose:

To evaluate the clinical outcome of Descemet membrane endothelial keratoplasty (DMEK) performed in eyes with corneal endothelial decompensation and previous radial keratotomy (RK).

Methods:

Five consecutive eyes of 3 patients with previous RK underwent DMEK for endothelial decompensation; best spectacle-corrected visual acuity, maximum keratometry (Kmax), central corneal thickness, and intraoperative and postoperative complications were assessed.

Results:

By 6 months postoperative, all eyes had achieved a best spectacle-corrected visual acuity of ≥20/40 (≥0.5), 4/5 (80%) were ≥20/25 (≥0.8), and 2/5 (40%) were ≥20/20 (≥1.0). On average, central corneal thickness decreased by 122 μm, and Kmax decreased by 4.2 diopters. Successful rebubbling was performed on 1 eye at 3 weeks postoperatively; another eye experienced gaping of an old RK wound, that spontaneously resolved.

Conclusions:

DMEK is technically feasible in eyes with previous RK and may provide excellent outcomes. A significant change in the anterior corneal contour and associated refractive power of the eye may be anticipated depending on the amount of preoperative corneal edema and the number of RK incisions.
The Fovea-BMO Axis Angle and Macular Thickness Vertical Asymmetry Across The Temporal Raphe
Authors: Ghassabi Zeinab , Nguyen Andrew H. , Amini Navid , Henry Sharon , Caprioli Joseph , Nouri-Mahdavi Kouros
Published: August 2018

Purpose:

To test the hypothesis that the fovea-Bruch’s membrane opening (FoBMO) axis angle influences the thickness symmetry of the macular ganglion cell/inner plexiform layer (GCIPL) across the temporal horizontal meridian in normal subjects.

Design:

Cross-sectional diagnostic study at a tertiary academic center.

Methods:

One hundred sixteen eyes of 60 normal subjects aged 40 to 85 years underwent spectral domain optical coherence tomography(SD-OCT) imaging. The FoBMO angle was estimated on en face infrared SD-OCT images. Posterior Pole algorithm images acquired with Spectralis SD-OCT were used to define vertical asymmetry as follows. The average thickness difference between the 3 most temporal superpixels above and below the horizontal meridian, the second row of superpixels from the horizontal meridian, and 3 central superpixels above and below the horizontal meridian were calculated. Factors influencing GCIPL thickness asymmetry were explored and changes in thickness asymmetry as a function of FoBMO angle were investigated.

Results:

No demographic or clinical factors affected temporal GCIPL asymmetry (P>0.05 for all). A more (negatively) tilted FoBMO angle was associated with relatively thinner inferior compared with superior GCIPL thickness in superpixels immediately adjacent to the temporal raphe (P<0.001). The second row of temporal superpixels from the horizontal meridian (P=0.349) or central superpixels (P=0.292) did not show this tendency.

Conclusions:

Vertical GCIPL symmetry across the horizontal meridian is influenced by the FoBMO angle. SD-OCT algorithms using vertical asymmetry as a diagnostic index should be adjusted for the FoBMO angle.
Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Analysis of Unreadable Fundus Images
Authors: Hark Lisa A. , Myers Jonathan S. , Rahmatnejad Kamran , Wang Qianqian , Zhan Tingting , Hegarty Sarah E. , Leiby Benjamin E. , Udyaver Sanika , Waisbourd Michael , Leite Stela , Henderer Jeffrey D. , Pasquale Louis R. , Lee Paul P. , Haller Julia A. , Katz L. Jay
Published: August 2018

Purpose:

The purpose of this study was to ascertain determinants of unreadable fundus images for participants enrolled in the Philadelphia Telemedicine Glaucoma Detection and Follow-up Study.

Methods:

Individuals were screened for glaucoma at 7 primary care practices and 4 Federally Qualified Health Centers using telemedicine. Screening (visit 1) included fundus photography, assessing family history of glaucoma, and intraocular pressure (IOP) measurements. Participants with an unreadable image in at least one eye were deemed unreadable and invited to return for a confirmatory eye examination (visit 2).

Results:

A total of 906 participants completed the visit 1 eye screening and 17.1% (n=155/906) were “unreadable.” In the multivariable logistic regression analysis, older age, male sex, smoking, and worse visual acuity were significantly associated with an unreadable fundus image finding at the eye screening (P<0.05). Of the 89 participants who were invited for the confirmatory eye examination solely for unreadable images and attended visit 2, 58 (65.2%) were diagnosed with at least one ocular pathology. The most frequent diagnoses were cataracts (n=71; 15 visually significant, 56 nonvisually significant), glaucoma suspects (n=27), and anatomical narrow angle (n=10).

Conclusions:

Understanding the causes of unreadable fundus images will foster improvements in telemedicine techniques to optimize the predictive accuracy, efficiency, and cost in ophthalmology. A high proportion of participants with unreadable images (65.2%) in our study were diagnosed with some ocular pathology, indicating that the finding of an unreadable fundus image warrants a referral for a comprehensive follow-up eye examination.
Investigating Serious Adverse Drug Reactions in Patients Receiving Erythropoiesis-Stimulating Agents: A Root Cause Analysis Using the “ANTICIPATE” Framework
Authors: Jacob Sony , Nichols Judy , Macdougall Iain C. , Qureshi Zaina , Chen Brian , Yang Y. Tony , Norris LeAnn B. , Bennett Charles L.
Published: August 2018

Background:

Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts.

Methods:

A 10-step framework termed “ANTICIPATE,” focusing on signal identification, incidence, causality, and eradication guided our evaluations.

Results:

Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives.

Conclusion:

Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.
Is Patent Foramen Ovale Closure More Effective Than Medical Therapy in Preventing Stroke Recurrence in Patients With Cryptogenic Stroke?
Authors: Valencia-Sanchez Cristina , Fortuin F. David , Sweeney John P. , Ingall Timothy J. , Marks Lisa A. , Wingerchuk Dean M. , O’Carroll Cumara B.
Published: August 2018

Background:

The clinical benefit of patent foramen ovale (PFO) closure in patients with cryptogenic stroke (CS) for recurrent stroke prevention has been a subject of extensive debate. Prior clinical trials failed to show superiority of PFO closure versus medical therapy. Meta-analyses suggested a possible benefit of PFO closure in select patients.

Objective:

The objective of this study was to critically assess current evidence regarding the efficacy of PFO closure compared with medical therapy for recurrent stroke prevention in patients with CS.

Methods:

The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, and vascular neurology and interventional cardiology content experts.

Results:

A randomized, controlled trial was selected for critical appraisal. This trial compared the efficacy of PFO closure and medical therapy in recurrent stroke prevention. A total of 663 patients who had a recent CS attributed to PFO, with a large interatrial shunt or with an associated atrial septal aneurysm were included. No stroke occurred among the 238 patients in the PFO closure group, whereas 14 of the 235 patients in the antiplatelet therapy group had recurrent strokes.

Conclusions:

Among patients who had a recent CS attributed to PFO with a large interatrial shunt or with an associated atrial septal aneurysm, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone.
A Vision Enhancement System to Improve Face Recognition with Central Vision Loss
Authors: Calabrèse Aurélie , Aguilar Carlos , Faure Géraldine , Matonti Frédéric , Hoffart Louis , Castet Eric
Published: August 2018

SIGNIFICANCE

The overall goal of this work is to validate a low vision aid system that uses gaze as a pointing tool and provides smart magnification. We conclude that smart visual enhancement techniques as well as gaze contingency should improve the efficiency of assistive technology for the visually impaired.

PURPOSE

A low vision aid, using gaze-contingent visual enhancement and primarily intended to help reading with central vision loss, was recently designed and tested with simulated scotoma. Here, we present a validation of this system for face recognition in age-related macular degeneration patients.

METHODS

Twelve individuals with binocular central vision loss were recruited and tested on a face identification–matching task. Gaze position was measured in real time, thanks to an eye tracker. In the visual enhancement condition, at any time during the screen exploration, the fixated face was segregated from background and considered as a region of interest that could be magnified into a region of augmented vision by the participant, if desired. In the natural exploration condition, participants also performed the matching task but without the visual aid. Response time and accuracy were analyzed with mixed-effects models to (1) compare the performance with and without visual aid and (2) estimate the usability of the system.

RESULTS

On average, the percentage of correct response for the natural exploration condition was 41%. This value was significantly increased to 63% with visual enhancement (95% confidence interval, 45 to 78%). For the large majority of our participants (83%), this improvement was accompanied by moderate increase in response time, suggesting a real functional benefit for these individuals.

CONCLUSIONS

Without visual enhancement, participants with age-related macular degeneration performed poorly, confirming their struggle for face recognition and the need to use efficient visual aids. Our system significantly improved face identification accuracy by 55%, proving to be helpful under laboratory conditions.
Childhood Idiopathic Pulmonary Arterial Hypertension Complicated by Esophageal Intubation
Authors: Balmert Nathaniel J. , Prahlow Joseph A.
Published: August 2018

Childhood idiopathic pulmonary arterial hypertension (CIPAH) represents a rare disorder of childhood characterized by dyspnea, exercise limitation, and syncope. Common organ-specific pathology includes right ventricular myocardial hypertrophy. The case presented represents a classic case of CIPAH, where death was partially attributable to an unrecognized esophageal intubation, which was placed during emergency transport to an emergency department. The features of CIPAH are presented, along with a discussion related to esophageal intubation and death.
Horticultural Homicide
Authors: Hlavaty Leigh , Sung LokMan
Published: August 2018

Instruments that create stab wounds are required to possess tips of sufficient strength and rigidity to breach the integrity of the skin. Knives, the most common weapons used to create stab wounds, have cutting edges that cleave the skin, leaving unabraded margins. On rare occasions, blunt objects are driven with sufficient force to pierce the skin and become impaled within the body. The morphologic differences between the cutaneous injuries and wound tracks of stab wounds from sharp objects and impalement with blunt ones provide clear delineation of the two. However, elements from the scene and obscuring hemorrhage can make initial differentiation difficult. The authors report the death of a 59-year-old woman found near the entryway steps of her home with a stab wound to her chest. Law enforcement did not discover any weapons. Investigation focused on blood around and on a broken rose bush planted near the steps with the belief that the decedent had fallen upon the vegetation. When presented with information that conflicts with autopsy findings, careful consideration of proposed weapons and thorough examination of the wound are required to discount confounding material.
Recommendations on RBC Transfusion in General Critically Ill Children Based on Hemoglobin and/or Physiologic Thresholds From the Pediatric Critical Care Transfusion and Anemia Expertise Initiative
Authors: Doctor Allan , Cholette Jill M. , Remy Kenneth E. , Argent Andrew , Carson Jeffrey L. , Valentine Stacey L. , Bateman Scot T. , Lacroix Jacques
Published: August 2018

Objectives:

To present the consensus recommendations and supporting literature for RBC transfusions in general critically ill children from the Pediatric Critical Care Transfusion and Anemia Expertise Initiative.

Design:

Consensus conference series of international, multidisciplinary experts in RBC transfusion management of critically ill children.

Methods:

The panel of 38 experts developed evidence-based and, when evidence was lacking, expert-based recommendations and research priorities regarding RBC transfusions in critically ill children. The subgroup on RBC transfusion in general critically ill children included six experts. Electronic searches were conducted using PubMed, EMBASE, and Cochrane Library databases from 1980 to May 30, 2017, using a combination of keywords to define concepts of RBC transfusion and critically ill children. Recommendation consensus was obtained using the Research and Development/UCLA Appropriateness Method. The results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method.

Results:

Three adjudicators reviewed 4,399 abstracts; 71 papers were read, and 17 were retained. Three papers were added manually. The general Transfusion and Anemia Expertise Initiative subgroup developed, and all Transfusion and Anemia Expertise Initiative members voted on two good practice statements, six recommendations, and 11 research questions; in all instances, agreement was reached (> 80%). The good practice statements suggest a framework for RBC transfusion in PICU patients. The good practice statements and recommendations focus on hemoglobin as a threshold and/or target. The research questions focus on hemoglobin and physiologic thresholds for RBC transfusion, alternatives, and risk/benefit ratio of transfusion.

Conclusions:

Transfusion and Anemia Expertise Initiative developed pediatric-specific good practice statements and recommendations regarding RBC transfusion management in the general PICU population, as well as recommendations to guide future research priorities. Clinical recommendations emphasized relevant hemoglobin thresholds, and research recommendations emphasized a need for further understanding of physiologic thresholds, alternatives to RBC transfusion, and hemoglobin thresholds in populations with limited pediatric literature.
Use of Simulation to Improve the Comfort of Pediatric Residents Managing Critically Ill Emergency Department Patients
Authors: Saavedra Heather R. , Turner Joseph S. , Cooper Dylan D.
Published: August 2018

Objectives

The aims of this study were to identify the needs for further critical care experience for pediatric and internal medicine–pediatric residents, to describe a multidisciplinary approach to education, and to assess the impact of high-fidelity simulation on critical care comfort and perceived competence in pediatric residents. In addition, this study assessed pediatric residents' attitudes toward simulation as a means of providing additional education with critically ill patients.

Methods

Residents on their pediatric emergency medicine (PEM) rotation voluntarily participated in a 2-hour simulation session. Each session involved the evaluation and management of 3 critically ill pediatric patients with emergency medicine and pediatric/PEM faculty facilitating and debriefing as a team. All resident participants were asked to complete a presession and postsession survey including questions rating their comfort level with common emergent pediatric disease processes and procedures on a 5-point Likert scale.

Results

Overall, the participants reported a significant improvement in comfort level in most categories with P < 0.05. The majority of the resident participants rated the simulation program as a valuable learning tool for managing pediatric emergencies and felt that it would be beneficial to have additional simulation experiences in the PEM curriculum.

Conclusions

This simulation program improved resident comfort in important aspects of the care of critically ill pediatric patients. The use of simulation as an educational tool for pediatric emergencies is considered valuable to residents in our program. In addition, simulation provides an opportunity for educational collaboration between academic departments.
Constipation-Associated Stercoral Colitis
Authors: Proulx Erik , Glass Casey
Published: August 2018

A 9-year-old white girl with a history of constipation presented to the emergency department with a few weeks of intermittent stool incontinence without any reported changes in diet or difficulty tolerating food or fluids by mouth. On the day of presentation, she developed nausea and nonbloody, nonbilious emesis, as well as multiple, loose, nonbloody stools, after becoming acutely ill during lunch at school. There was no reported fever or suspicious food intake. On examination, she was noted to be afebrile, hypotensive, and tachycardic with abdominal tenderness. Her blood work was notable for a marked leukocytosis of 66,000 and a subsequent computed tomography scan of her abdomen was performed. The imaging test identified a large fecaloma with surrounding colonic inflammation concerning for stercoral colitis. The child underwent urgent manual disimpaction and was hospitalized for supportive care with subsequent recovery and return to her normal state of health. Follow-up testing during her hospital stay did not reveal any other infectious or physiologic cause for her constipation and colitis.
Ganglion Cyst of the Temporomandibular Joint Mimicking Auriculotemporal Neuralgia
Authors: Aguilo-Seara Gabriela , Runyan Christopher Michael
Published: August 2018

Ganglion cysts within the temporomandibular joint (TMJ), although uncommon, typically present with swelling, pain, trismus, and difficulty with mastication. The authors report an unusual case of a ganglion cyst in the TMJ of a 52-year-old man who presented with chief complaints of severe headaches and dizziness that had not subsided following treatment with medication, trigger point injections, or sphenopalatine ganglion blocks. The cyst appeared as a nonenhancing, T2 hyperdensity adjacent to the left TMJ condyle on magnetic resonance imaging, supported by the presence of chronic erosion and remodeling of the anterior aspect of the left condylar head on computed tomography. The cyst was surgically removed, and the patient reported that the migraines and accompanying dizziness had ceased 6 months postoperatively. The patient's presentation and improvement following surgery suggest that the location of the cyst in the TMJ and its proximity to the course of the auriculotemporal nerve may have caused auriculotemporal neuralgia, mimicking the symptoms of migraine.
Toward a Consensus on Centralization in Surgery
Authors: Vonlanthen René , Lodge Peter , Barkun Jeffrey S. , Farges Olivier , Rogiers Xavier , Soreide Kjetil , Kehlet Henrik , Reynolds John V. , Käser Samuel A. , Naredi Peter , Borel-Rinkes Inne , Biondo Sebastiano , Pinto-Marques Hugo , Gnant Michael , Nafteux Philippe , Ryska Miroslav , Bechstein Wolf O. , Martel Guillaume , Dimick Justin B. , Krawczyk Marek , Oláh Attila , Pinna Antonio D. , Popescu Irinel , Puolakkainen Pauli A. , Sotiropoulos Georgius C. , Tukiainen Erkki J. , Petrowsky Henrik , Clavien Pierre-Alain
Published: August 2018

Objectives:

To critically assess centralization policies for highly specialized surgeries in Europe and North America and propose recommendations.

Background/Methods:

Most countries are increasingly forced to maintain quality medicine at a reasonable cost. An all-inclusive perspective, including health care providers, payers, society as a whole and patients, has ubiquitously failed, arguably for different reasons in environments. This special article follows 3 aims: first, analyze health care policies for centralization in different countries, second, analyze how centralization strategies affect patient outcome and other aspects such as medical education and cost, and third, propose recommendations for centralization, which could apply across continents.

Results:

Conflicting interests have led many countries to compromise for a health care system based on factors beyond best patient-oriented care. Centralization has been a common strategy, but modalities vary greatly among countries with no consensus on the minimal requirement for the number of procedures per center or per surgeon. Most national policies are either partially or not implemented. Data overwhelmingly indicate that concentration of complex care or procedures in specialized centers have positive impacts on quality of care and cost. Countries requiring lower threshold numbers for centralization, however, may cause inappropriate expansion of indications, as hospitals struggle to fulfill the criteria. Centralization requires adjustments in training and credentialing of general and specialized surgeons, and patient education.

Conclusion/Recommendations:

There is an obvious need in most areas for effective centralization. Unrestrained, purely “market driven” approaches are deleterious to patients and society. Centralization should not be based solely on minimal number of procedures, but rather on the multidisciplinary treatment of complex diseases including well-trained specialists available around the clock. Audited prospective database with monitoring of quality of care and cost are mandatory.
Total lung capacity without plethysmography
Authors: Adam Ori , Cohen Inon , Yip Wai-Ki , Shiner Robert J. , Calverley Peter , Peles Zachi , LaPrad Adam , Dagan Yoni , Brown Robert , Solway Julian , Fredberg Jeffrey J.
Published: August 2018

Background

Among the most basic measures of respiratory function is the total lung capacity (TLC). TLC is the pulmonary gas volume at maximal lung inflation, which is the sum of the volume of gas that can be exhaled –the vital capacity (VC)– and the volume of gas that cannot –the residual volume (RV). Determination of VC requires only spirometry whereas determination of RV or TLC requires body plethysmography, gas dilution or washout, or thoracic imaging, each of which is more complex than spirometry, and none of which is suited to routine office practice, population screening, or community medicine. To fill this gap, we describe here a new approach to determine TLC without plethysmography.

Methods

In a heterogeneous population of 434 volunteers (265 male, 169 female; 201 healthy, 170 with airflow obstruction, and 63 with ventilatory restriction), we determined TLC in the standard fashion using conventional body plethysmography (TLCpleth). In the same individuals, we also determined TLC in a novel fashion using the MiniBox ™ (TLCMB). To obtain TLCMB, population-based data from traditional spirometry together with flow-interruption transients were subjected to data mining and machine-learning to create for each individual subject an unbiased statistical determination of TLC.

Results

For the combined heterogeneous population, we found TLCpleth= 1.02TLCMB−0.091 L, adjustedr2=0.824. For the heterogeneous population as a whole, and for each subpopulation, TLCMBclosely tracked TLCpleth. For 26 healthy subjects measured on different days, the coefficient of variation for repeated measurements in was 3.3% for TLCplethversus 1.6% for TLCMB.

Conclusions

These results establish the validity and potential utility of a new method for rapid, accurate, and repeatable determination of TLC in a heterogeneous patient population, but without the need of a plethysmograph.
Green autofluorescence intensity of skin and fingernails: A novel biomarker for non-invasive evaluation of pathological state of blood vessels
Authors: Zhang Mingchao , Wu Danhong , Tao Yue , Li Yujia , Zhang Shufan , Chen Xin , Ying Weihai
Published: August 2018

Stroke and myocardial infarction (MI) are two leading causes of death around the world. It is of great significance to establish novel and non-invasive approaches for evaluating pathological state of blood vessels, so that early interventions may be carried out to prevent incidence of stroke or MI. Our recent studies have suggested that altered Pattern of Autofluorescence (AF) of skin and fingernails are novel biomarkers of acute ischemic stroke (AIS) and MI. In particular, our studies have shown characteristic increases in the green AF intensity of the fingernails and certain regions of the skin of AIS patients and MI patients. By determining the green AF of skin of the Healthy Group, the Low-Risk Group for Developing AIS, and the High-Risk Group for Developing AIS, our current study has indicated that the green AF intensity in the fingernails and certain regions of the skin, including the right and left Dorsal Index Fingers, Ventroforefingers, Dorsal Antebrachium and Index Fingernails as well as right Dorsal Centremetacarpus, is highly correlated with the risk to develop AIS. There is also evidence suggesting that increased oxidative stress may account for the increased AF intensity in the Low-Risk Group for Developing AIS and the High-Risk Group for Developing AIS. These findings have suggested that the green AF intensity of the fingernails and certain regions of the skin is a novel biomarker for non-invasive evaluation of the pathological state of blood vessels and the risk for developing AIS or MI.
Molecular evolution of non-fertilizing sperm in Lepidoptera suggests minimal direct involvement in sperm competition
Authors: Mongue Andrew J. , Hansen Megan E. , Gu Liuqi , Sorenson Clyde E. , Walters James R.
Published: August 2018

Sperm are among the most variable cells in nature. Some of this variation results from non-adaptive errors in spermatogenesis, but many species consistently produce multiple sperm morphs, the adaptive significance of which remains unknown. Here, we investigate the evolution of dimorphic sperm in Lepidoptera, the butterflies and moths. Males of this order produce both fertilizing sperm and a secondary, non-fertilizing type that lacks DNA. Previous organismal studies suggested a role for non-fertilizing sperm in sperm competition, but this hypothesis has never been evaluated from a molecular framework. We combined published datasets with new sequencing in two species, the monandrous Carolina sphinx moth and the highly polyandrous monarch butterfly. Based on population genetic analyses, we see evidence for increased adaptive evolution in fertilizing sperm, but only in the polyandrous species. This signal comes primarily from a decrease in non-synonymous polymorphism in sperm proteins compared to the rest of the genome, suggesting stronger purifying selection, consistent with selection via sperm competition. Non-fertilizing sperm proteins, in contrast, do not show an effect of mating system and do not appear to evolve differently from the background genome in either species, arguing against the involvement of non-fertilizing sperm in direct sperm competition. Based on our results and previous work, we suggest that non-fertilizing sperm may be used to delay female remating in these insects and decrease the risk of sperm competition rather than directly affect its outcome.
Biotransformation of 2,4-dinitrotoluene in a phototrophic co-culture of engineeredSynechococcus elongatusandPseudomonas putida
Authors: Fedeson Derek T. , Saake Pia , Calero Patricia , Nikel Pablo Iván , Ducat Daniel C.
Published: August 2018

In contrast to the current paradigm of using microbial monocultures in most biotechnological applications, increasing efforts are being directed towards engineering mixed-species consortia to perform functions that are difficult to program into individual strains. Additionally, the division of labor between specialist species found in natural consortia can lead to increased catalytic efficiency and stability relative to a monoculture or a community composed of generalists. In this work, we have designed a synthetic co-culture for phototrophic degradation of xenobiotics, composed of a cyanobacterium, (Synechococcus elongatusPCC 7942) and a heterotrophic bacterium (Pseudomonas putidaEM173). Cyanobacteria fix CO2through photosynthetic metabolism and secrete sufficient carbohydrates to support the growth and active metabolism ofP. putida, which has been engineered to consume sucrose as the only carbon source and to degrade the environmental pollutant 2,4-dinitrotoluene (2,4-DNT). The synthetic consortium is able to degrade 2,4-DNT with only light and CO2as inputs for the system, and it was stable over time through repeated backdilutions. Furthermore, cycling this consortium through low nitrogen medium promoted the accumulation of polyhydroxyalkanoate (PHA)–an added-value biopolymer–inP. putida, thus highlighting the versatility of this production platform. Altogether, the synthetic consortium allows for simultaneous bioproduction of PHA and remediation of the industrial pollutant 2,4-DNT, using light and CO2as inputs.

Importance

In this study, we have created an artificial consortium composed of two bacterial species that enables the degradation of the industrially-produced environmental pollutant 2,4-DNT while simultaneously producing PHA bioplastic. In these co-cultures, the photosynthetic cyanobacteria fuel an engineeredP. putidastrain programmed both to use sucrose as a carbon source and to perform the biotransformation of 2,4-DNT. The division of labor in this synthetic co-culture is reminiscent of that commonly observed in microbial communities and represents a proof-of-principle example of how artificial consortia can be employed for bioremediation purposes. Furthermore, this co-culture system enabled the utilization of freshwater sources that could not be utilized in classical agriculture settings, reducing the potential competition of this alternative method of bioproduction with current agricultural practices, as well as remediation of contaminated water streams.
Molecular Characterisation of the Synovial Fluid Microbiome in Rheumatoid Arthritis Patients and Healthy Control Subjects
Authors: Hammad Dargham Bayan Mohsen , Liyanapathirana Veranja , Tonge Daniel Paul
Published: August 2018

The colonisation of specific body sites in contact with the external environment by microorganisms is both well-described and universally accepted, whereas, the existence of microbial evidence in other “classically sterile” locations including the blood, synovial space, and lungs, is a relatively new concept. Increasingly, a role for the microbiome in disease is being considered, and it is therefore necessary to increase our understanding of these. To date, little data support the existence of a “synovial fluid microbiome”.

Methods

The presence and identity of bacterial and fungal DNA in the synovial fluid of rheumatoid arthritis (RA) patients and healthy control subjects was investigated through amplification and sequencing of the bacterial 16S rRNA gene and fungal internal transcribed spacer region 2 respectively. Synovial fluid concentrations of the cytokines IL-6, IL-17A, IL22 and IL-23 were determined by ELISA.

Results

Bacterial 16S rRNA genes were detected in 87.5% RA patients, and all healthy control subjects. At the phylum level, the microbiome was predominated byProteobacteria(Control = 83.5%, RA = 79.3%) andFirmicutes(Control = 16.1%, RA = 20.3%), and to a much lesser extent,Actinobacteria(Control = 0.2%, RA = 0.3%) andBacteroidetes(Control = 0.1%, RA = 0.1%). Fungal DNA was identified in 75% RA samples, and 88.8% healthy controls. At the phylum level, synovial fluid was predominated by members of the Basidiomycota (Control = 53.9%, RA = 46.9%) and Ascomycota (Control = 35.1%, RA = 50.8%) phyla. Statistical analysis revealed key taxa that were differentially present or abundant dependent on disease status.

Conclusions

This study reports the presence of a synovial fluid microbiome, and determines that this is modulated by disease status (RA) as are other classical microbiome niches.
Tauopathy in theAPPswe/PS1ΔE9mouse model of familial Alzheimer’s disease
Authors: Metaxas Athanasios , Thygesen Camilla , Kempf Stefan J. , Anzalone Marco , Vaitheeswaran Ramanan , Petersen Sussanne , Landau Anne M. , Audrain Hélène , Teeling Jessica L. , Darvesh Sultan , Brooks David J. , Larsen Martin R. , Finsen Bente
Published: August 2018

Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes cortical MAPT (tau) aggregation in familial and idiopathic Alzheimer’s disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. The absence of neurofibrillary lesions in amyloidosis mice remains a challenge for the amyloidocentric paradigm of AD pathogenesis. It has resulted in the generation of transgenic mice harboring mutations in theirtaugene, which may be inappropriate for studying a disease with no knownTAUmutations, such as AD. Here, we have usedAPPswe/PS1ΔE9mice to show that tau pathology can develop spontaneously in murine models of familial AD. Tauopathy was abundant around Aβ deposits, with Gallyas- and thioflavin-S-positive perinuclear inclusions accumulating in theAPPswe/PS1ΔE9cortex by 18 months of age. Age-dependent increases in Gallyas signal correlated positively with binding levels of the paired helical filament (PHF) ligand [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Tandem mass tag proteomics identified sequences of hyperphosphorylated tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Human frontal gyrus tissue was used to validate these findings, revealing primarily quantitative differences between the tauopathy observed in AD patient vs. transgenic mouse tissue. Levels oftaumRNA were not different betweenAPPswe/PS1ΔE9and littermate control animals. As physiological levels of endogenous, ‘wild-type’ tau aggregate secondarily to Aβ in transgenic mice, this study demonstrates that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.
Anodal Transcranial Direct Current Stimulation (tDCS) of hMT+ Does Not Affect Motion Perception Learning
Authors: Larcombe Stephanie J. , Kennard Christopher , O’Shea Jacinta , Bridge Holly
Published: August 2018

Background

Human visual cortical area hMT+, like its homologue MT in the macaque monkey, has been shown to be particularly selective to visual motion. After damage to the primary visual cortex (V1), patients often exhibit preserved ability to detect moving stimuli, which is associated with neural activity in area hMT+. As an anatomical substrate underlying residual function in the absence of V1, promoting functional plasticity in hMT+ could potentially boost visual performance despite cortical damage.

Objective

To establish in healthy participants whether it is possible to use transcranial direct current stimulation (tDCS) over hMT+ to potentiate learning of visual motion direction discrimination.

Methods

Participants were trained daily for five days on a visual motion direction discrimination task. Task difficulty was increased as performance improved, by decreasing the proportion of coherently moving dots, such that participants were always performing at psychophysical threshold. tDCS, either anodal or sham, was applied daily during the 20-minute training session. Task performance was assessed at baseline and at the end of the training period.

Results

All participants showed improved task performance both during and after training. Contrary to our hypothesis, anodal tDCS did not further improve performance compared to sham stimulation. Bayesian statistics indicated significant evidence in favour of the null hypothesis.

Conclusion

Anodal tDCS to hMT+ does not enhance visual motion direction discrimination learning in the young healthy visual system.
Identification of subject-specific immunoglobulin alleles from expressed repertoire sequencing data
Authors: Gadala-Maria Daniel , Gidoni Moriah , Marquez Susanna , Heiden Jason A. Vander , Kos Justin T. , Watson Corey T. , O’Connor Kevin C. , Yaari Gur , Kleinstein Steven H.
Published: August 2018

The adaptive immune receptor repertoire (AIRR) contains information on an individuals’ immune past, present and potential in the form of the evolving sequences that encode the B cell receptor (BCR) repertoire. AIRR sequencing (AIRR-seq) studies rely on databases of known BCR germline variable (V), diversity (D) and joining (J) genes to detect somatic mutations in AIRR-seq data via comparison to the best-aligning database alleles. However, it has been shown that these databases are far from complete, leading to systematic misidentification of mutated positions in subsets of sample sequences. We previously presented TIgGER, a computational method to identify subject-specific V gene genotypes, including the presence of novel V gene alleles, directly from AIRR-seq data. However, the original algorithm was unable to detect alleles that differed by more than 5 single nucleotide polymorphisms (SNPs) from a database allele. Here we present and apply an improved version of the TIgGER algorithm which can detect alleles that differ by any number of SNPs from the nearest database allele, and can construct subject-specific genotypes with minimal prior information. TIgGER predictions are validated both computationally (using a leave-one-out strategy) and experimentally (using genomic sequencing), resulting in the addition of three new immunoglobulin heavy chain V (IGHV) gene alleles to the IMGT repertoire. Finally, we develop a Bayesian strategy to provide a confidence estimate associated with genotype calls. All together, these methods allow for much higher accuracy in germline allele assignment, an essential step in AIRR-seq studies.
A deep learning framework for imputing missing values in genomic data
Authors: Qiu Yeping Lina , Zheng Hong , Gevaert Olivier
Published: August 2018

Motivation

The presence of missing values is a frequent problem encountered in genomic data analysis. Lost data can be an obstacle to downstream analyses that require complete data matrices. State-of-the-art imputation techniques including Singular Value Decomposition (SVD) and K-Nearest Neighbors (KNN) based methods usually achieve good performances, but are computationally expensive especially for large datasets such as those involved in pan-cancer analysis.

Results

This study describes a new method: a denoising autoencoder with partial loss (DAPL) as a deep learning based alternative for data imputation. Results on pan-cancer gene expression data and DNA methylation data from over 11,000 samples demonstrate significant improvement over standard denoising autoencoder for both data missing-at-random cases with a range of missing percentages, and missing-not-at-random cases based on expression level and GC-content. We discuss the advantages of DAPL over traditional imputation methods and show that it achieves comparable or better performance with less computational burden.

Availability

https://github.com/gevaertlab/DAPL

Contact

ogevaert@stanford.edu
Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1)
Authors: Ungerbäck Jonas , Hosokawa Hiroyuki , Wang Xun , Strid Tobias , Williams Brian A. , Sigvardsson Mikael , Rothenberg Ellen V.
Published: August 2018

SPI1 (also known as PU.1) is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T-cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later down-regulated. Pioneering activity of PU.1 was tested in this developmentally dynamic context by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T-cell development and by using stage-specific gain- and loss-of-function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborator, CEBPA. RUNX motifs and RUNX1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without RUNX1. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative trade-offs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At nonpromoter sites, PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at nonpromoter sites where local chromatin accessibility depended on the presence of PU.1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA-binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition, served by non-DNA-binding domains of PU.1.