bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysphagia lusoria: problem or incidentaloma?
Authors: Epperson Madison V. , Howell Rebecca
Published: October 2019

Purpose of review

To address the incidental versus pathogenic nature of dysphagia lusoria and to provide a review of the cause, clinical presentation, diagnosis, and treatment of this condition with respect to recent literature.

Recent findings

Case reports comprise the majority of recent literature concerning dysphagia lusoria. Many patients with an aberrant right subclavian artery (ARSA) have additional coexisting vascular anomalies. While most individuals present around age 50, some present as children and neonates. Of note, this population may present with dysphagia as opposed to respiratory findings alone, as previously described. In the diagnostic workup, most patients receive a battery of radiologic tests, which may not be necessary. Significantly, dietary modifications and medical management alone may resolve symptoms. Nonetheless, a wide range of operative techniques are available for the treatment of dysphagia lusoria.

Clinicians should have a higher suspicion for dysphagia lusoria in patients with known vascular, heart, or chromosomal anomalies. Diagnosis should begin with a barium esophagram followed by a computed tomography angiogram or magnetic resonance angiogram. Avoid unnecessary studies. In many cases, an ARSA may be an incidental finding with comorbid gastroesophageal reflux disease or another medical condition responsible for the symptoms. Medical versus surgical management should be considered on a case-by-case basis.
Liver Transplantation for Propionic Acidemia
Authors: Alexopoulos Sophoclis P. , Matsuoka Lea , Hafberg Einar , Morgan Thomas , Thurm Cary , Hall Matt , Godown Justin
Published: October 2019

Objectives:

Propionic acidemia (PA) is a rare inborn error of metabolism resulting from deficiency in the enzyme necessary for catabolism of branched‐chain amino acids, some odd chain fatty acids and cholesterol. Despite optimal medical management, PA often leads to acute and progressive neurological injury. Reports on liver transplantation (LT) as a cellular therapy are limited and varied. The objective of this study was to examine the largest collection of patients who underwent LT for PA.

Methods:

Examining the Scientific Registry of Transplant Recipients and the Pediatric Health Information System administrative billing databases, we performed a multicenter, retrospective analysis of LT over a 16‐year period. During this period, 4849 pediatric LT were performed out of which 23 were done for PA at 10 different centers.

Results:

The majority of recipients were 5 years of age or younger and had status 1b exception points at the time of transplant. The 1‐, 3‐, and 5‐year graft survival for PA LT recipients was 84.6% and the 1‐, 3, and 5‐year patient survival was 89.5%. There was no significant difference in graft or patient survival between PA and non‐PA LT recipients. Despite historical data to the contrary, we did not find an increased incidence of hepatic arterial thrombosis in patients undergoing LT for PA. Patients in the PA LT group, however, had a significantly higher postoperative rate of readmission compared with the non‐PA LT group (90.5% vs 72.8%, P = 0.021).

Conclusion:

LT for children with PA is a viable treatment option with acceptable outcomes.
Improving Perinatal Care Through Theory Application
Authors: Côté-Arsenault Denise , Hubbard Lori Johnson
Published: October 2019

Theories from various perspectives can increase nurses' understanding of maternal behaviors throughout the developmental process of pregnancy and postpartum. The purpose of this article is to present relevant theories that maternity nurses will likely find useful, and to demonstrate their applicability through an unfolding exemplar case. Nurses can provide improved and more sensitive care when guided by psychosocial theories such as Rubin's tasks of pregnancy, prenatal attachment, pregnancy as a liminal phase, and the grief work in postpartum as proposed by Mercer. Use of relevant theories can promote holistic nursing care, increase critical thinking, and improve nursing responsiveness to unique family situations such as pregnancy after loss and premature birth.
Knowledge of HIV Status Is Associated With a Decrease in the Severity of Depressive Symptoms Among Female Sex Workers in Uganda and Zambia
Authors: Ortblad Katrina F. , Musoke Daniel Kibuuka , Chanda Michael M. , Ngabirano Thomson , Velloza Jennifer , Haberer Jessica E. , McConnell Margaret , Oldenburg Catherine E. , Bärnighausen Till
Published: October 2019

Background:

Knowledge of HIV-positive status may result in depressive symptoms, which may be a concern to scaling novel HIV testing interventions that move testing outside the health system and away from counselor support.

Setting:

Uganda and Zambia.

Methods:

We used longitudinal data from 2 female sex worker (FSW) cohorts in Uganda (n = 960) and Zambia (n = 965). Over 4 months, participants had ample opportunity to HIV testing using standard-of-care services or self-tests. At baseline and 4 months, we measured participants' perceived knowledge of HIV status, severity of depressive symptoms (continuous PHQ-9 scale, 0–27 points), and prevalence of likely depression (PHQ-9 scores ≥10). We estimated associations using individual fixed-effects estimation.

Results:

Compared with unknown HIV status, knowledge of HIV-negative status was significantly associated with a decrease in depressive symptoms of 1.06 points in Uganda (95% CI −1.79 to −0.34) and 1.68 points in Zambia (95% CI −2.70 to −0.62). Knowledge of HIV-positive status was significantly associated with a decrease in depressive symptoms of 1.01 points in Uganda (95% CI −1.82 to −0.20) and 1.98 points in Zambia (95% CI −3.09 to −0.88). The prevalence of likely depression was not associated with knowledge of HIV status in Uganda but was associated with a 14.1% decrease with knowledge of HIV-negative status (95% CI −22.1% to −6.0%) and a 14.3% decrease with knowledge of HIV-positive status (95% CI −23.9% to −4.5%) in Zambia.

Conclusions:

Knowledge of HIV status, be it positive or negative, was significantly associated with a decrease in depressive symptoms in 2 FSW populations. The expansion of HIV testing programs may have mental health benefits for FSWs.
Cloverleaf Sign in Pelvic Magnetic Resonance Imaging for Deep Infiltrating Endometriosis
Authors: Härmä Kirsi , Binda Aleksandra , Ith Michael , Poellinger Alexander , Siegenthaler Franziska , Heverhagen Johannes , Imboden Sara , Mueller Michael
Published: October 2019

Objectives

The aim of this study was to evaluate the significance of a new imaging sign, the “cloverleaf sign,” in diagnosing deep infiltrating endometriosis (DIE) with magnetic resonance imaging (MRI) in concordance to intraoperative findings.

Materials and Methods

This retrospective study included 103 patients operated during the January 2016 to June 2018 period with preoperative 1.5 T and 3 T MRI, with or without vaginal and rectal gel filling. Magnetic resonance imaging scans were read blinded to intraoperative findings by a specialized gynecologic radiologist and a junior radiologist, and then compared with intraoperative findings by looking at the operation report, postoperative diagnosis, and intraoperative images and videos by an experienced gynecologist surgeon specialized in endometriosis surgery. All endometriosis lesions were confirmed by pathology. The “cloverleaf sign” was defined as a cloverleaf-like figure in imaging morphology; the “leaves” formed by at least 3 different organs come together in the center of the figure formed by constrictive adhesions including T2-weighted (T2W) hypointense DIE. Operation times, intraoperative blood loss, and the frequency of DIE and bowel resections were analyzed in cloverleaf and noncloverleaf groups. The 2-sample Wilcoxon rank-sum (Mann-Whitney U) test and multivariate analysis of variance were used to calculate the significance of an overall impact of cloverleaf sign on operation time, blood loss, and the amount of the bowel resection rate. P < 0.05 was considered statistically significant.

Results

The prevalence of DIE in the study population was 79.6%. A total of 11.5% of the patients had no endometriosis, 32.6% had rASRM I and II, and 55.9% had rASRM III and IV. Forty-six patients (45%) had received rectal and vaginal gel opacification before scanning, 57 (55%) did not. A cloverleaf sign on MRI was detected in 34 patients (15 in gel filling and 19 in nonfilling group). The interreader agreement was almost perfect 0.91 (κ). The median operation time in the cloverleaf group was 248 minutes (interquartile range [IQR], 165–330) compared with 145 minutes in the noncloverleaf group (IQR, 90–210), that is, significantly higher (P < 0.001). Intraoperative blood loss was also significantly higher in the conglomerate group (125 vs 50 mL; IQR, 100–300 vs 50–100; P < 0.001). Of the bowel resections in our study population, 41% (14/34) were performed on patients with a cloverleaf sign in the MRI, compared with 13% (9/69) in patients without the cloverleaf sign.

Conclusions

The “cloverleaf” MRI sign was associated with significantly longer operation time, increased intraoperative blood loss, and higher rates of bowel resection in DIE patients.
Low-Radiation-Dose Stress Myocardial Perfusion Measurement Using First-Pass Analysis Dynamic Computed Tomography
Authors: Hubbard Logan , Malkasian Shant , Zhao Yixiao , Abbona Pablo , Kwon Jungnam , Molloi Sabee
Published: October 2019

Objectives

The aim of this study was to assess the feasibility of a prospective first-pass analysis (FPA) dynamic computed tomography (CT) perfusion technique for accurate low-radiation-dose global stress perfusion measurement.

Materials and Methods

The prospective FPA technique was evaluated in 10 swine (42 ± 12 kg) by direct comparison to a previously validated retrospective FPA technique. Of the 10 swine, 3 had intermediate stenoses with fractional flow reserve severities of 0.70 to 0.90. In each swine, contrast and saline were injected peripherally followed by dynamic volume scanning with a 320-slice CT scanner. Specifically, for the reference standard retrospective FPA technique, volume scans were acquired continuously at 100 kVp and 200 mA over 15 to 20 seconds, followed by systematic selection of only 2 volume scans for global perfusion measurement. For the prospective FPA technique, only 2 volume scans were acquired at 100 kVp and 50 mA for global perfusion measurement. All prospective global stress perfusion measurements were then compared with the corresponding reference standard retrospective global stress perfusion measurements through regression analysis. The CTDIvol
32 and size-specific dose estimate of the prospective FPA technique were also determined.

Results

All prospective global stress perfusion measurements (PPRO) at 50 mA were in good agreement with the reference standard retrospective global stress perfusion measurements (PREF) at 200 mA (PPRO = 1.07 PREF −0.09, r = 0.94; root-mean-square error = 0.30 mL/min per gram). The CTDIvol
32 and size-specific dose estimate of the prospective FPA technique were 2.3 and 3.7 mGy, respectively.

Conclusions

Accurate low-radiation-dose global stress perfusion measurement is feasible using a prospective FPA dynamic CT perfusion technique.
Sex Disparity in Academic Rank and Industry Payments to Plastic Surgeons
Authors: Ngaage Ledibabari M. , Harris Chelsea , Rosen Carly , Ge Shealinna , Kim Cecelia , Rada Erin M. , Manahan Michele , Silverman Ronald P. , Slezak Sheri , Rasko Yvonne M.
Published: October 2019

Introduction

Despite increasing representation in surgery, women continue to lag behind men in important metrics. Little is known on how industry funding may also contribute to this ongoing disparity. This article seeks to quantify industry payments to academic plastic surgeons (APSs) by sex and examine the relationship between funding and academic achievement.

Methods

We conducted a cross-sectional analysis of industry payments disbursed to APSs in 2017. Faculty were identified using departmental listings of Accreditation Council for Graduate Medical Education plastic surgery residency programs. Payments were identified via the Center for Medicare and Medicaid Services open payment database. Academic achievement was assessed using rank (eg, assistant professor), leadership designation (eg, division head), and Scopus H-index and then controlled for time in practice.

Results

Of the 805 APSs, the majority were male (82% male vs 18% female, P < 0.0001). Significant sex differences emerged in average yearly industry contributions (men, US $3202, vs women, US $707; P < 0.0001). Across all academic ranks, men received significantly higher payments than women (P < 0.0500). Men constituted 93% of full professors and were almost twice as likely to hold additional leadership positions compared with women (odds ratio, 1.82; P = 0.0143). After adjustment for time in practice, there was no difference in H-indices between male and female APSs, although payment disparity persisted (P < 0.0001).

Conclusions

Substantial sex-based disparities exist among APSs' academic rank and leadership attainment, which is not attributed to differences in academic qualifications or experience. To better elucidate the sources of this disparity, future studies should assess sexed differences in payment types. Furthermore, we urge for increased transparency in the selection process for industry payments.
Happiness in Plastic Surgery
Authors: Sterling David A. , Grow Jacob N. , Vargo James D. , Nazir Niaman , Butterworth James A.
Published: October 2019

Background

Despite a heightened appreciation for wellness in medicine, there exists little information specific to plastic surgery. The purpose of this research was to assess happiness within the field of plastic surgery.

Methods

A cross-sectional study was conducted in July of 2017 by distributing an American Society of Plastic Surgeons sponsored survey to a random cohort of current practicing American Society of Plastic Surgeons members, residents and fellows. In addition, the same survey was sent to medical students applying to integrated plastic surgery residency. Total happiness scores (Subjective Happiness Scale) were averaged and compared between and within surveyed groups.

Results

A total of 595 individuals completed surveys, including 287 practicing surgeons, 116 residents, 12 fellows, and 180 medical students. Differences in happiness scores between the groups were statistically significant (P < 0.01). For practicing physicians, happiness scores were significantly greater for those more than 20 years out from training (P < 0.01). Furthermore, a significantly positive correlation was found between practice expectations coming out of residency and happiness scores (Pearson correlation coefficient, 0.2; P < 0.01).

Conclusions

Despite the prevalence of burnout and mental health disorders associated with a career in medicine, plastic surgeons and trainees report high levels of happiness. Practicing plastic surgeons report increased happiness further out from training and when meeting practice expectations coming out of training. Otherwise, there were no significant differences in happiness between groups. Regarding sex, it is encouraging to report no significant sex discrepancies with happiness in a field where women still face significant adversity.
Ultrasonographic Features of Trigger Finger in Patients With Hyperuricemia
Authors: Wang Ping-Hui , Hsieh Tai-Jung , Wu Tung-Tai , Wu Kuo-Chen , Jou I-Ming
Published: October 2019

Purpose

The purpose of the current study was to compare demographic differences and ultrasonographic features in primary trigger finger and trigger finger in association with hyperuricemia.

Methods

Between October 2008 and February 2010, a prospective review of consecutive cases of 54 patients with trigger finger and hyperuricemia, 76 patients with a trigger finger without hyperuricemia, and 80 control cases were enrolled. The clinical results were analyzed by descriptive epidemiology, an ultrasonographic measurement of the thickness of A1 pulley, cross-sectional area of the flexor tendon and synovium.

Results

The middle finger was primarily affected, followed by the index and ring fingers in both trigger finger groups. The thickness of A1 pulley, cross-sectional area of the flexor tendon, and flexor tendon with synovium in trigger finger without hyperuricemia group were significantly larger than that in trigger finger with hyperuricemia and control groups. There was no significant difference between trigger finger with hyperuricemia and control groups. Double-contour sign and tophus were only observed in trigger finger with hyperuricemia group.

Conclusions

Thickness of A1 pulley, cross-sectional area of the flexor tendon, and flexor tendon with synovium were significantly larger in trigger finger without hyperuricemia group. These findings were not evident in trigger finger with hyperuricemia group.
Virtual Surgical Planning for Mandibular Reconstruction With the Fibula Free Flap
Authors: Barr Meaghan L. , Haveles Christos S. , Rezzadeh Kameron S. , Nolan Ian T. , Castro Ruben , Lee Justine C. , Steinbacher Derek , Pfaff Miles J.
Published: October 2019

Background

The fibula free flap (FFF) remains the criterion standard for complex mandibular reconstruction. Surgeons have incorporated virtual surgical planning (VSP) into the reconstructive algorithm with the assertion that VSP increases operative efficiency and may improve clinical outcomes. To date, no large-scale studies have analyzed these claims. This study examines the literature and tests the hypothesis that VSP improves operative efficiency, clinical outcomes, and accuracy when compared with traditional techniques.

Methods

A systematic review was performed to identify articles utilizing VSP and traditional techniques for FFF-based mandibular reconstruction. Two reviewers independently assessed all articles for methodological quality using a validated instrument (weighted Cohen κ for interrater reliability = 0.70). Outcomes included operative time, length of stay, complications, and accuracy. Meta-analytic comparisons were performed using data from comparative studies using a random-effects model and differences of means analysis for outcomes measured on identical scales.

Results

One hundred thirty-one articles were identified, and 25 met the inclusion criteria: 12 were VSP only, whereas 13 were comparative. There were 241 VSP patients and 214 traditional patients available for meta-analysis. Patients undergoing reconstruction with VSP had a significant reduction in operative time by 44.64 minutes (95% confidence interval [CI], −74.69 to −14.58 minutes; P < 0.01) and demonstrated a mean trend toward shorter hospital admission (mean difference, −1.24 days; 95% CI, −4.00 to 1.52 days; P = 0.38). There was no statistical difference between cohorts for major (odds ratio, 1.03; 95% CI, 0.46–2.31; P = 0.95) or minor complications (odds ratio, 0.97; 95% CI, 0.54–1.71; P = 0.90). Insufficient data were available for cost analysis and accuracy.

Conclusions

Virtual surgical planning–guided mandibular reconstruction with FFF is associated with significantly decreased operative time and a mean trend toward shorter hospital admission. While multiple studies reported a high degree of accuracy, no standard measurement was available for meta-analysis.
Deep Inferior Epigastric Perforator Breast Reconstruction With Computer-Aided Design/Computer-Aided Manufacturing Sizers
Authors: Gelati Chiara , Lozano Miralles Maria Elisa , Morselli Paolo Giovanni , Fabbri Erich , Cipriani Riccardo
Published: October 2019

Background

The goal of microsurgical breast reconstruction is to return to the precancer state, maximizing symmetry with less morbidity. This requires a long learning curve, in particular where modeling is concerned. In this context, reverse engineering technologies found an application, allowing the creation of molds that can be used during the surgery.

Method

We created 10 molds named DIEP sizers, which help to simplify deep inferior epigastric perforator (DIEP) flap insetting. For this, we designed a virtual model using Geomagic X software to construct the sizers. Our model has a thorax circumference, breast projection, and footprint correspondent to an average of the measurements we collected from 15 patients undergoing such surgery. We made a comparative study between 2 groups each of 24 patients, using as comparison criteria surgical times in patients undergoing breast microsurgical reconstruction with or without DIEP sizers. In both groups, we included immediate and delayed reconstructions as well as monolateral, bilateral and monolateral with contralateral symmetrization.

Result

In all the cases we performed with DIEP sizers, we achieved an average time saving of 105 minutes in monolateral reconstruction, 80 minutes in monolateral reconstruction with contralateral symmetrization, and 120 minutes in bilateral reconstruction (P < 0.001). No major complications occurred.

Conclusions

We performed 24 breast reconstructions with preformed molds, obtaining a proper “library” with different DIEP sizers that can be used both in preoperative planning and in intraoperative modeling. We recommend the use of a preformed mold in microsurgical breast reconstruction to improve symmetry, to shorten the learning curve and to save time.
Assessment of Clinical and Histological Changes in the Skin Paddle of Pectoralis Major Myocutaneous Flap in Intraoral Reconstruction
Authors: Behera Saswati , Mohsina Subair , Tripathy Satyaswarup , John Jerry R. , Sharma Ramesh Kumar , Panda Naresh Kumar , Bakshi Jaimanti , Radotra Bishan Dass , Sahu Ranjit Kumar
Published: October 2019

Purpose

This study was carried out to characterize the clinical and histological changes in the cutaneous portion of the transferred pedicled pectoralis major myocutaneous flaps used in intraoral reconstruction in patients with head and neck malignancy.

Methods

This was a prospective cohort study carried out from July 2016 to 2018. All patients underwent ablative surgery for oropharyngeal cancers and primary reconstruction with pedicled pedicled pectoralis major myocutaneous flaps. The intraoral flaps were examined for color, texture, presence of hair, chronic inflammatory changes, and ulceration. At 12 months, incisional biopsies were taken from the skin paddle of the intraoral flap and contralateral normal buccal mucosa, and flap histology was compared with that of the contralateral buccal mucosa.

Results

Twenty patients were included in the final analysis (M/F, 4:1; mean ± SD age, 51.38 ± 6.76 years). Fourteen flaps resembled oral mucosa, 3 had a mixed appearance of both skin and mucosa, and 3 had appearance of normal skin at 1 year follow-up. The epidermis and stratum corneum were retained in all the flap biopsies; however, severe attenuation was noted in 7 patients (had mucosal appearance) but was significantly different from oral mucosa(P = 0.0003). Cutaneous appendages were found in all the flap epithelia. Thirteen flaps showed grossly attenuation, of which 11 patients had a gross appearance resembling oral mucosa and 2 had a mixed appearance. The biopsies showed varied degree of chronic changes like desquamation in around 35% (7 patients), hyperkeratosis in 35% (7 patients), and chronic candidiasis in 30% (6 patients).

Conclusions

Although the intraorally transferred flaps demonstrate a morphological appearance similar to oral mucosa, there is a histological preservation of skin elements and architecture.
Surgical Treatment of Mandible Fracture Using Unsintered Hydroxyapatite/Poly l-Lactide Composite Fixation System
Authors: Lee Sun Jae , Park Eun Soo , Nam Seung Min , Choi Chang Yong , Shin Ho Sung , Kim Yong Bae
Published: October 2019

Recently, absorbable plates have been used for various types of facial fractures. However, in the case of mandibular fractures, a large amount of force is applied after fixation. Thus, a firm fixation is necessary. In particular, unfavorable fractures are more frequent in mandibular fractures. Therefore, plates should be strong enough to withstand forces at the time of surgery. The purpose of this study was to determine clinical efficacy and usefulness of unsintered hydroxyapatite (u-HA)/poly (l-lactide) (PLLA) composite system by clinical application and follow-up of fixation in patients with mandible fracture. A total of 13 patients with mandible fractures were assessed for compliance with the selection criteria. Fracture site was confirmed with radiographic findings including X-ray and facial computed tomography images. Subjects who fulfilled all criteria underwent operation using HA/PLLA composite fixation system (OSTEOTRANS; Takiron Co Ltd, Osaka, Japan). After reduction of fracture site through oral or skin incision, we placed OSTEOTRANS plates on fracture line and performed rigid fixation with OSTEOTRANS-MX screws. Follow-up was performed at 1 week, 1, 3, and 6 months after surgery. Occlusion and mouth opening were checked by physical examination and radiographic finding. We also confirmed bone approximation status, bony gap change, and bone union status. All patients finished every follow-up. They were satisfied with outcomes without complications such as malocclusion, foreign body sensation, or tenderness. This study confirms that OSTEOTRANS can be used appropriately for mandibular fractures.
Fougerite: the not so simple progenitor of the first cells
Authors: Duval Simon , Baymann Frauke , Schoepp-Cothenet Barbara , Trolard Fabienne , Bourrié Guilhem , Grauby Olivier , Branscomb Elbert , Russell Michael J. , Nitschke Wolfgang
Published: October 2019

We here review the extraordinary mineralogical properties of green rusts and their naturally occurring form, fougerite, and discuss the pertinence of these properties within the alkaline hydrothermal vent (AHV) hypothesis for life's emergence. We put forward an extended version of the AHV scenario which enhances the conformity between extant life and its earliest progenitor by extensively making use of fougerite's mechanistic and catalytic particularities.
Bringing Proportional Recovery into Proportion: Bayesian Hierarchical Modelling of Post-Stroke Motor Performance
Authors: Bonkhoff Anna K. , Hope Thomas , Bzdok Danilo , Guggisberg Adrian G. , Hawe Rachel L. , Dukelow Sean P. , Rehme Anne K. , Fink Gereon R. , Grefkes Christian , Bowman Howard
Published: October 2019

Accurate predictions of motor performance after stroke are of cardinal importance for the patient, clinician, and health care system. More than ten years ago, the proportional recovery rule was introduced by promising just that: high-fidelity predictions of recovery following stroke based only on the initially lost motor performance, at least for a specific fraction of patients. However, emerging evidence suggests that this recovery rule is subject to various confounds and may apply less universally than assumed by many.

We systematically revisited stroke outcome predictions by casting the data in a less confounded form and employing more integrative and flexible hierarchical Bayesian models. We jointly analyzedn=385 post-stroke trajectories from six separate studies – the currently largest overall dataset of upper limb motor recovery. We addressed confounding ceiling effects by introducing a subset approach and ensured correct model estimation through synthetic data simulations. Finally, we used model comparisons to assess the underlying nature of recovery within our empirical recovery data.

The first model comparison, relying on the conventional fraction of patients calledfitters, pointed to a combination of constant and proportional to lost function recovery. Proportional to lost here describes the original notion of proportionality, indicating greater recovery in case of a more pronounced initial deficit. This combination explained only 32% of the variance in recovery, which is in stark contrast to previous reports of >80%. When instead analyzing the complete spectrum of subjects, model comparison selected a composite of constant and proportional to spared function recovery, implying a more significant improvement in case of more preserved function. Explained variance was at 53%.

Therefore, our data suggest that motor recovery post-stroke may exhibit some characteristics of proportionality. However, the levels of explanatory value were substantially reduced compared to what has previously been reported. This finding motivates future research moving beyond solely behavior scores to explain stroke recovery and establish robust single-subject predictions.
Fluorescence and light scatter calibration allow comparisons of small particle data in standard units across different flow cytometry platforms and detector settings
Authors: Welsh J.A. , Jones J.C. , Tang V.A.
Published: October 2019

Flow cytometers have been utilized for the analysis of submicron-sized particles since the late 1970s. Initially, virus analyses preceded extracellular vesicle (EV), which began in the 1990s. Despite decades of documented use, the lack of standardization in data reporting has resulted in a growing body of literature that cannot be easily interpreted, validated, or reproduced. This has made it difficult for objective assessments of both assays and instruments, in-turn leading to significant hindrances in scientific progress, specifically in the study of EVs, where the phenotypic analysis of these submicron-sized vesicles is becoming common-place in every biomedical field. Methods for fluorescence and light scatter standardization are well established and the reagents to perform these analyses are commercially available. However, fluorescence and light scatter calibration are not widely adopted by the small particle community as methods to standardize flow cytometry data. In this proof-of-concept study carried out as a resource for use at the CYTO2019 workshop, we demonstrate for the first-time simultaneous fluorescence and light scatter calibration of small particle data to show the ease and feasibility of this method for standardized flow cytometry data reporting. This data was acquired using standard configuration commercial flow cytometers, with commercially available materials, published methods, and freely available software tools. We show that application of light scatter, fluorescence, and concentration calibration can result in highly concordant data between flow cytometry platforms independent of instrument collection angle, gain/voltage settings, and flow rate; thus, providing a means of cross-comparison in standard units.
Personalized Network Modeling of the Pan-Cancer Patient and Cell Line Interactome
Authors: Bhattacharyya Rupam , Ha Min Jin , Liu Qingzhi , Akbani Rehan , Liang Han , Baladandayuthapani Veerabhadran
Published: October 2019

ABSTRACT

Purpose

Personalized network inference on diverse clinical andin vitromodel systems across cancer types can be used to delineate specific regulatory mechanisms, uncover drug targets and pathways, and develop individualized predictive models in cancer.

Datasets and methods

We developed TransPRECISE, a multi-scale Bayesian network modeling framework, to analyze the pan-cancer patient and cell line interactome to identify differential and conserved intra-pathway activities, globally assess cell lines as representative models for patients and develop drug sensitivity prediction models. We assessed pan-cancer pathway activities for a large cohort of patient samples (>7700) from The Cancer Proteome Atlas across ≥30 tumor types and a set of 640 cancer cell lines from the M.D. Anderson Cell Lines Project spanning16 lineages, and ≥250 cell lines’ response to >400 drugs.

Results

TransPRECISE captured differential and conserved proteomic network topologies and pathway circuitry between multiple patient and cell line lineages: ovarian and kidney cancers shared high levels of connectivity in the hormone receptor and receptor tyrosine kinase pathways, respectively, between the two model systems. Our tumor stratification approach found distinct clinical subtypes of the patients represented by different sets of cell lines: head and neck patient tumors were classified into two different subtypes that are represented by head and neck and esophagus cell lines, and had different prognostic patterns (456 vs. 654 days of median overall survival; P=0.02). The TransPRECISE-based sample-specific pathway scores achieved high predictive accuracy for drug sensitivities in cell lines across multiple drugs (median AUC >0.8).

Conclusion

Our study provides a generalizable analytical framework to assess the translational potential of preclinical model systems and guide pathway-based personalized medical decision-making, integrating genomic and molecular data across model systems.
The cryo-EM structure of the bacterial flagellum cap complex suggests a molecular mechanism for filament elongation
Authors: Al-Otaibi Natalie S. , Taylor Aidan J. , Farrell Daniel P. , Tzokov Svetomir B. , DiMaio Frank , Kelly David J. , Bergeron Julien R.C.
Published: October 2019

The bacterial flagellum is a remarkable molecular motor, present at the surface of many bacteria, whose primary function is to allow motility through the rotation of a long filament protruding from the bacterial cell. A cap complex, consisting of an oligomeric assembly of the protein FliD, is localized at the tip of the flagellum, and is essential for filament assembly, as well as adherence to surfaces in some bacteria. However, the structure of the intact cap complex, and the molecular basis for its interaction with the filament, remains elusive. Here we report the cryo-EM structure of the Campylobacter jejuni cap complex. This structure reveals that FliD is pentameric, with the N-terminal region of the protomer forming an unexpected extensive set of contacts across several subunits, that contribute to FliD oligomerization. We also demonstrate that the native C. jejuni flagellum filament is 11-stranded and propose a molecular model for the filament-cap interaction.
A Brain to Spine Interface for Transferring Artificial Sensory Information
Authors: Yadav Amol P. , Li Daniel , Nicolelis Miguel A. L.
Published: October 2019

Lack of sensory feedback is a major obstacle in the rapid absorption of prosthetic devices by the brain. While electrical stimulation of cortical and subcortical structures provides unique means to deliver sensory information to higher brain structures, these approaches require highly invasive surgery and are dependent on accurate targeting of brain structures. Here, we propose a semi-invasive method, Dorsal Column Stimulation (DCS) as a tool for transferring sensory information to the brain. Using this new approach, we show that rats can learn to discriminate artificial sensations generated by DCS and that DCS-induced learning results in corticostriatal plasticity. We also demonstrate a proof of concept brain-to-spine interface (BTSI), whereby tactile and artificial sensory information are decoded from the brain of an “encoder” rat, transformed into DCS pulses, and delivered to the spinal cord of a second “decoder” rat while the latter performs an analog-to-digital conversion during a tactile discrimination task. These results suggest that DCS can be used as an effective sensory channel to transmit prosthetic information to the brain or between brains, and could be developed as a novel platform for delivering tactile and proprioceptive feedback in clinical applications of brain-machine interfaces.
An ecophysiological model of plant-pest interactions: the role of nutrient and water availability
Authors: Zaffaroni Marta , Cunniffe Nik J. , Bevacqua Daniele
Published: October 2019

Empirical studies have shown that particular irrigation/fertilization regimes can control pest populations in agroecosystems. This appears to promise that the ecological concept of bottom-up control can be applied to pest management. However, a conceptual framework is necessary to develop a mechanistic basis for empirical evidence. Here we couple a mechanistic plant growth model with a pest population model. We demonstrate its utility by applying it to the peach - green aphid system. Aphids are herbivores which feed on the plant phloem, deplete plants’ resources and (potentially) transmit viral diseases. The model reproduces system properties observed in field studies and shows under which conditions the diametrically-opposed plant vigour and plant stress hypotheses find support. We show that the effect of fertilization/irrigation on the pest population cannot be simply reduced as positive or negative. In fact, the magnitude and direction of any effect depends on the precise level of fertilization/irrigation and on the date of observation. We show that a new synthesis of experimental data can emerge by embedding a mechanistic plant growth model, widely studied in agronomy, in a consumer-resource modelling framework, widely studied in ecology. The future challenge is to use this insight to inform practical decision making by farmers and growers.
Viral manipulation of functionally distinct neurons from mice to humans
Authors: Vormstein-Schneider Douglas , Lin Jessica , Pelkey Kenneth , Chittajallu Ramesh , Guo Baolin , Garcia Mario Arias , Allaway Kathryn , Sakopoulos Sofia , Schneider Gates , Stevenson Olivia , Vergara Josselyn , Sharma Jitendra , Zhang Qiangge , Franken Tom , Smith Jared , Ibrahim Leena , Mastro Kevin , Sabri Ehsan , Huang Shuhan , Favuzzi Emilia , Burbridge Timothy , Xu Qing , Guo Lihua , Vogel Ian , Sanchez Vanessa , Saldi Giuseppe , Yuan Xiaoqing , Zaghloul Kareem , Devinsky Orrin , Sabatini Bernardo , Batista-Brito Renata , Reynolds John , Feng Guoping , Fu Zhanyan , McBain Chris , Fishell Gord , Dimidschstein Jordane
Published: October 2019

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.
Identification of putative effector genes across the GWAS Catalog using molecular quantitative trait loci from 68 tissues and cell types
Authors: Guo Cong , Sieber Karsten B. , Esparza-Gordillo Jorge , Hurle Mark R. , Song Kijoung , Yeo Astrid J. , Yerges-Armstrong Laura M. , Johnson Toby , Nelson Matthew R.
Published: October 2019

Identifying the effector genes from genome-wide association studies (GWAS) is a crucial step towards understanding the biological mechanisms underlying complex traits and diseases. Colocalization of expression and protein quantitative trait loci (eQTL and pQTL, hereafter collectively called “xQTL”) can be effective for mapping associations to genes in many loci. However, existing colocalization methods require full single-variant summary statistics which are often not readily available for many published GWAS or xQTL studies. Here, we present PICCOLO, a method that uses minimum SNP p-values within a locus to determine if pairs of genetic associations are colocalized. This method greatly expands the number of GWAS and xQTL datasets that can be tested for colocalization. We applied PICCOLO to 10,759 genome-wide significant associations across the NHGRI-EBI GWAS Catalog with xQTLs from 28 studies. We identified at least one colocalized gene-xQTL in at least one tissue for 30% of associations, and we pursued multiple lines of evidence to demonstrate that these mappings are biologically meaningful. PICCOLO genes are significantly enriched for biologically relevant tissues, and 4.3-fold enriched for targets of approved drugs.
Effective connectivity during autobiographical memory search
Authors: Nawa Norberto Eiji , Ando Hiroshi
Published: October 2019

Autobiographical memory (AM) retrieval is known to recruit a widely distributed network of brain regions but much less is known regarding how these regions interact during the various phases that presumably take place during episodic memory retrieval in general and AM retrieval in particular. Here, we used dynamic causal modeling (DCM) to examine effective connectivity during cued AM search in a sub-network consisting of six major regions within this large network. Functional MRI data was acquired while participants were visually presented verbal cues describing common life events and requested to search for a personal memory that could be associated with each cue. We examined directed couplings between the ventromedial (vmPFC), dorsomedial (dmPFC) and dorsolateral prefrontal cortices (dlPFC), hippocampus, angular gyrus and a region in the posterior midline cortex (RSC/PCC/Prec), all located in the left hemisphere. Results indicated that during AM search, the vmPFC, dlPFC and RSC/PCC/Prec acted as primary drivers of activity in the rest of the network. Moreover, when AM search was completed successfully (Hits), an up-modulation of the effective connectivity of the hippocampus in the vmPFC and angular gyrus was observed. In the same way, there was an increase in the influence of the RSC/PCC/Prec in the activity of the dlPFC and dmPFC. Furthermore, during Hits the angular gyrus showed to have an inhibitory effect in all other nodes of the network. These results are consistent with the notion that midline cortical regions are crucial in supporting the retrieval of AMs, and highlight the interplay between the vmPFC and the RSC/PCC/Prec and the dlPFC during AM search.
Sex differences in electrophysiological properties of mouse mPOA neurons revealed by in vitro whole-cell recordings
Authors: Zhang Wen , Li Shuai-shuai , Jiao Zhuo-lei , Han Ying , Wang Zi-yue , Xu Xiao-Hong
Published: October 2019

The medial preoptic area (mPOA) of the hypothalamus is sexually dimorphic and controls sexually dimorphic display of male mating and parental care. Yet, despite extensive characterization of sex differences in the mPOA, we know surprisingly little about whether or how male and female mPOA neurons differ electrophysiologically, which relate more directly to neuronal firing and behavioral pattern generation. In this study, we performed whole-cell patch clamp recordings of the mPOA in acute brain slices cut from virgin adult mice, and compared in total 29 electrophysiological parameters between male and female mPOA neurons. We find that resting membrane potential (Vm), input resistance (Rm), time constant (τm), threshold (Vth) and minimum current (rheobase) required to generate an action potential differ significantly between male and female in a cell-type dependent manner. Nonetheless, there is little evidence for profuse sex differences in neuronal excitability, except for a higher probability of rebound neurons in males. Depletion of male gonadal hormones in adulthood partially de-masculinizes sexually dimorphic electrophysiological parameters, suggesting that some of these sex differences may establish during development. Furthermore, as a demonstration of the behavioral relevance of these sex differences, we show that pharmacologic blockage of currents mediated by T-type Ca2+ channel, which underlie rebound and tends to be larger in male mPOA neurons, result in behavioral deficits in male mating. In summary, we have identified key sex differences in electrophysiological properties of mPOA neurons that likely contribute to sexually dimorphic display of behaviors.

Significance Statement

Sex represents an important biological variable that impact an individual’s behaviors, physiology and disease susceptibility. Indeed, sex differences in the nervous system manifest across many different levels and scales. Yet, throughout previous multifaceted investigations on sex differences in the brain, electrophysiological characterizations, which could potentially bridge cellular and molecular sex differences with sexually dimorphic brain functions and behaviors, remains scant. Here, focusing on an evolutionarily conserved sexually dimorphic nucleus, we investigated sex differences in electrophysiological properties of mPOA neurons and its modulation by gonadal hormones in adult males via in vitro whole-cell patch clamp. As a result, we identified novel sex differences in electrophysiological properties that likely contribute to sexually dimorphic display of behaviors and physiological functions.
A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome
Authors: Bekhouche Bahia , Tourville Aurore , Ravichandran Yamini , Tacine Rachida , Abrami Laurence , Dussiot Michael , Khau-Dancasius Andrea , Boccara Olivia , Khirat Meriem , Mangeney Marianne , Bellon Nathalia , Fraitag Sylvie , Hadj-Rabia Smail , Blanche Stéphane , Puel Anne , Etienne-Manneville Sandrine , van der Goot F. Gisou , Cherfils Jacqueline , Hermine Olivier , Casanova Jean-Laurent , Bodemer Christine , Smahi Asma , Delon Jérôme
Published: October 2019

Background

Autoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis.

Objective

We report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype.

Methods

We have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements.

Results

We show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-κB activation.

Conclusions

Our study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.