bluuebunny/crossref_metadata_2025 huggingface dataset:
Joint Contact Changes With Undersized Prosthetic Radial Heads
Authors: Bachman Daniel R. , Park Sangeun , Thaveepunsan Sutee , Fitzsimmons James S. , An Kai-Nan , O'Driscoll Shawn W.
Published: August 2018

Objective:

To evaluate the effect of intentional undersizing of prosthetic radial head implant diameters on joint contact pressures.

Methods:

Eight fresh-frozen cadaveric elbows were aligned in neutral extension and loaded with 100 N using a custom testing apparatus. Radiocapitellar contact pressures were recorded using a Tekscan thin-film pressure sensor. Prosthetic radial head replacement was performed with 2 prostheses: the Anatomic Radial Head and the Evolve Proline Radial Head prostheses. Each design was sized according to the manufacturer's recommendations and then again using 2-mm smaller radial heads.

Results:

Average and peak pressures were significantly higher with the Evolve than the Anatomic prostheses (P < 0.03 and 0.02, respectively). Peak pressures decreased from 4.2 ± 0.5 MPa to 2.9 ± 0.3 MPa for the Anatomic Radial Heads and from 5.6 ± 0.5 MPa to 3.9 ± 0.6 MPa when the Evolve Radial Heads were undersized by 2 mm. The mean pressures of the Anatomic Radial Heads (1.4 ± 0.1 MPa) did not change significantly with undersizing (1.3 ± 0.1 MPa, P = 0.12), whereas the mean pressures of the Evolve Radial Heads (1.6 ± 0.1 MPa) were significantly reduced with undersizing (1.4 ± 0.1 MPa, P < 0.02).

Conclusion:

Both mean and peak pressures were initially high for the Evolve Radial Head sized based on the short axis diameter and were improved with further undersizing by 2 mm. Peak, but not mean, contact pressures were improved by undersizing the Anatomic prosthesis based on the long axis diameter.

Clinical Relevance:

These findings support the clinical recommendation of some surgeons to undersize the Evolve prosthesis by 2-mm smaller diameter than the current manufacturer's suggestion and give reason to consider doing the same for the Anatomic prosthesis.
Klhl14 Antisense RNA is a Target of Key Skeletogenic Transcription Factors in the Developing Intervertebral Disc
Authors: Kraus Petra , Sivakamasundari V. , Olsen Victoria , Villeneuve Victoria , Hinds Abbey , Lufkin Thomas
Published: August 2018

Study Design.

RNA in situ hybridization (RISH) allows for validation and characterization of the long noncoding (lnc) natural antisense RNA (NAT) Klhl14as in the embryonic murine intervertebral disc (IVD) in the context of loss-of-function mutants for key transcription factors (TFs) in axial skeleton development.

Objective.

Validation of Klhl14as in the developing murine IVD.

Summary of Background Data.

The IVD is a focus of regenerative medicine; however, processes and signaling cascades resulting in the different cell types in a mature IVD still require clarification in most animals including humans. Technological advances increasingly point to implications of lnc NATs in transcription/translation regulation. Transcriptome data generation and analysis identified a protein encoding transcript and related noncoding antisense transcript as downregulated in embryos devoid of key TFs during axial skeleton development. Here, primarily, the antisense transcript is analyzed in this loss-of-function context.

Methods.

4930426D05Rik and 6330403N15Rik were identified as Klhl14as and sense, respectively, two transcripts downregulated in the vertebral column of midgestation Pax1 and Pax9 mutant mouse embryos. RISH on wildtype and mutant embryos for the TF encoding genes Pax1/Pax9, Sox5/Sox6/Sox9, and Bapx1 was used to further analyze Klhl14as in the developing IVD.

Results.

Klhl14as and Klhl14 were the top downregulated transcripts in Pax1

-/-

; Pax9

-/-
E12.5 embryos. Our data demonstrate expression of Klhl14as and sense transcripts in the annulus fibrosus (AF) and notochord of the developing IVD. Klhl14as expression in the inner annulus fibrosus (iAF) seems dependent on the TFs Pax1/Pax9, Sox6, Sox9, and Bapx1.

Conclusion.

We are the first to suggest a role for the lncRNA Klhl14as in the developing IVD. Our data link Klhl14as to a previously established gene regulatory network during axial skeleton development and contribute further evidence that lnc NATs are involved in crucial gene regulatory networks in eukaryotic cells.

Level of Evidence: N/A.
Correlation Between Postoperative Distribution of Lordosis and Reciprocal Progression of Thoracic Kyphosis and Occurrence of Proximal Junctional Kyphosis Following Surgery for Adult Spinal Deformity
Authors: Ohba Tetsuro , Ebata Shigeto , Oba Hiroki , Koyama Kensuke , Haro Hirotaka
Published: August 2018

Study Design:

This was a retrospective cohort study using consecutive patients.

Objectives:

The objectives of this study were to evaluate the effect of lumbar lordosis (LL) construction on postoperative reciprocal progression of thoracic kyphosis (TK) and occurrence of proximal junctional kyphosis (PJK) following surgery for adult spinal deformity (ASD).

Summary of Background Data:

A large postoperative TK has been reported as an iatrogenic risk factor for PJK following surgery for ASD. Therefore, knowing how to anticipate and regulate postoperative reciprocal progression in TK with LL restorative surgery is important to prevent PJK. The LL proportion including distribution of the lordosis (lordosis distribution index: LDI) in the lower (L4–S1) and upper (L1–L3) arcs has been known as important because it alters the distribution of load. However, the influence of postoperative LL construction on postoperative reciprocal change in TK resulting in PJK is largely unknown.

Methods:

Sixty-six consecutive patients with ASD treated with LL restorative surgery with a fusion level consistently selected from T8–T10 to the pelvis and followed-up for a minimum of 1 year. Abnormal PJK was evaluated according to the Boachie-Adjei classification. Roland-Morris Disability Questionnaire and Oswestry Disability Index were measured at 1 year after surgery.

Results:

The prevalence of PJK in the present study was 33.3%. Outcomes of patients with PJK were significantly worse than in patients without PJK, regardless of PJK grade. Postoperative reciprocal progression in TK with LL restorative surgery was found. Preoperative risk factors of PJK were older age and smaller sacral slope angle. Postoperative risk factors for PJK included increased TK and decreased LDI. We found a strong correlation between postoperative LDI and reciprocal progression of TK resulting in PJK.

Conclusions:

Postoperative LDI is crucial to prevent excess reciprocal progression of TK resulting in PJK.
Multiple-Level Lumbar Total Disk Replacement
Authors: Rasouli Alexandre , Cuellar Jason M. , Kanim Lea , Delamarter Rick
Published: August 2018

Background:

Recent studies demonstrate the efficacy of lumbar arthroplasty using the ProDisc-L. Patients frequently present with multilevel pathology and may be candidates for multilevel disk replacement.

Purpose:

To evaluate clinical outcomes and sagittal range of motion of operated levels and adjacent lumbar motion segments in multiple-level ProDisc-L constructs after 2–6 years follow-up.

Patient Sample:

A total of 159 patients underwent adjacent 2-level (n=114), 3-level (n=41), or 4-level (n=4) lumbar total disk replacement (TDR).

Study-Design:

This is a prospective cohort.

Outcome Measures:

Clinical measures: Oswestry Disability Index and Visual Analog Score of patient satisfaction (VAS-S) and pain (VAS-P) data were collected. Radiographic measures: sagittal motion on preoperative and postoperative lumbar radiographs at each operative segment and adjacent segment.

Methods:

Patients were evaluated with radiographic and clinical outcomes measures preoperatively, at 6 weeks, 3 months, 6 months, and annually for 24–72 months postoperatively.

Results:

Radiographic: at the motion segment adjacent to the TDR, mean preoperative range of motion (ROM) was 8.20±2.88 degrees, compared with 8.40±2.4 degrees postoperatively at last follow-up (P>0.05). Between the 3 TDR groups, there were no significant differences in ROM at any time point except at L5–S1. Across both groups for TDR motion segments, the mean preoperative ROM was 10.15±2.71 versus 12.30±2.25 degrees postoperatively (P=0.011) at last follow-up. At L5–S1 mean preoperative motion was 7.60±3.90 versus 5.81±3.1 degrees postoperatively (P=0.60). Clinical: at 24–72 months postoperatively, all patients had significant reductions in Oswestry Disability Index, VAS-P, and VAS-S scores (P<0.05). At up to 72 months of follow-up, no patient underwent adjacent-level surgery but there were 3 cases of index-level revision surgery.

Conclusions:

Multilevel TDR preserves ROM at the individual TDR levels. Most significantly, the nonoperative adjacent level maintains its preoperative ROM at 2–6 years postoperatively. At up to 6 years of follow-up, there has been no need for revision or adjacent-segment surgery. Patients also demonstrate significant improvement in pain and disability at latest follow-up.
Intersphincteric Resection Has Similar Long-term Oncologic Outcomes Compared With Abdominoperineal Resection for Low Rectal Cancer Without Preoperative Therapy: Results of Propensity Score Analyses
Authors: Tsukamoto Shunsuke , Miyake Mototaka , Shida Dai , Ochiai Hiroki , Yamada Kazunosuke , Kanemitsu Yukihide
Published: August 2018

BACKGROUND:

Intersphincteric resection has been performed for very low rectal cancer in place of abdominoperineal resection to avoid permanent colostomy.

OBJECTIVE:

This study aimed to evaluate long-term oncologic outcomes of intersphincteric resection compared with abdominoperineal resection.

DESIGN:

In this retrospective study, propensity score matching and stratification analyses were performed to reduce the effects of confounding factors between groups, including age, sex, BMI, CEA value, tumor height, tumor depth, lymph node enlargement, and circumferential resection margin measured by MRI.

SETTING:

A database maintained at our institute was used to identify patients during the period between 2000 and 2014.

PATIENTS:

A total of 285 patients who underwent curative intersphincteric resection (n = 112) or abdominoperineal resection (n = 173) for stage I to III low rectal cancer without preoperative chemoradiotherapy were enrolled in this study.

MAIN OUTCOME MEASURE:

The main outcome was recurrence-free survival.

RESULTS:

Patients in the abdominoperineal resection group were more likely to have a preoperative diagnosis of advanced cancer before case matching. After case matching, clinical outcomes were similar between intersphincteric resection and abdominoperineal resection groups. Five-year relapse-free survival rates were 69.9% for the intersphincteric resection group and 67.9% for abdominoperineal resection group (p = 0.64), and were similar in the propensity score-matched cohorts (89 matched pairs). Three-year cumulative local recurrence rates were 7.3% for intersphincteric resection and 3.9% for abdominoperineal resection (p = 0.13). In the propensity score-matched model, the hazard ratio for recurrence after intersphincteric resection in comparison with abdominoperineal resection was 0.90. Stratification analysis revealed similar recurrence rates (HR, 0.75–1.68) for intersphincteric resection in comparison with abdominoperineal resection.

LIMITATION:

Eight covariates were incorporated into the model, but other covariates were not included.

CONCLUSIONS:

Our findings suggest similar oncologic outcomes for intersphincteric resection and abdominoperineal resection without preoperative chemoradiotherapy in patients with low rectal cancer adjusted for background variables. See Video Abstract at http://links.lww.com/DCR/A661.
Perioperative Transcutaneous Tibial Nerve Stimulation to Reduce Postoperative Ileus After Colorectal Resection: A Pilot Study
Authors: Venara Aurélien , Bougard Marie , Mucci Stéphanie , Lemoult Annabelle , Le Naoures Paul , Darsonval Astrid , Barbieux Julien , Neunlist Michel , Hamy Antoine P.
Published: August 2018

BACKGROUND:

Postoperative ileus involves an inflammatory pathway characterized by an increase of inflammation mediators in the colon wall; this could probably be prevented by sacral nerve neuromodulation. The posterior tibial nerve can be stimulated electrically to mimic neuromodulation.

OBJECTIVE:

The aims of this study were to assess the efficacy of transcutaneous posterior tibial nerve stimulation in reducing the delay in GI motility recovery, to assess the safety of posterior tibial nerve stimulation in a perioperative setting, and to assess the efficacy of posterior tibial nerve stimulation in reducing the occurrence of postoperative ileus.

DESIGN:

This was a preliminary randomized controlled study.

SETTINGS:

This study was conducted in 1 academic hospital in France.

PATIENTS:

Forty patients undergoing an elective colectomy were included and randomly assigned into 2 groups, posterior tibial nerve stimulation or placebo, according to the side of colectomy and the surgical access size.

INTERVENTION:

Perioperative posterior tibial nerve stimulation or placebo was performed 3 times per day according to the randomly assigned group.

MAIN OUTCOME MEASURES:

Delay in GI motility recovery (passage of stool and tolerance of solid food) was measured.

RESULTS:

Of the 40 patients included, 34 were included in the final analysis, in which 2 patients in the placebo group were allocated the incorrect device. The 6 other patients were secondarily excluded because of protocol deviation. In the intention-to-treat analysis, the mean delay in GI motility recovery was 3.6 and 3.11 days (in the placebo and tibial nerve stimulation groups; p = 0.60). Occurrence of postoperative ileus was not significantly higher in the placebo group (35.3% vs 17.6%; p = 0.42). In the per-protocol analysis, we observed the same trends except for the occurrence of postoperative ileus, which was significantly higher in the placebo group (p = 0.045). Tolerance to posterior tibial nerve stimulation was good, and all of the patients completed the protocol.

LIMITATIONS:

The amplitude of stimulation is set according to patient sensation, so some patients could have been aware of their group. In addition there were some inherent limitations because of the preliminary nature of the study and several deviations from the protocol.

CONCLUSIONS:

Posterior tibial nerve stimulation was safe in a perioperative setting and had a potential effect on GI motility recovery. The results of this study will be useful for sample size calculations in a larger prospective randomized trial. See Video Abstract at http://links.lww.com/DCR/A708.
Stress Distribution Patterns within Viscero- and Neurocranium during Nasoalveolar Molding: a Finite Element Analysis
Authors: Ritschl Lucas M. , Heinrich Veronika , Grill Florian D. , Roth Maximilian , Hedderich Dennis M. , Rau Andrea , Wolff Klaus-Dietrich , Bauer Franz X. , Loeffelbein Denys J.
Published: August 2018

Background:

The purpose of this study was to evaluate the stress distribution patterns within the viscero- and neurocranium of neonates during nasoalveolar molding.

Methods:

Finite element models of 3 different healthy neonates at different times of life (date of birth, 4 weeks, and 3.5 months) were generated on the basis of computed tomography scans. A validated workflow, including segmentation, meshing, setting of boundary conditions, and implementation of a bone density–dependent material model, was carried out for each model. A small and a large unilateral alveolar and hard palatal cleft were virtually cut in each model. The stress distribution pattern in each model was then analyzed by using Ansys APDL.

Results:

Convergence analysis validated the results. The virtual experiments at the date of birth showed a stress pattern above a previously defined threshold value of 30,000 Pa in the ipsilateral naso-orbital-complex, frontal sinus, and the anterior fossa of the base of the skull, with von Mises values > 35,000 Pa. Stress patterns at the age of 4 weeks and 3.5 months showed reduced von Mises values at < 15,000 Pa.

Conclusions:

Nasoalveolar molding therapy is a safe presurgical treatment modality without significant influence on the viscero- and neurocranium of neonates. Treatment, considering the stress distribution at the naso-orbital-complex and anterior fossa of the base of the skull, should begin in the second week of life, and treatment initiation of preterm infants should be adapted respectively.
Shaping a Flap Using a Bioabsorbable Mold—A Preliminary Report
Authors: Nishibayashi Akimitsu , Tomita Koichi , Taminato Mifue , Yano Kenji , Hosokawa Ko
Published: August 2018

Background:

We previously reported that good surgical outcomes can be obtained with breast mold made by 3-dimensional printing. However, detailed breast shape is often difficult to create. Accordingly, we aimed to determine whether transplanting a flap and bioabsorbable mold in vivo would yield better results by retaining the flap shape inside the mold during the scar formation period.

Methods:

Vascularized adipose flaps were elevated in the bilateral inguinal region of male Sprague-Dawley rats (n = 7). A cone-shaped, bioabsorbable mold (LactoSorb mesh) was created using a template. On the experimental side, the flap was inserted into the mold and fixed. On the control side, a conical flap was created using absorbable sutures, based on a template.

Results:

The flaps were harvested 3 months postoperatively, and flap volume, base area, and projection were measured with 3-dimensional imaging. Volume and base area on the mold side tended to be smaller than those on the control side (P = 0.18 and 0.13, respectively) and close to the values of the template. In addition, the ratio of projection and base area value was significantly greater on the mold side than on the control side (P = 0.04). Histology revealed little inflammatory cell invasion, and scar tissue thickness around the flap showed no significant difference between the 2 groups (P = 0.76).

Conclusions:

This study demonstrated that soft-tissue morphology can be controlled to some extent with a bioabsorbable mold. Its clinical application in breast reconstruction requires further investigation.
MACULAR VORTEX VEIN IN A HIGHLY MYOPIC EYE IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY
Authors: Kaplan Richard I. , Walsh Joseph B. , Rosen Richard B. , Gupta Meenakashi
Published: August 2018

Purpose:

To report a case of macular vortex vein imaged with indocyanine green angiography, spectral domain optical coherence tomography, and optical coherence tomography angiography.

Methods:

Observational case report.

Results:

A 51-year-old myopic man presented with the complaint of a floater in his left eye for the previous 2 weeks. His visual acuity was 20/25 in the right eye and 20/40 in the left eye. Biomicroscopy was normal. Retinoscopy revealed lattice degeneration and posterior vitreous detachment of both eyes with dilated submacular vasculature in the right eye and submacular hemorrhage in the left eye. Spectral domain optical coherence tomography demonstrated dilated vessels in the choroid of the right eye and a choroidal neovascular membrane in the left eye. Fluorescein angiography and indocyanine green angiography showed a macular vortex vein in the right eye. Optical coherence tomography angiography demonstrated normal vessel densities in the superficial and deep capillary plexuses. No abnormalities were detected in the outer retina or choriocapillaris. Optical coherence tomography angiography delineated the macular vortex vein with a relative flow void in the right eye. His vision remained stable in the right eye.

Conclusion:

Macular vortex veins may be a prominent, albeit rare, incidental finding in highly myopic eyes. Further studies with application of newer optical coherence tomography angiography modalities, such as swept-source optical coherence tomography angiography, are recommended to improve our understanding and monitoring of these structures.
Using Charlson Comorbidity Index to Predict Short-Term Clinical Outcomes in Hospitalized Older Adults
Authors: Sinvani Liron , Kuriakose Roshini , Tariq Sara , Kozikowski Andrzej , Patel Vidhi , Smilios Christopher , Akerman Meredith , Qiu Guang , Makhnevich Alex , Cohen Jessica , Wolf-Klein Gisele , Pekmezaris Renee
Published: August 2018

This study examined the prognostic value of the Charlson Comorbidity Index (CCI) in predicting short-term clinical outcomes in hospitalized older adults. We conducted a retrospective cohort study of patients, older than 75 years, admitted to the medicine service at a large tertiary hospital (New York). We used the Enhanced International Classification of Disease, 9th Revision, Clinical Modification adaptation to abstract the CCI from electronic medical records. The CCI scores were compared, using the standard Deyo version and the Schneeweiss version. Outcome measures included in-hospital mortality, length of stay (LOS), and 30-day readmissions. When comparing Charlson/Deyo and Charlson/Deyo/Schneeweiss with and without age, we found similar significant association with regard to in-hospital mortality, with a moderate predictive ability (area under the curve [AUC]: 0.5906–0.6433). However, for 30-day readmissions and LOS, the predictive ability was poor (AUC: 0.5598–0.6106 and ρ: 0.11–0.12, respectively). The CCI is, at most, a moderate predictor of in-hospital mortality and a poor predictor of other important healthcare outcomes relevant to administrative healthcare practices.
An Educational Intervention Using Steno Balance Cards to Improve Glycemic Control in Patients With Poorly Controlled Type 2 Diabetes Mellitus
Authors: WU Yueh-Chu , KORNELIUS Edy , YANG Yi-Sun , CHEN Yih-Fen , HUANG Chien-Ning
Published: August 2018

Background:

Type 2 diabetes mellitus (T2DM) is largely attributableto lifestyle factors. Although physiological and medical care needs must be met, psychosocial factors should not be neglected.

Purpose:

The aim of this study was to determine whether a 6-month intervention consisting of educational sessions using Steno Balance Cards, which involves guided group dialogue, resulted in better glycemic outcomes than conventional diabeteseducation.

Methods:

Patients with T2DM whose glycolated hemoglobin A1c levels were higher than 8% were recruited from September to October 2015. Ninety-two patients were assigned to either the psychosocial balance dialogue (PBD) group (n = 46) or the standard care (SC) group (n = 46). The PBD group received instructions about diabetes using the Steno “Balance Card” method, which involves the use of themed picture cards to elicit group dialogue. The Balance Cards were developed by the Danish Steno Diabetes Center. In the SC group, patients received general diabetes education using a conventional teachingmode.

Results:

In the PBD group, glycolated hemoglobin A1c decreased 1.3% from 8.1% ± 0.7% to 6.8% ± 0.8%, whereas it decreased 0.6% in the SC group from 8.0% ± 0.6% to 7.4% ± 0.7%, with p < .05. At the end of the 6-month study period, the PBD group and the SC group completed a health-related quality of life questionnaire(12-item Short-Form Health Survey) and a well-being index (WHO-5) questionnaire. In the PBD group, the difference before and after the intervention showed that the well-being (WHO-5) score increased by 45.4 points, whereas the physiological score increased by 28.0, and the mental component score increased by 29.0. In the SC group, the well-being (WHO-5) score increased by 6.4, whereas the physiological score increased by 4.7, and the mental component score increased by 9.6. There were statistically significant differences in questionnairescores between the two groups (p < .05).

Conclusions/Implications for Practice:

The results of this study indicate that the dialogue sessions using Steno Balance Cards are beneficial for patients with T2DM in terms of improved glycemic control and quality of life.
Risk Factors of Post-Large Loop Excision of the Transformation Zone Recurrent High-Grade Cervical Intraepithelial Lesion: A Prospective Cohort Study
Authors: Demarquet Emilie , Mancini Julien , Preaubert Lise , Gondry Jean , Chevreau Julien , Lamblin Gery , Lebail Karine , Lavoué Vincent , Pinsard Marion , Baldauf Jean-Jacques , Bryand Angélique , Henno Sebastien , Agostini Aubert , Douvier Serge , Jarniat Adelaïde , Riethmuller Didier , Mendel Anne , Brun Jean-Luc , Rakotomahenina Hajanirina , Carcopino Xavier
Published: August 2018

Objective

The aim of the study was to identify the risk factors of post-large loop excision of the transformation zone (LLETZ) recurrent disease and the impact of colposcopic guidance at the time of LLETZ on that risk.

Materials and Methods

From December 2013 to July 2014, 204 patients who had undergone LLETZ for the treatment of high-grade intraepithelial lesion with fully visible cervical squamocolumnar junction were included. The use of colposcopy during each procedure was systematically documented. The dimensions and volume of LLETZ specimens were measured at the time of the procedure before formaldehyde fixation. All participants were invited for a follow-up. The primary endpoint was the diagnosis of post-LLETZ recurrent disease defined as the histologic diagnosis of a high-grade cervical intraepithelial lesion.

Results

The median duration of post-LLETZ follow-up was 25.8 months. Recurrent disease was diagnosed in 8 (3.6%) patients. Older than 38 years (adjusted hazard ratio [aHR] = 11.9, 95% CI = 1.6–86.0), history of excisional therapy (aHR = 21.6, 95% CI = 3.5–135.3), and the absence of colposcopy for the guidance of LLETZ (aHR = 6.4, 95% CI = 1.1–37.7) were found to significantly increase the risk of post-LLETZ recurrent disease. The dimensions and volume of the specimen were not found to have any impact. Only positive endocervical margins were identified to significantly increase the risk of post-LLETZ recurrent disease (aHR = 14.4, 95% CI = 2.0–101.1).

Conclusions

Risk factors of post-LLETZ recurrent disease are older than 38 years, history of excisional therapy, positive endocervical margins, and lack of colposcopic guidance at the time of LLETZ.
Brief Report: A Panel Management and Patient Navigation Intervention Is Associated With Earlier PrEP Initiation in a Safety-Net Primary Care Health System
Authors: Spinelli Matthew A. , Scott Hyman M. , Vittinghoff Eric , Liu Albert Y. , Morehead-Gee Alicia , Gonzalez Rafael , Gandhi Monica , Buchbinder Susan P.
Published: August 2018

Background:

Timely pre-exposure prophylaxis (PrEP) initiation is critical in at-risk populations, given that HIV acquisition risk persists during delays. Time to treatment initiation, a key metric in HIV care, has not been explored among PrEP users. Interventions that reduce time to PrEP initiation could prevent HIV infections.

Setting:

Individuals initiating PrEP in a large primary care health network of 15 clinics, the San Francisco Primary Care Clinics (SFPCC), from July 2012 to July 2017 (N = 411).

Methods:

We examined factors associated with time from first PrEP discussion with a provider to PrEP initiation date using an adjusted Cox proportional-hazards model, with hazard ratios (HRs) >1 indicating earlier initiation. We also examined the relationship between delayed PrEP initiation and PrEP persistence (staying on PrEP) in an adjusted Cox proportional-hazards model.

Results:

PrEP users initiated PrEP after a median of only 7 days. However, there were notable outliers, with 29% waiting >30 days and 12% waiting >90 days. In an adjusted proportional-hazards model, a panel management and patient navigation intervention was associated with earlier PrEP initiation [HR: 1.5; 95% confidence interval (CI): 1.1 to 2.0], whereas only other race/ethnicity compared with white race was associated with delayed PrEP initiation (HR: 0.7; 95% CI: 0.5 to 1.0). Delayed PrEP initiation >30 days was associated with shorter PrEP persistence in an adjusted proportional-hazards model (HR: 1.3; 95% CI: 1.0 to 1.7).

Conclusions:

PrEP initiation within a week is feasible in a primary care safety-net health system. Setting a goal of rapid PrEP initiation, with the support of panel management and patient navigation, could address delays in at-risk groups.
Role of 18F-FDG PET/CT in Restrictive Allograft Syndrome After Lung Transplantation
Authors: Verleden Stijn E. , Gheysens Olivier , Goffin Karolien E , Vanaudenaerde Bart M. , Verbeken Erik K. , Weynand Birgit , Van Raemdonck Dirk E. , Verleden Geert M. , Vos Robin
Published: August 2018

Background.

Differential diagnosis of phenotypes of chronic lung allograft dysfunction (CLAD) remains troublesome. We hypothesized that 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) may help in differential diagnosis of CLAD phenotypes, as it showed promising results regarding diagnosis and prognosis in interstitial lung diseases.

Methods.

A monocentric, retrospective study was performed including all lung transplant recipients suffering from bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) who underwent 18F-FDG PET/CT scan, in comparison with stable lung transplant recipients. Maximum standardized uptake value (SUVmax) was associated with pulmonary function and survival. Proof-of-concept microCT and glucose transporter-1 staining served as morphologic validation for regions with different SUVmax.

Results.

Maximum standardized uptake value was higher in RAS (median, 2.6; n = 29) compared with BOS (median, 1.0; n = 15) and stable patients (median, 0.59; n = 8) (P < 0.0001). In RAS, high SUVmax was associated with worse survival after 18F-FDG PET/CT (P = 0.0004; hazard ratio, 1.82). Forced vital capacity at 18F-FDG PET/CT inversely correlated with SUVmax (R = −0.40, P = 0.03). MicroCT analysis revealed extensive fibrosis in regions of high SUVmax, with an increased number of glucose transporter-1–positive cells.

Conclusions.

18F-fluorodeoxyglucose positron emission tomography with CT may noninvasively differentiate RAS from BOS. RAS patients with areas of increased lung metabolism have worse outcome, demonstrating the potential use of 18F-FDG PET/CT during follow-up after lung transplantation.
Neural underpinnnings of auditory salience natural soundscapes
Authors: Huang Nicholas , Elhilali Mounya
Published: August 2018

Salience is the mechanism whereby attention is automatically directed towards critical stimuli. Measuring the salience of a stimulus using behavioral methods risks confounds with top-down attention, particularly in the case of natural soundscapes. A distraction paradigm is employed here to measure physiological effects of salient auditory stimuli using electroencephalography. Several such effects are presented. In particular, a stimulus entrainment response is reduced by the presentation of distractor salient sounds. A reduction in oscillatory neural responses in the gamma frequency band is also observed following salient stimuli. These measures are used to identify salient portions of the natural scene. Finally, envelope decoding methods also indicate that salient stimuli attract attention away from other, task-related sounds.
Single-cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development
Authors: Boroviak Thorsten , Stirparo Giuliano G , Dietmann Sabine , Hernando-Herraez Irene , Mohammed Hisham , Reik Wolf , Smith Austin , Sasaki Erika , Nichols Jennifer , Bertone Paul
Published: August 2018

The mouse embryo is the canonical model for mammalian preimplantation development. Recent advances in single-cell profiling allow detailed analysis of embryogenesis in other eutherian species, including human, to distinguish conserved from divergent regulatory programs and signalling pathways in the rodent paradigm. Here, we identify and compare transcriptional features of human, marmoset and mouse embryos by single-cell RNA-seq. Zygotic genome activation correlates with the presence of Polycomb Repressive Complexes in all three species, while ribosome biogenesis emerges as a predominant attribute in primate embryos, supporting prolonged translation of maternally deposited RNAs. We find that transposable element expression signatures are species-, stage- and lineage-specific. The pluripotency network in the primate epiblast lacks certain regulators operative in mouse, but encompasses WNT components and genes associated with trophoblast specification. Sequential activation of GATA6, SOX17 and GATA4 markers of primitive endoderm identity is conserved in primates. Unexpectedly, OTX2 is also associated with primitive endoderm specification in human and nonhuman primate blastocysts. Our cross-species analysis demarcates both conserved and primate-specific features of preimplantation development and underscores the molecular adaptability of early mammalian embryogenesis.
Nanobody-antigen catch-bond reveals NK cell mechanosensitivity
Authors: Gonzalez Cristina , Chames Patrick , Kerfelec Brigitte , Baty Daniel , Robert Philippe , Limozin Laurent
Published: August 2018

Antibodies are key tools in biomedical research and medicine. Their binding properties are classically measured in solution and characterized by an affinity. However, in physiological conditions, antibodies can bridge an immune effector cell and an antigen presenting cell, implying that mechanical forces apply to the bonds. For example, in antibody-dependent cell cytotoxicity, a major mode of action of therapeutic monoclonal antibodies, the Fab domains bind the antigens on the target cell, while the Fc domain binds to the activating receptor CD16 (also known as FcgRIII) of an immune effector cell, in a quasi bi-dimensional environment (2D). Therefore, there is a strong need to investigating antigen/antibody binding under force (2D), to better understand and predict antibody activityin vivo.We used two anti-CD16 nanobodies targeting two different epitopes and laminar flow chamber assay to measure the association and dissociation of single bonds formed between microsphere-bound CD16 antigens and surface-bound anti-CD16 nanobodies (or single domain antibodies), simulating 2D encounters. The two nanobodies exhibit similar 2D association kinetics, characterized by a strong dependence on the molecular encounter duration. However, their 2D dissociation kinetics strongly differ as a function of applied force: one exhibits a slip bond behaviour where off-rate increases with force; the other exhibits a catch bond behaviour with off-rate decreasing with force. This is the first time, to our knowledge, that catch bond behaviour was reported for antigen-antibody bond. We further exploit this property to show how Natural Killer cells spread differentially on surfaces coated with these molecules, revealing NK cells mechanosensitivity. Our results may also have strong implications for the design of efficient bispecific antibodies for therapeutic applications.
Protein-level assembly increases protein sequence recovery from metagenomic samples manyfold
Authors: Steinegger Martin , Mirdita Milot , Söding Johannes
Published: August 2018

The open-source de-novo Protein-level assembler Plass (https://plass.mmseqs.org) assembles six-frame-translated sequencing reads into protein sequences. It recovers 2 to 10 times more protein sequences from complex metagenomes and can assemble huge datasets. We assembled two redundancy-filtered reference protein catalogs, 2 billion sequences from 640 soil samples (SRC) and 292 million sequences from 775 marine eukaryotic metatranscriptomes (MERC), the largest free collections of protein sequences.
Development of plant regeneration andAgrobacterium tumefaciens-mediated transformation methodology forPhysalis pruinosa
Authors: Swartwood Kerry , Eck Joyce Van
Published: August 2018

Physalis pruinosa, also known as groundcherry, produces a small, yellow, highly nutritious edible fruit that is enveloped by a papery husk. In order for the potential of large-scale production ofP. pruinosafruit to be realized, undesirable characteristics, such as an unmanageable, sprawling growth habit and extensive fruit drop, need to be improved by exploiting approaches available through plant breeding, genetic engineering, and gene editing. In this study, we established plant regeneration andAgrobacterium tumefaciens-mediated methods to allow application of genetic engineering and gene editing ofP. pruinosa. Cotyledon and hypocotyl explants from 7 – 8-day-oldin vitro-grown seedlings were assessed for plant regeneration. Explants were cultured for 2 weeks on a Murashige and Skoog salts-based medium that contained 2 mg/L zeatin followed by transfer to medium containing 1 mg/L zeatin. Only hypocotyl explants regenerated shoots. Hypocotyl explants were infected withAgrobacterium tumefaciensstrain AGL1 containing the pJL33 binary vector that has the green fluorescent protein (GFP) reporter and neomycin phosphotransferase II (nptII) selectable marker genes. After cocultivation, explants were cultured on selective plant regeneration medium that contained 50, 100, 200, 250, and 300 mg/L kanamycin to determine the most effective level for efficient recovery of transgenic lines. Based on rooting of regenerated shoots on selective medium, GFP visualization, and PCR analysis for the presence of thenptIIgene, medium containing 200 mg/L kanamycin resulted in the highest transformation efficiency at 24%. This study sets the foundation for future genetic engineering and gene editing approaches for improvement ofP. pruinosa.
Strand Orientation Bias Detector (SOBDetector) to remove FFPE sequencing artifacts
Authors: Diossy Miklos , Sztupinszki Zsofia , Krzystanek Marcin , Borcsok Judit , Eklund Aron C. , Csabai István , Pedersen Anders Gorm , Szallasi Zoltan
Published: August 2018

Formalin-fixed paraffin-embedded (FFPE) tissue, the most common tissue specimen stored in clinical practice, presents challenges in the analysis due to formalin-induced artifacts. Here we present SOBDetector, that is designed to remove these artifacts from a list of variants, which were extracted from next-generation sequencing data, using the posterior predictive distribution of a Bayesian logistic regression model trained on TCGA whole exomes. Based on a concordance analysis, SOBDetector outperforms the currently publicly available FFPE-filtration techniques (Accuracy: 0.9 ± 0.015, AUC = 0.96). SOBDetector is implemented in Java 1.8 and is freely available online.
Knock-in rats expressing Cre and Flp recombinases at the Parvalbumin locus
Authors: Yu Jai Y. , Pettibone Jeffrey R. , Guo Caiying , Zhang Shuqin , Saunders Thomas L. , Hughes Elizabeth D. , Filipiak Wanda E. , Zeidler Michael G. , Bender Kevin J. , Hopf Frederic , Smyth Clay N. , Kharazia Viktor , Kiseleva Anna , Davidson Thomas J. , Frank Loren M. , Berke Joshua D.
Published: August 2018

Rats have the ability to learn and perform sophisticated behavioral tasks, making them very useful for investigating neural circuit functions. In contrast to the extensive mouse genetic toolkit, the paucity of recombinase-expressing rat models has limited the ability to monitor and manipulate molecularly-defined neural populations in this species. Here we report the generation and validation of two knock-in rat strains expressing either Cre or Flp recombinase under the control of Parvalbumin (Pvalb), a gene expressed in the critical “fast-spiking” subset of inhibitory interneurons (FSIs). These strains were generated with CRISPR-Cas9 gene editing and show highly specific and penetrant labeling of Pvalb-expressing neurons, as demonstrated by in situ hybridization and immunohistochemistry. We validated these models in both prefrontal cortex and striatum using both ex vivo and in vivo approaches, including whole-cell recording, optogenetics, extracellular physiology and photometry. Our results demonstrate the utility of these new transgenic models for a wide range of neuroscience experiments.
A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ TREG differentiation
Authors: Mamontov Polina , Eberwine Ryan A. , Perrigoue Jackie , Das Anuk , Friedman Joshua R. , Mora J. Rodrigo
Published: August 2018

The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively regulates TREG differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in primary human naïve peripheral blood CD4 T cells increased Foxp3+ TREG differentiation under both TREG and T effector (Teff) cell priming conditions. ITK knockdown also enhanced the expression of the co-inhibitory receptor PD-1 on FoxP3+ T cells. TREGS differentiated in vitro (iTREG) after ITK knockdown displayed suppressive capacity against effector CD4+ T cell proliferation. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and increased Th1 differentiation. Finally, a dual ITK/RLK Tec kinase inhibitor blocked TREG differentiation and T cell activation in general. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but non-specific inhibition of other Tec family kinases may broadly inhibit T cell activation.
ELYS coordinates NF-κB pathway dynamics during development inDrosophila
Authors: Mehta Saurabh Jayesh Kumar , Kumar Vimlesh , Mishra Ram Kumar
Published: August 2018

Summary Statement

ELYS, a nucleoporin spatiotemporally regulates NF-κB pathway dynamics during development inDrosophilaand its misregulation in post-embryonic stages leads to apoptosis mediated abnormalities.

Nuclear pores are the exclusive conduit to facilitate the nucleocytoplasmic transport in a precisely regulated manner. ELYS, a constituent protein of nuclear pores, initiates assembly of nuclear pore complexes (NPCs) into functional nuclear pores towards the end of mitosis. Using cellular, molecular and genetic tools, here, we report that ELYS orthologue (dElys) plays critical roles duringDrosophiladevelopment. Throughin silicoanalyses, we find all conserved structural features indElys except for the presence of non-canonical AT-hook motif strongly binding with DNA.dElys localized to nuclear rim in interphase cells, but during mitosis, it was present on chromatin. RNAi mediated depletion ofdElys leads to aberrant development and defects in the nuclear lamina and NPCs assembly at the cellular level. Furthermore, we demonstrate that indElys depletion NF-κB is activated and accumulates inside the nucleus which results in illimed expression of critical molecules.dElys depletion sustains NF-κB into the nucleus in post-embryonic stages. Prolonged NF-κB inside nucleus induces apoptosis in response to hitherto unknown quality check mechanism and highlights on the under-appreciated apoptotic paradigm of NF-κB pathway.
Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy
Authors: Sophie Belin , Ornaghi Francesca , Shackleford Ghjuvan'Ghjacumu , Wang Jie , Scapin Cristina , Lopez-Anido Camila , Silvestri Nicholas , Robertson Neil , Williamson Courtney , Ishii Akihiro , Taveggia Carla , Svaren John , Bansal Rashmi , Schwab Markus H. , Nave Klaus-Armin , Fratta Pietro , Poitelon Yannick , D'Antonio Maurizio , Feltri Maria Laura , Wrabetz Lawrence
Published: August 2018

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.
eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data
Authors: Guen Yann Le , Philippe Cathy , Riviere Denis , Lemaitre Hervé , Grigis Antoine , Fischer Clara , Dehaene-Lambertz Ghislaine , Mangin Jean-François , Frouin Vincent
Published: August 2018

The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3,435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (s.e.= 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer’s disease in which brain shrinkage is a key biomarker.
Quantitative synapse analysis for cell-type specific connectomics
Authors: Kuljis Dika A. , Zemoura Khaled , Telmer Cheryl A. , Lee Jiseok , Park Eunsol , Ackerman Daniel S. , Xu Weifeng , Watkins Simon C. , Arnold Don B. , Bruchez Marcel P. , Barth Alison L.
Published: August 2018

Anatomical methods for determining cell-type specific connectivity are essential to inspire and constrain our understanding of neural circuit function. We developed new genetically-encoded reagents for fluorescence-synapse labeling and connectivity analysis in brain tissue, using a fluorogen-activating protein (FAP)-or YFP-coupled, postsynaptically-localized neuroligin-1 targeting sequence (FAP/YFPpost). Sparse viral expression of FAP/YFPpost with the cell-filling, red fluorophore dTomato (dTom) enabled high-throughput, compartment-specific localization of synapses across diverse neuron types in mouse somatosensory cortex. High-resolution confocal image stacks of virally-transduced neurons were used for 3D reconstructions of postsynaptic cells and automated detection of synaptic puncta. We took advantage of the bright, far-red emission of FAPpost puncta for multichannel fluorescence alignment of dendrites, synapses, and presynaptic neurites to assess subtype-specific inhibitory connectivity onto L2 neocortical pyramidal (Pyr) neurons. Quantitative and compartment-specific comparisons show that PV inputs are the dominant source of inhibition at both the soma and across all dendritic branches examined and were particularly concentrated at the primary apical dendrite, a previously unrecognized compartment of L2 Pyr neurons. Our fluorescence-based synapse labeling reagents will facilitate large-scale and cell-type specific quantitation of changes in synaptic connectivity across development, learning, and disease states.