bluuebunny/crossref_metadata_2025 huggingface dataset:
The Tissue-Based Triad in Augmentation Mastopexy: Single-Stage Technical Refinements
Authors: Sanniec Kyle , Adams William P
Published: January 2019

Background

The number of patients seeking augmentation mastopexy has increased over the last several decades. The conflicting goals of augmentation (tissue expansion) and mastopexy (tissue reduction) have led to higher revision rates, decreased patient satisfaction, and pending litigation. Some have even argued for staging of all augmentation mastopexy procedures.

Objectives

The goal of this study was to review the senior author’s (W.P.A.) process-oriented approach to single-stage augmentation mastopexy and to detail the technical framework to produce reliable, reproducible, safe results in a 1-stage augmentation mastopexy.

Methods

A prospectively collected patient database from January 2007 until January 2018 was reviewed. All single-stage augmentation mastopexy patients were evaluated, including patient demographics, operative details, complications, and outcomes.

Results

A total of 251 patients were evaluated. Mean follow-up was 16.9 months, average patient age was 38.0 years, and average implant size was 285.8 cc. A total of 9 (3.6%) patients required reoperation and only 2 (0.8%) required explantation. Fourteen (5.6%) patients developed delayed wound healing that responded to local wound care alone.

Conclusions

Utilization of a safe and reliable processed approach to single-stage augmentation mastopexy is highly predictable with low reoperation rates. The technical refinements presented have led to increased consistency in delivering high-quality results to patients in a procedure fraught with challenges.

Level of Evidence: 4
Bloodstream Infection Due to Vancomycin-resistant Enterococcus Is Associated With Increased Mortality After Hematopoietic Cell Transplantation for Acute Leukemia and Myelodysplastic Syndrome: A Multicenter, Retrospective Cohort Study
Authors: Papanicolaou Genovefa A , Ustun Celalettin , Young Jo-Anne H , Chen Min , Kim Soyoung , Woo Ahn Kwang , Komanduri Krishna , Lindemans Caroline , Auletta Jeffery J , Riches Marcie L ,   CIBMTR® Infection and Immune Reconstitution Working Committee, Abdel-Azim Hisham , Ahmed Ibrahim A , Aljurf Mahmoud , Antin Joseph , Ballen Karen Kuhn , Beitinjaneh Amer , Brown Valerie I , Cerny Jan , Champlin Richard , Chao Nelson , Chhabra Saurabh , Dahi Parastoo B , Daly Andrew , Dandoy Christopher , Dvorak Christopher C , Forman Stephen , Ganguly Siddhartha , Hashmi Shahrukh K , Kharfan-Dabaja Mohamed A , Lazarus Hillard , Ljungman Per , Malone Adriana K , Murthy Guru , Nishihori Taiga , Page Kristin , Pingali Ravi (Sai Ravi) , Reddy Vijay , Saad Ayman , Savani Bipin N , Seftel Matthew , Szer Jeffrey , Vij Ravi , Weisdorf Daniel , William Basem M , Williams Kirsten , Wirk Baldeep , Yared Jean
Published: January 2019

Background

We examined the impact of vancomycin-resistant Enterococcus (VRE) bloodstream infection (BSI) on outcomes of allogeneic hematopoietic cell transplantation (HCT) utilizing the Center for International Blood and Marrow Transplant Research database.

Methods

Adult and pediatric patients (N = 7128) who underwent first HCT for acute leukemia or myelodysplastic syndrome from 2008 through 2012 were analyzed as 3 groups—VRE BSI, non-VRE BSI, without BSI—according to BSI status at 100 days (D100) after allogeneic HCT. Multivariable models examined the effect of VRE BSI for overall survival (OS) and nonrelapse mortality (NRM) at 1 year.

Results

Of 7128 patients, 258 (3.2%) had VRE BSI, 2398 (33.6%) had non-VRE BSI, and 4472 (63%) had no BSI. The median time to VRE BSI and non-VRE BSI were D11 and D15, respectively. Compared with non-VRE BSI patients, VRE BSI patients were older, had advanced-stage acute leukemia, and received umbilical cord blood (UCB) allografts. In multivariable models, VRE BSI was associated with lower OS (relative risk [RR], 2.9;(99% confidence interval [CI], 2.2–3.7) and increased NRM (RR, 4.7; 99% CI, 3.6–6.2) (P < .0001) for both. Other predictors for worse OS and increased NRM were non-VRE BSI, older age, advanced disease stage, UCB allograft, – mismatch, comorbidity index ≥3, and cytomegalovirus seropositivity (P < .001 for all variables).

Conclusions

VRE BSI is associated with lowest OS and highest NRM compared with patients without BSI or non-VRE BSI. Novel interventions that address the pathophysiology of VRE BSI have the potential of improving survival after HCT.
Extended Infusion of β-Lactams for Bloodstream Infection in Patients With Liver Cirrhosis: An Observational Multicenter Study
Authors: Bartoletti Michele , Giannella Maddalena , Lewis Russell E , Caraceni Paolo , Tedeschi Sara , Paul Mical , Schramm Christoph , Bruns Tony , Merli Manuela , Cobos-Trigueros Nazaret , Seminari Elena , Retamar Pilar , Muñoz Patricia , Tumbarello Mario , Burra Patrizia , Torrani Cerenzia Maria , Barsic Bruno , Calbo Ester , Maraolo Alberto Enrico , Petrosillo Nicola , Galan-Ladero Maria Angeles , D’Offizi Gianpiero , Zak-Doron Yael , Rodriguez-Baño Jesus , Baldassarre Maurizio , Verucchi Gabriella , Domenicali Marco , Bernardi Mauro , Viale Pierluigi ,   ESGBIS/BICHROME study group, Campoli Caterina , Pascale Renato , Stallmach Andreas , Venditti Mario , Lucidi Cristina , Ludovisi Serena , de Cueto Marina , Dolores Navarro Maria , Eduardo Lopez Cortes , Bouza Emilo , Valerio Maricela , Eworo Alia , Losito Raffaella , Senzolo Marco , Nadal Elena , Ottobrelli Antonio , Varguvic Martina , Badia Cristina , Guglielmo Borgia , Gentile Ivan , Buonomo Antonio Riccardo , Boumis Evangelo , Beteta-Lopez Alicia , Rianda Alessia , Taliani Gloria , Grieco Stefania
Published: January 2019

Background

We analyzed the impact of continuous/extended infusion (C/EI) vs intermittent infusion of piperacillin-tazobactam (TZP) and carbapenems on 30-day mortality of patients with liver cirrhosis and bloodstream infection (BSI).

Methods

The BICRHOME study was a prospective, multicenter study that enrolled 312 cirrhotic patients with BSI. In this secondary analysis, we selected patients receiving TZP or carbapenems as adequate empirical treatment. The 30-day mortality of patients receiving C/EI or intermittent infusion of TZP or carbapenems was assessed with Kaplan-Meier curves, Cox-regression model, and estimation of the average treatment effect (ATE) using propensity score matching.

Results

Overall, 119 patients received TZP or carbapenems as empirical treatment. Patients who received C/EI had a significantly lower mortality rate (16% vs 36%, P = .047). In a Cox-regression model, the administration of C/EI was associated with a significantly lower mortality (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.11–0.936; P = .04) when adjusted for severity of illness and an ATE of 25.6% reduction in 30-day mortality risk (95% CI, 18.9–32.3; P < .0001) estimated with propensity score matching. A significant reduction in 30-day mortality was also observed in the subgroups of patients with sepsis (HR, 0.21; 95% CI, 0.06–0.74), acute-on-chronic liver failure (HR, 0.29; 95% CI, 0.03–0.99), and a model for end-stage liver disease score ≥25 (HR, 0.26; 95% CI, 0.08–0.92). At competing risk analysis, C/EI of beta-lactams was associated with significantly higher rates of hospital discharge (subdistribution hazard [95% CI], 1.62 [1.06–2.47]).

Conclusions

C/EI of beta-lactams in cirrhotic patients with BSI may improve outcomes and facilitate earlier discharge.
High-Risk Ileocolic Anastomoses for Crohn’s Disease: When Is Diversion Indicated?
Authors: Neary Peter M , Aiello Alexandra C , Stocchi Luca , Shawki Sherief , Hull Tracy , Steele Scott R , Delaney Conor P , Holubar Stefan D
Published: January 2019

Background and Aims

Patients with Crohn’s disease undergoing ileocolectomy and primary anastomosis are often at increased risk of anastomotic leak. We aimed to determine whether diverting ileostomy was protective against anastomotic leak after ileocolic resection for Crohn’s disease using a large international registry.

Methods

We analysed the National Surgical Quality Improvement Program Colectomy Module from 2012 to 2016. Multivariable logistic regression analysis and propensity-score matching were used to identify independent risk factors for leak, and to test the hypothesis that diverting ileostomy was protective against anastomotic leakage.

Results

A total of 4172 [92%] patients underwent primary anastomosis, and 365 [8%] underwent anastomosis plus ileostomy. The leak rates in the two groups were 4.5% and 2.7%, [p = 0.12], respectively. Multivariate analysis indicated ileostomy omission, emergency surgery, smoking, inpatient status, wound classification 3 or 4, weight loss, steroid use, and prolonged operative time were independently associated with leak. Patients with 0–6 risk factors had leak rates of 1.6%, 2.7%, 4.3%, 6.7%, 8.8%, 11.5%, and 14.3% [p ≤ 0.001], respectively. Following propensity-score matching, ileostomy reduced the risk of leak rate by 55% [p = 0.005]. Patients with primary anastomosis who leaked most frequently required reoperation [57.8%], but anastomosis plus ileostomy patients who leaked most frequently were managed by percutaneous drainage [70%], p = 0.04.

Conclusions

After ileocolic resection for Crohn’s disease, anastomotic leak may be predicted by simple addition of risk factors. We found that diverting ileostomy mitigated against leak, reducing both the leak rate and the likelihood of unplanned reoperations. Faecal diversion should be considered when ≥3 risk factors are present.
Gene and Mirna Regulatory Networks During Different Stages of Crohn’s Disease
Authors: Verstockt Sare , De Hertogh Gert , Van der Goten Jan , Verstockt Bram , Vancamelbeke Maaike , Machiels Kathleen , Van Lommel Leentje , Schuit Frans , Van Assche Gert , Rutgeerts Paul , Ferrante Marc , Vermeire Séverine , Arijs Ingrid , Cleynen Isabelle
Published: January 2019

Background and Aims

Early treatment of Crohn’s disease [CD] is required in order to optimize patient outcomes. To this end, we need to gain a better understanding of the molecular changes at the onset of CD.

Methods

As a model for the earliest mucosal CD lesions, we study post-operative recurrent CD [Rutgeerts score ≥ i2b]. We are the first to analyse gene and microRNA [miRNA] expression profiles in ileal biopsies from these patients, and compare them with those of newly diagnosed [≤18 months] and late-stage [>10 years after diagnosis] CD patients.

Results

Except for one gene [WNT5A], there are no differential genes in CD patients without post-operative recurrence [i0], showing that previous disease did not influence gene expression in the neoterminal ileum, and that this model can be used to study early mucosal CD lesions. Gene expression and co-expression network dysregulation is more pronounced in newly diagnosed and late-stage CD than in post-operative recurrent CD, with most important modules associated with [a]granulocyte adhesion/diapedesis, and cholesterol biosynthesis. In contrast, we found a role for snoRNAs/miRNAs in recurrent CD, highlighting the potential importance of regulatory RNAs in early disease stages. Immunohistochemistry confirmed the expression of key dysregulated genes in damaged/regenerating epithelium and immune cells in recurrent CD.

Conclusions

Aside from regulatory RNAs, there are no clear gene signatures separating post-operative recurrent, newly diagnosed, and late-stage CD. The relative contribution of dysregulated genes and networks differs, and suggests that surgery may reset the disease at the mucosal site, and therefore post-operative recurrent CD might be a good model a good model to study to study early mucosal CD lesions.
Preventable premature deaths (PYLL) in Northern Dimension partnership countries 2003–13
Authors: Vienonen Mikko A , Jousilahti Pekka J , Mackiewicz Karolina , Oganov Rafael G , Pisaryk Vital M , Denissov Gleb R , Nurm Ulla-Karin , Pudule Iveta , Gurevicius Romualdas J , Zabłocki Bartosz M , Friberg Marita I , Krasilnikov Igor A , Koistinen Veli O , Vohlonen Ilkka J
Published: January 2019

Background

Objective was to measure preventable premature loss of life in countries from same geographical area but with considerable differences in social and economic development. By comparing inter-country differences and similarities in premature mortality, acceleration of health-in-all-policies is enhanced.

Methods

Preventable premature deaths were described by Potential Years of Life Lost (PYLL). Data consisted of death registers for 2003, 2009 and 2013. PYLL-rates were age-standardized by using standard OECD population from 1980 and expressed as sum of lost life years per 100 000 citizens.

Results

In Northern Dimension area, PYLL-rates had declined from 2003 to 2013. In 2013, worst PYLL-rate was in Belarus 9851 and best in Sweden 2511. PYLL-rates among men were twice as high as among women. Most premature losses (1023) were due to external causes. Malignant neoplasms came second (921) and vascular diseases third (816). Alcohol was also an important cause (270) and country differences were over 10-fold.

Conclusions

In ND-area, the overall development of public health has been good during 2003–13. Nevertheless, for all countries foci for public health improvement and learning from each other could be identified. Examining the health of populations in countries from relatively similar geographical area with different social history and cultures can provide them with evidence-based tools for health-in-all-policies to advocate health promotion and disease prevention. Gender differences due to preventable premature deaths are striking. The higher the national PYLL-rate, the bigger the PYLL-rate difference between men and women and the loss of human capital.
Housing Plus Services, IADL Impairment, and Healthcare Expenditures: Evidence from the Medicare Current Beneficiaries Survey
Authors: Akincigil Ayse , Greenfield Emily A
Published: January 2019

Background and Objectives

Despite enthusiasm for the potential cost savings of embedding supportive services in senior housing, few population health studies have empirically examined such associations. We investigated the extent to which associations between housing plus services in senior housing and healthcare expenditures depend upon residents’ instrumental activities of daily living (IADL) impairment and the level of services available.

Research Design and Methods

We used data from 2,601 participants aged 65 or older in the 2001–2013 Medicare Current Beneficiary Survey, who reported living in senior or retirement housing. Based on survey self-reports, we created a measure of housing with different levels of services, including the categories of housing without services, housing plus services (i.e., assistance with IADLs, but not with medications), and housing plus enhanced services (i.e., assistance with IADLs including medications). Administrative and survey data were used to create measures of healthcare expenditures paid by all sources. We estimated generalized linear models based on pooled data from participants across the 13 years of data collection.

Results

Residents with IADL impairment—who lived in housing plus enhanced services—had lower total healthcare expenditures than their counterparts in housing without services and housing plus services. Upon examining component healthcare costs, this pattern of results was similar for inpatient/subacute care, as well as ambulatory care, but not for home health care.

Discussion and Implications

Findings indicate the importance of studies on the cost savings of housing-based service programs to consider resident IADL status and the types of services available.
The thermal boundary layer due to viscous dissipation in impulsively started Poiseuille flow
Authors: Kay Anthony
Published: January 2019

Viscous dissipation occurs in the boundary layers on the walls of a channel in which a flow is accelerated from rest by the sudden imposition of a pressure gradient. We analyse the thermal boundary layer due to this dissipative heating, obtaining numerical solutions and also asymptotic solutions for the cases of both large and small Prandtl number, with both isothermal and adiabatic wall conditions. With large $\mathrm{Pr}$ the temperature rise is controlled by the viscous layer, so is independent of $\mathrm{Pr}$ and of the wall condition. With small $\mathrm{Pr}$ heat is conducted away from the viscous layer more rapidly, so the temperature rise is reduced as $\mathrm{Pr}$ decreases.
Breastfeeding by Women Living With Human Immunodeficiency Virus in a Resource-Rich Setting: A Case Series of Maternal and Infant Management and Outcomes
Authors: Nashid N , Khan S , Loutfy M , MacGillivray J , Yudin M H , Campbell D M , Barozzino T , Baqi M , Read S E , Bitnun A
Published: January 2019

The reduction in human immunodeficiency virus (HIV) transmission through breastmilk with maternal combination antiretroviral therapy (cART) has led many pregnant women living with HIV and healthcare providers to question exclusive formula feeding in resource-rich settings. Here, we describe cART prophylaxis in 3 breastfed infants whose mothers had sustained virologic suppression; all 3 of these infants remained uninfected.
Health care-associated invasive Candida infections in children
Authors: Öncü Bahaettin , Belet Nurşen , Emecen Ahmet Naci , Birinci Asuman
Published: January 2019

The aims of the study were to examine the distribution of Candida spp. isolated from sterile body sites, the antifungal susceptibility of the isolates to amphotericin B, and fluconazole, risk factors and clinical outcomes associated with invasive health care-associated Candida infections in neonates and children. Between January 2007 and January 2012, the patients with invasive candidiasis were detected from microbiology laboratary records and medical records were examined retrospectively. Candida spp. were isolated from sterile body sites in 94 patients. The most common underlying diseases were prematurity in neonates and surgery in children. Parenteral nutrition, stay in intensive care unit (ICU), and mechanical ventilation (MV) were major risk factors in neonates. Hospitalization before infection and immunosuppressant therapy were significantly more frequent in children. Of Candida infection episodes, 29.8% was due to C. albicans and 70.2% was due to non-albicans Candida spp. The most common isolated species was C. parapsilosis. Of the Candida species, 90.8% were sensitive, and 9.2% were resistant to fluconazole. The rate of amphotericin B resistant was 1.3%; 23.4% of the patients died in the first 30 days. The main variables associated with mortality were neonates, prematurity, stay in the ICU, parenteral nutrition, MV, length of stay, amphotericin B susceptibility, and high levels of C-reactive protein.
Vascular access in children requiring maintenance haemodialysis: a consensus document by the European Society for Paediatric Nephrology Dialysis Working Group
Authors: Shroff Rukshana , Calder Francis , Bakkaloğlu Sevcan , Nagler Evi V , Stuart Sam , Stronach Lynsey , Schmitt Claus P , Heckert Karl H , Bourquelot Pierre , Wagner Ann-Marie , Paglialonga Fabio , Mitra Sandip , Stefanidis Constantinos J ,   European Society for Paediatric Nephrology Dialysis Working Group, Aufricht C , Van de Walle J , Vondrak K , Holtta T , Ranchin B , Zaloszyc A , Krid S , Pietrement C , Schmitt C P , Klaus G , Muller D , Thumfart J , Stefanidis C , Printza N , Stabouli S , Edefonti A , Paglialonga F , Peruzzi L , Verrina E , Vidal E , Allinovi M , Guzzo I , Jankauskiene A , Zurowska A , Tkaczyk M , Do Sameiro Faria M , Ariceta G , Sartz L , Bakkaloglu S , Duzova A , Ekim M , Karabay-Bayazit A , Düşünsel R , Çalışkan S , Alpay H , Sinha M , Hothi D , Shroff R
Published: January 2019

Background

There are three principle forms of vascular access available for the treatment of children with end stage kidney disease (ESKD) by haemodialysis: tunnelled catheters placed in a central vein (central venous lines, CVLs), arteriovenous fistulas (AVF), and arteriovenous grafts (AVG) using prosthetic or biological material. Compared with the adult literature, there are few studies in children to provide evidence based guidelines for optimal vascular access type or its management and outcomes in children with ESKD.

Methods

The European Society for Paediatric Nephrology Dialysis Working Group (ESPN Dialysis WG) have developed recommendations for the choice of access type, pre-operative evaluation, monitoring, and prevention and management of complications of different access types in children with ESKD.

Results

For adults with ESKD on haemodialysis, the principle of “Fistula First” has been key to changing the attitude to vascular access for haemodialysis. However, data from multiple observational studies and the International Paediatric Haemodialysis Network registry suggest that CVLs are associated with a significantly higher rate of infections and access dysfunction, and need for access replacement. Despite this, AVFs are used in only ∼25% of children on haemodialysis. It is important to provide the right access for the right patient at the right time in their life-course of renal replacement therapy, with an emphasis on venous preservation at all times. While AVFs may not be suitable in the very young or those with an anticipated short dialysis course before transplantation, many paediatric studies have shown that AVFs are superior to CVLs.

Conclusions

Here we present clinical practice recommendations for AVFs and CVLs in children with ESKD. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system has been used to develop and GRADE the recommendations. In the absence of high quality evidence, the opinion of experts from the ESPN Dialysis WG is provided, but is clearly GRADE-ed as such and must be carefully considered by the treating physician, and adapted to local expertise and individual patient needs as appropriate.
Minimally Invasive Transforaminal Lumbar Interbody Fusion: 2-Dimensional Surgical Video
Authors: McMordie Joseph H , Chen Eric X , Ehlers Landon D , Gillis Christopher C
Published: January 2019

This operative video is a detailed look at minimally invasive transforaminal lumbar interbody fusion. We provide a step-by-step guide with appropriate narration and operative video to enhance the educational experience. We review clinical and radiographic evaluation, patient positioning, intraoperative navigation, localization, percutaneous pedicle screw placement, minimally invasive approach, disc space preparation, placement of interbody device, and closure. By presenting up-to-date minimally invasive and intraoperative navigation techniques, this video provides educational benefit to all neurosurgeons regardless of training level.
Frameless Robot-Assisted Deep Brain Stimulation Surgery: An Initial Experience
Authors: Ho Allen L , Pendharkar Arjun V , Brewster Ryan , Martinez Derek L , Jaffe Richard A , Xu Linda W , Miller Kai J , Halpern Casey H
Published: January 2019

BACKGROUND

Modern robotic-assist surgical systems have revolutionized stereotaxy for a variety of procedures by increasing operative efficiency while preserving and even improving accuracy and safety. However, experience with robotic systems in deep brain stimulation (DBS) surgery is scarce.

OBJECTIVE

To present an initial series of DBS surgery performed utilizing a frameless robotic solution for image-guided stereotaxy, and report on operative efficiency, stereotactic accuracy, and complications.

METHODS

This study included the initial 20 consecutive patients undergoing bilateral robot-assisted DBS. The prior 20 nonrobotic, frameless cohort of DBS cases was sampled as a baseline historic control. For both cohorts, patient demographic and clinical data were collected including postoperative complications. Intraoperative duration and number of Microelectrode recording (MER) and final lead passes were recorded. For the robot-assisted cohort, 2D radial errors were calculated.

RESULTS

Mean case times (total operating room, anesthesia, and operative times) were all significantly decreased in the robot-assisted cohort (all P-values < .02) compared to frameless DBS. When looking at trends in case times, operative efficiency improved over time in the robot-assisted cohort across all time assessment points. Mean radial error in the robot-assisted cohort was 1.40 ± 0.11 mm, and mean depth error was 1.05 ± 0.18 mm. There was a significant decrease in the average number of MER passes in the robot-assisted cohort (1.05) compared to the nonrobotic cohort (1.45, P < .001).

CONCLUSION

This is the first report of application of frameless robotic-assistance with the Mazor Renaissance platform (Mazor Robotics Ltd, Caesarea, Israel) for DBS surgery, and our findings reveal that an initial experience is safe and can have a positive impact on operative efficiency, accuracy, and safety.
Suboccipital Craniotomy for Resection of a Dorsal Medullary Cerebral Cavernous Malformation: 2-Dimensional Operative Video
Authors: Yagmurlu Kaan , Norat Pedro , Park Min , Kalani M Yashar S
Published: January 2019

This video illustrates the case of a patient with familial cerebral cavernous malformation syndrome with a history of multiple symptomatic hemorrhages attributable to a medullary malformation. The patient had swallowing difficulties and gait instability that was progressively worsening. Informed consent was obtained for surgical exploration. The lesion was noted to abut the floor of the fourth ventricle and was approached using a suboccipital craniotomy. Several safe-entry zones on the floor of the fourth ventricle have been described. For lesions that abut the floor, or those that are exophytic, a direct point of entry into the lesion is selected. When possible, the opening into the floor of the fourth ventricle should be placed off midline. The technique of piecemeal resection of the lesion from the brainstem and preservation of normal, hemosiderin-stained brain is presented. Careful patient selection and respect for normal anatomy are of paramount importance in obtaining excellent outcomes in operations within or adjacent to the brainstem. This medullary lesion was resected completely.
Interfund Lending in Mutual Fund Families: Role in Liquidity Management
Authors: Agarwal Vikas , Zhao Haibei
Published: January 2019

The Investment Company Act of 1940 restricts interfund lending and borrowing within a mutual fund family, but families can apply for regulatory exemptions to participate in such transactions. We find that the monitoring mechanisms and investment restrictions influence the family’s decision to apply for the interfund lending programs. We document several benefits of such programs for equity funds. First, participating funds reduce cash holdings and increase investments in illiquid assets. Second, fund investors exhibit less run-like behavior. Third, it helps mitigate asset fire sales after extreme investor redemptions. Offsetting these benefits, money market funds in participating families experience investor outflows.

Received May 26, 2018; editorial decision November 27, 2018 by Editor Itay Goldstein. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Characterizing variants of unknown significance in rhodopsin: a functional genomics approach
Authors: Wan Aliete , Place Emily , Pierce Eric A. , Comander Jason
Published: January 2019

Characterizing the pathogenicity of DNA sequence variants of unknown significance (VUS) is a major bottleneck in human genetics, and is increasingly important in determining which patients with inherited retinal diseases could benefit from gene therapy. A library of 210 rhodopsin (RHO) variants from literature and in-house genetic diagnostic testing was created to efficiently detect pathogenicRHOvariants that fail to express on the cell surface. This study, while focused onRHO, demonstrates a streamlined, generalizable method for detecting pathogenic VUS. A relatively simple next generation sequencing (NGS)-based readout was developed so that a flow cytometry-based assay could be performed simultaneously on all variants in a pooled format, without the need for barcodes or viral transduction. The resulting dataset characterized surface expression of everyRHOlibrary variant with a high degree of reproducibility (Z’=0.94, R2=0.92-0.95), recategorizing 37 variants. For example, three retinitis pigmentosa pedigrees were solved by identifying VUS which showed low expression levels (G18D, G101V, P180T). Results were validated across multiple assays and correlated with clinical disease severity. This study presents a parallelized, higher-throughput cell-based assay for the functional characterization of VUS in rhodopsin, and can be applied more broadly to other inherited retinal disease genes and other disorders.
Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input
Authors: Baaske Magdalena K. , Kormann Eszter , Holt Abbey B. , Gulberti Alessandro , McNamara Colin G. , Pötter-Nerger Monika , Westphal Manfred , Engel Andreas K. , Hamel Wolfgang , Brown Peter , Moll Christian K.E. , Sharott Andrew
Published: January 2019

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson’s disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.
A genetic system for biasing the sex ratio in mice
Authors: Yosef Ido , Edry-Botzer Liat , Globus Rea , Shlomovitz Inbar , Munitz Ariel , Gerlic Motti , Qimron Udi
Published: January 2019

The ability to preselect the sex of livestock is economically beneficial and significantly increases the welfare and proper use of animals. In the poultry industry, for example, almost all males are brutally and unnecessarily killed shortly after hatching. The labor and associated costs of separation of females from males, as well as the massive killing of males, could be reduced by using a system that biases the sex of the progeny. Here, we provide a first proof of concept for such a system by crossing two genetically engineered mouse lines. The maternal line encodes a functional Cas9 protein on an autosomal chromosome, whereas the paternal line encodes guide RNAs on the Y chromosome targeting vital mouse genes. After fertilization, the presence of both the Y-encoded guide RNAs from the paternal sperm and the Cas9 protein from the maternal egg target the vital genes in males. We show that this breeding consequently self-destructs solely the males. Our results pave the way for a biased sex production of livestock, thus saving labor, costs, and eliminating substantial animal suffering.
Challenges and opportunities for strain verification by whole-genome sequencing
Authors: Gallegos Jenna E , Hayrynen Sergei , Adames Neil , Peccoud Jean
Published: January 2019

Laboratory strains, cell lines, and other genetic materials change hands frequently in the life sciences. Despite evidence that such materials are subject to mix-ups, contamination, and accumulation of secondary mutations, verification of strains and samples is not an established part of many experimental workflows. With the plummeting cost of next generation technologies, it is conceivable that whole genome sequencing (WGS) could be applied to routine strain and sample verification in the future. To demonstrate the need for strain validation by WGS, we sequenced haploid yeast segregants derived from a popular commercial mutant collection and identified several unexpected mutations. We determined that available bioinformatics tools may be ill-suited for verification and highlight the importance of finishing reference genomes for commonly-used laboratory strains.
Immune gene expression profiling reveals heterogeneity in luminal breast tumors
Authors: Zhu Bin , Ah Tse Shelly Lap , Wang Difei , Koka Hela , Zhang Tongwu , Abubakar Mustapha , Lee Priscilla , Wang Feng , Wu Cherry , Tsang Koon Ho , Chan Wing-cheong , Law Sze Hong , Li Mengjie , Li Wentao , Wu Suyang , Liu Zhiguang , Huang Bixia , Zhang Han , Tang Eric , Kan Zhengyan , Lee Soohyeon , Park Yeon Hee , Nam Seok Jin , Wang Mingyi , Sun Xuezheng , Jones Kristine , Zhu Bin , Hutchinson Amy , Hicks Belynda , Prokunina-Olsson Ludmila , Shi Jianxin , Garcia-Closas Montserrat , Chanock Stephen , Yang Xiaohong R.
Published: January 2019

Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.
Evaluation of a potential redox switch in blood coagulation tenase
Authors: Cook Kristina M. , Butera Diego , Hogg Philip J.
Published: January 2019

Blood coagulation factor IXa (FIXa) activates factor X that leads to thrombin and fibrin formation and a stable thrombus. FIXa catalytic efficiency is markedly enhanced when bound to the co-factor, factor VIII (FVIII), and a negatively charged phospholipid surface in the tenase complex. Small redox active peptides and protein oxidoreductases have been shown previously to have some FIXa co-factor activity and thiol modifying agents have been reported to influence FVIII activity. These observations suggested that FIXa might contain an allosteric disulfide that is regulated by FVIII. This idea was tested by measuring the influence of FVIII on the redox state of FIXa disulfide bonds and the effect of plasma oxidoreductases on FIXa activity. The redox state of nine of the 11 disulfide bonds in FIXa was measured using differential cysteine labelling and mass spectrometry and all were oxidized in the protein, and this did not change upon binding of the enzyme to FVIII. All eight disulfide bonds in FVIII were also predominantly oxidized and this did not appreciably change upon FIXa binding. In addition, relevant protein reductants in the circulation inhibited rather than activated FIXa activity. In conclusion, we found no evidence that the co-factor function of FVIII involves a change in the redox state of one or more FIXa disulfide bonds.
The origin of the central dogma through conflicting multilevel selection
Authors: Takeuchi Nobuto , Kaneko Kunihiko
Published: January 2019

The central dogma of molecular biology rests on two kinds of asymmetry between genomes and enzymes: informatic asymmetry, where information flows from genomes to enzymes but not from enzymes to genomes; and catalytic asymmetry, where enzymes provide chemical catalysis but genomes do not. How did these asymmetries originate? Here we show that these asymmetries can spontaneously arise from conflict between selection at the molecular level and selection at the cellular level. We developed a model consisting of a population of protocells, each containing a population of replicating catalytic molecules. The molecules are assumed to face a trade-off between serving as catalysts and serving as templates. This trade-off causes conflicting multilevel selection: serving as catalysts is favoured by selection between protocells, whereas serving as templates is favoured by selection between molecules within protocells. This conflict induces informatic and catalytic symmetry breaking, whereby the molecules differentiate into genomes and enzymes, establishing the central dogma. We show mathematically that the symmetry breaking is caused by a positive feedback between Fisher’s reproductive values and the relative impact of selection at different levels. This feedback induces a division of labour between genomes and enzymes, provided variation at the molecular level is sufficiently large relative to variation at the cellular level, a condition that is expected to hinder the evolution of altruism. Taken together, our results suggest that the central dogma is a logical consequence of conflicting multilevel selection.
Multiplexed temporally focused light shaping through a GRIN lens for precise in-depth optogenetic photostimulation
Authors: Accanto Nicolò , Chen I-Wen , Ronzitti Emiliano , Molinier Clément , Tourain Christophe , Papagiakoumou Eirini , Emiliani Valentina
Published: January 2019

In the past 10 years, the use of light has become irreplaceable for the optogenetic study and control of neurons and neural circuits. Optical techniques are however limited by scattering and can only see through a depth of few hundreds µm in living tissues. GRIN lens based micro-endoscopes represent a powerful solution to reach deeper regions. In this work we demonstrate that cutting edge optical methods for the precise photostimulation of multiple neurons in three dimensions can be performed through a GRIN lens. By spatio-temporally shaping a laser beam in the two-photon regime we project several tens of targets, spatially confined to the size of a single cell, in a volume of 150×150×400 μm3. We then apply such concept to the optogenetic stimulation of multiple neurons simultaneously in vivo in mice. Our work paves the way for an all-optical investigation of neural circuits at previously unattainable depths.
Description ofKlebsiella africanensissp. nov.,Klebsiella variicolasubsp.tropicalensissubsp. nov. andKlebsiella variicolasubsp.variicolasubsp. nov
Authors: Rodrigues Carla , Passet Virginie , Rakotondrasoa Andriniaina , Diallo Thierno Abdoulaye , Criscuolo Alexis , Brisse Sylvain
Published: January 2019

The bacterial pathogenKlebsiella pneumoniaecomprises several phylogenetic groups (Kp1 to Kp7), two of which (Kp5 and Kp7) have no taxonomic status. Here we show that group Kp5 is closely related toKlebsiella variicola(Kp3), with an average nucleotide identity (ANI) of 96.4%, and that group Kp7 has an ANI of 94.7% with Kp1 (K. pneumoniae sensu stricto). Biochemical characteristics and chromosomal beta-lactamase genes also distinguish groups Kp5 and Kp7 from otherKlebsiellataxa. We propose the namesK. africanensisfor Kp7 (type strain, 200023T) andK. variicolasubsp.tropicalensisfor Kp5 (type strain, 1266T).
Morse-clustering of a Topological Data Analysis Network Identifies Phenotypes of Asthma Based on Blood Gene Expression Profiles
Authors: Schofield James P R , Strazzeri Fabio , Bigler Jeannette , Boedigheimer Michael , Adcock Ian M , Chung Kian Fan , Bansal Aruna , Knowles Richard , Dahlen Sven-Erik , Wheelock Craig E. , Sun Kai , Pandis Ioannis , Riley John , Auffray Charles , De Meulder Bertrand , Lefaudeux Diane , Ramanan Devi , Sousa Ana R , Sterk Peter J , Ewing Rob. M , Macarthur Ben D , Djukanovic Ratko , Sanchez-Garcia Ruben , Skipp Paul J
Published: January 2019

Stratified medicine requires discretisation of disease populations for targeted treatments. We have developed and applied a discrete Morse theory clustering algorithm to a Topological Data Analysis (TDA) network model of 498 gene expression profiles of peripheral blood from asthma and healthy participants. The Morse clustering algorithm defined nine clusters, BC1-9, representing molecular phenotypes with discrete phenotypes including Type-1, 2 & 17 cytokine inflammatory pathways. The TDA network model and clusters were also characterised by activity of glucocorticoid receptor signalling associated with different expression profiles of glucocorticoid receptor (GR), according to microarray probesets targeted to the start or end of the GR mRNA’s 3’ UTR; suggesting differential GR mRNA processing as a possible driver of asthma phenotypes including steroid insensitivity.
Themir-35family links maternal germline sex to embryonic viability inC. elegans
Authors: Benner Lars , Prothro Katherine , McJunkin Katherine
Published: January 2019

The germline sex determination pathway inC. elegansdetermines whether germ cells develop as oocytes or sperm, with no previously known effect on viability. Themir-35family of microRNAs are expressed in theC. elegansgermline and embryo and are essential for both viability and normal hermaphroditic sex determination, preventing aberrant male gene expression in XX hermaphrodite embryos. Here we show that combining feminizing mutations with partial loss of function of themir-35family results in enhanced penetrance embryonic lethality that preferentially kills XO animals. This lethal phenotype is due to altered signaling through the germline sex determination pathway, and maternal germline feminization is sufficient to induce enhanced lethality. These findings reveal a surprising pleiotropy of sperm-fate promoting pathways on organismal viability. Overall, our results demonstrate an unexpectedly strong link between sex determination and embryonic viability, and suggest that in wild type animals,mir-35family members buffer against misregulation of pathways outside the sex determination program, allowing for clean sex reversal rather than deleterious effects of perturbing sex determination genes.
Nucleus Accumbens Fast-Spiking Interneurons Constrain Impulsive Action
Authors: Pisansky Marc T. , Lefevre Emilia M. , Retzlaff Cassandra L. , Trieu Brian H. , Leipold David W. , Rothwell Patrick E.
Published: January 2019

Background

The nucleus accumbens (NAc) controls multiple facets of impulsivity, but is a heterogeneous brain region with diverse microcircuitry. Prior literature links impulsive behavior in rodents to gamma aminobutyric acid (GABA) signaling in the NAc. Here, we studied the regulation of impulsive behavior by fast-spiking interneurons (FSIs), a strong source of GABA-mediated synaptic inhibition in the NAc.

Methods

Male and female transgenic mice expressing Cre recombinase in FSIs allowed us to identify these sparsely distributed cells in the NAc. We used a 5-choice serial reaction time task (5-CSRTT) to measure both impulsive action and sustained attention. During the 5-CSRTT, we monitored FSI activity with fiber photometry calcium imaging, and manipulated FSI activity with chemogenetic and optogenetic methodology. We used electrophysiology, optogenetics, and fluorescent in situ hybridization to confirm these methods were robust and specific to FSIs.

Results

In mice performing the 5-CSRTT, NAc FSIs showed sustained activity on trials ending with correct responses, but declined over time on trials ending with premature responses. The number of premature responses increased significantly after sustained chemogenetic inhibition or temporally delimited optogenetic inhibition of NAc FSIs, without any changes in response latencies or general locomotor activity.

Conclusions

These experiments provide strong evidence that NAc FSIs constrain impulsive actions, most likely through GABA-mediated synaptic inhibition of medium spiny projection neurons. Our findings may provide insight into the pathophysiology of disorders associated with impulsivity, and inform the development of circuit-based therapeutic interventions.
Microtubules are necessary for proper Reticulon localization during mitosis
Authors: Bergman Zane J. , Diaz Ulises , Sims Amanda , Riggs Blake
Published: January 2019

During mitosis, the structure of the Endoplasmic Reticulum (ER) displays a dramatic reorganization and remodeling event, however the mechanism driving these changes is poorly understood. Recently, the Reticulon family of ER shaping proteins has been identified as possible factors to promote these drastic changes in ER morphology. In addition, the Reticulons and other ER shaping proteins have been directly linked to several hereditary neurodegenerative disorders. Here, we provide key insight into the cytoskeletal factors involved in the Drosophila Reticulon, Reticulon-like 1 (Rtnl1) during mitosis in the early embryo. At prometaphase, Rtnl1 localizes at the spindle poles just prior to the bulk of ER localization suggesting a role in recruitment. Using precise temporal injections of cytoskeletal inhibitors in the early syncytial Drosophila embryo, we show that microtubules, not microfilaments are necessary for proper Rtnl1 localization and function during mitosis. Lastly, we show that astral microtubules are necessary for Rtnl1 localization at the spindle poles early in mitosis. This work highlights the role of the microtubule cytoskeleton in Rtnl1 localization and ER dynamics during mitosis and sheds light on a pathway towards inheritance of this major organelle.
GFP transformation sheds more light on a widespread mycoparasitic interaction
Authors: Németh Márk Z. , Pintye Alexandra , Horváth Áron N. , Vági Pál , Kovács Gábor M. , Gorfer Markus , Kiss Levente
Published: January 2019

Powdery mildews (PMs), ubiquitous obligate biotrophic plant pathogens, are often attacked in the field by mycoparasitic fungi belonging to the genus Ampelomyces. Some Ampelomyces strains are commercialized biocontrol agents of crop pathogenic PMs. Using Agrobacterium tumefaciens-mediated transformation (ATMT), we produced stable Ampelomyces transformants that constitutively expressed the green fluorescent protein (GFP), to (i) improve the visualization of the PM-Ampelomyces interaction; and (ii) decipher the environmental fate of Ampelomyces before and after acting as a mycoparasite. Detection of Ampelomyces structures, and especially hyphae, was greatly enhanced when diverse PM, leaf and soil samples containing GFP transformants were examined with fluorescence microscopy compared to brightfield and DIC optics. We showed for the first time that Ampelomyces can persist up to 21 days on PM-free host plant surfaces, where it can attack PM structures as soon as these appear after this period. As a saprobe in decomposing, PM-infected leaves on the ground, and also in autoclaved soil, Ampelomyces developed new hyphae, but did not sporulate. These results indicate that Ampelomyces occupies a niche in the phyllosphere where it acts primarily as a mycoparasite of PMs. Our work has established a framework for a molecular genetic toolbox for Ampelomyces using ATMT.