bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-Rated Health and Inflammation: A Test of Depression and Sleep Quality as Mediators
Authors: Uchino Bert N. , Landvatter Joshua , Cronan Sierra , Scott Emily , Papadakis Michael , Smith Timothy W. , Bosch Jos A. , Joel Samantha
Published: February 2019

Objective

Despite its simplicity, single-item measures of self-rated health have been associated with mortality independent of objective health conditions. However, little is known about the mechanisms potentially responsible for such associations. This study tested the association between self-rated heath and inflammatory markers as biological pathways, and whether sleep quality and/or depression statistically mediated such links.

Method

Eighty-six heterosexual married couples completed a standard measure of self-rated health, the Center of Epidemiological Studies-Depression Scale, and the Pittsburgh Sleep Quality Index. Participants also had blood drawn for determination of plasma levels of interleukin 6 and high-sensitivity C-reactive protein. The Monte Carlo method was used to construct confidence intervals for mediation analyses.

Results

Results indicated that poor self-rated health was associated with higher CRP levels (B = .31, SE = .14, p = .028). Importantly, the Monte Carlo mediational analyses showed that these results were statistically mediated by sleep quality (aXb = 0.10, 95% confidence interval = 0.003 to 0.217) but not depressive symptoms (aXb = 0.03, 95% confidence interval = −0.03 to 0.10).

Conclusions

These results highlight the biological and behavioral mechanisms potentially linking self-rated health to longer-term health outcomes. Such work can inform basic theory in the area as well as intervention approaches that target such pathways.
Neurologic Injury After Sacral Neuromodulation
Authors: Yuan Angela S. , Almodovar Jorge L. , Erekson Elisabeth
Published: February 2019

Objective

Neurologic injury after sacral nerve stimulation (SNS) is rare, but the incidence is unknown. Infection is a potential mechanism for neurologic damage. This report illustrates the presentation, pathophysiology, diagnostic considerations, and treatment of epidural infection causing neurologic deficits after SNS.

Case Report

We present a case of a woman with severe fecal incontinence due to Crohn’s disease who underwent SNS implantation and subsequently developed a wound infection requiring complete device explantation. A few days later, she presented with leg pain and weakness. Urgent evaluation and treatment of epidural infection were performed. She had persistent neurologic deficits 6 months later.

Conclusions

Neurologic sequelae from an infection after SNS are a rare event and should be considered in patients with fevers, leg pain, and neurologic deficits.
Diet Modifications in Older Women With Fecal Incontinence: A Qualitative Study
Authors: Andy Uduak U. , Ejike Nancy , Khanijow Kavita D. , Flick Lorraine C. , Markland Alayne D. , Arya Lily A. , Frasso Rosemary
Published: February 2019

Objective

The aim of the study was to investigate dietary modification strategies used by community-dwelling older women to manage their fecal incontinence (FI).

Methods

We conducted a qualitative study with focus groups wherein women 65 years and older with FI shared their experiences managing the condition. We explored the following: (1) association between diet and FI symptoms, (2) dietary strategies and modifications used by older women to manage FI, and (3) patient input about disseminating diet modification information and strategies. All focus groups were audio recorded, transcribed, coded, and qualitatively analyzed to identify relevant themes.

Results

Twenty-one women participated in 3 focus groups. All participants were aware that diet plays a key role in their experience of FI and women described a method of “trial and error” in identifying specific aspects of their diet that contributed to their FI symptoms. Women reported modifications including avoiding or limiting several foods and food categories, changing certain methods of food preparation, as well as varying the amounts and frequency of meals to manage their FI. Women articulated several suggestions including the importance of physician input, using a balanced approach when making recommendations, and the value of sharing individual experiences.

Conclusions

Older women with FI make several dietary modifications to manage their symptoms including limiting certain foods, changing methods of food preparation, and decreasing the amounts and frequency of meals. These strategies may be considered for inclusion in a diet modification plan that is culturally competent for older women with FI.
Recurrent Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits in Kidney Allografts Treated With Anti-CD20 Antibodies
Authors: Buxeda Anna , Said Samar M. , Nasr Samih H. , Leung Nelson , El Ters Mireille , Cosio Fernando G.
Published: February 2019

Background.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a distinct form of glomerulonephritis that often recurs after kidney transplantation causing severe graft injury and often failure.

Methods.

We describe post transplant outcomes and response to therapy in 20 recipients with PGNMID. Evidence of PGNMID recurrence or lack thereof was determined by protocol and clinical biopsies.

Results.

Histologic recurrence (deposition of monoclonal immunoglobulin) occurred in 18 of 20 recipients (90%), a median of 7 (1 to 65) months post transplant. At diagnosis, recurrence was generally associated with mild or no clinical manifestations and often with mild glomerular morphologic changes by light microcopy. Four of the 18 patients with recurrence did not progress and were not treated. Another 4 patients with recurrences were treated with cyclophosphamide with or without plasmapheresis, and 2 of these grafts were lost from glomerulonephritis. Nine patients with recurrences were treated with anti-CD20 antibodies (rituximab) alone, resulting in improvements in estimated glomerular filtration rate (31.5 ± 16 versus 38.8 ± 13.3 mL/min/1.73 m2, P = 0.011) and proteinuria (1280 [117 to 3752] versus 168 [83 to 1613] mg/24 h, P = 0.012) although complete clinical remission was rare. One graft in this later group was lost from recurrence 141 months post transplant. Posttreatment biopsies demonstrated stable or improved glomerular histology in most cases. However, PGNMID did not resolve in any case. Four patients received rituximab 4 months pretransplant to prevent recurrence. However, 3 had mild recurrences.

Conclusions.

Rituximab treatment of early PGNMID recurrence is effective, resulting in reasonable, long-term graft survival. Whether pretransplant rituximab modifies the course of recurrence requires additional studies.
Analysis of Risk Factors Affecting the Development of Infection in Artificial Vascular Grafts Used for Reconstruction of Middle Hepatic Vein Tributaries in Living Donor Liver Transplantation
Authors: Koc Cemalettin , Akbulut Sami , Ozdemir Fatih , Kose Adem , Isik Burak , Yologlu Saim , Yilmaz Sezai
Published: February 2019

Background.

To analyze the risk factors affecting the development of infection in artificial vascular grafts (AVGs) used for reconstruction of middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT).

Methods.

Between January 2009 and January 2018, 1253 right lobe LDLTs were performed at our Transplant Institute, and MHV tributaries of the 640 right lobe liver grafts were reconstructed with AVG. Reconstructed MHV tributaries were removed due to AVG infection in 25 of these patients (case group; n = 25). To determine risk factors for AVG infection, right lobe LDLT patients without AVG infections were selected as control group (n = 615). Both groups were compared about demographic parameter, transcystic catheter usage, bile leakage, type of biliary anastomosis (duct-to-duct, telescopic duct-to-duct), number of graft biliary duct (=1 versus >1), number of biliary anastomosis (=1 versus >1), AVG thrombosis, AVG types (Dacron versus polytetrafluoroethylene). Univariate analyses were used for comparison of different variables, and variables with P ≤ 0.20 were taken into logistic regression model.

Results.

Univariate analysis shows that statistically significant differences were found between groups regarding bile leakage (P < 0.001), graft thrombosis (P = 0.002), transcystic catheter (P = 0.049), and AVG types (P = 0.013). Variables with P ≤ 0.20 were taken into logistic regression model. Multivariate analysis shows that bile leakage (odds ratio, 13.3) and AVG thrombosis (odds ratio, 9.8) were determined as independent and strong risk factors for development of AVG infection.

Conclusions.

This study revealed that bile leakage and graft thrombosis are independent and strong risk factors for infections of AVGs used for anterior sector drainage reconstruction.
Memory B Cells and Long-lived Plasma Cells
Authors: Ionescu Lavinia , Urschel Simon
Published: February 2019

The importance of B cell and antibody-mediated immune response in the acute and long-term persistence of transplanted solid organs has become increasingly evident in recent years. A variety of therapeutic innovations target antibodies directed toward HLA or blood groups (ABO) to allow better allocation and posttransplant longevity of organs. Antibodies originate from plasma cells (PCs), which are terminally differentiated B cells. Long-term production and persistence of these antibodies is partly due to fast reactivation of previously generated memory B cells; however, there is increasing evidence that some differentiated PCs can persist independently in the bone marrow for years or even decades, producing specific antibodies or even experiencing regeneration without proliferation without need to be replaced by newly differentiating B cells. This review outlines the currently presumed pathways of differentiation, antibody, and memory generation on both B-cell and PC levels. On this background, current therapeutic concepts for antibody reduction before and after solid organ transplantation are considered, to better understand their mechanisms, possible synergisms, and specific risks. Specific differences in regards to ABO versus HLA antibodies as well as practical relevance for generation of desensitization and posttransplant antibody-directed therapy protocols are discussed.
Suppression of Hepatocellular Carcinoma by Mycophenolic Acid in Experimental Models and in Patients
Authors: Chen Kan , Sheng Jiexin , Ma Buyun , Cao Wanlu , Hernanda Pratika Y. , Liu Jiaye , Boor Patrick P.C. , Tjon Angela S.W. , Felczak Krzysztof , Sprengers Dave , Pankiewicz Krzysztof W. , Metselaar Herold J. , Ma Zhongren , Kwekkeboom Jaap , Peppelenbosch Maikel P. , Pan Qiuwei
Published: February 2019

Background.

Tumor recurrence is a major complication following liver transplantation (LT) as treatment for hepatocellular carcinoma (HCC). Immunosuppression is an important risk factor for HCC recurrence, but conceivably may depend on the type of immunosuppressive medication. Mycophenolic acid (MPA) is a currently widely used immunosuppressant. This study investigated the effects of MPA on HCC.

Methods.

Three human HCC cell lines and organoids from mouse primary liver tumor were used as experimental models. MTT, Alamar Blue assay, cell cycle analysis, colony formation, and [3H]-thymidine assays were performed. An LT database was used for retrospective analysis of the effect of mycophenolate mofetil, the prodrug of MPA, on HCC recurrence.

Results.

With clinically achievable concentrations, MPA effectively inhibited HCC cell proliferation and single-cell colony-forming unit. In short-term experiments, MPA effectively elicited S phase arrest in HCC cell lines. In addition, the initiation and growth of liver tumor organoids were effectively inhibited by MPA. Most importantly, the use of mycophenolate mofetil in patients with HCC-related LT was significantly associated with less tumor recurrence and improved patient survival.

Conclusions.

MPA can specifically counteract HCC growth in vitro and tumor recurrence in LT patients. These results warrant prospective clinical trials into the role of MPA-mediated immunosuppression following LT of patients with HCC.
Should All Status 1A Patients Be Prioritized Over High MELD Patients? Concept of Risk Stratification in Extremely Ill Liver Transplant Recipients
Authors: Safwan Mohamed , Nwagu Uche , Collins Kelly , Abouljoud Marwan , Nagai Shunji
Published: February 2019

Background.

Status 1A patients are prioritized over liver disease patients regardless of Model for End-stage Liver Disease (MELD) score. We aimed to identify groups with high waitlist mortality in Status 1A and MELD ≥40 patients to determine who would most benefit from transplantation.

Methods.

Data on patients listed as Status 1A (n = 4447) and MELD ≥40 (n = 3663) over 15 years (2002–2017) was obtained from United Network for Organ Sharing/Organ Procurement and Transplant Network registry. They were divided into 2—derivation and validation groups. Risk factors associated with 28-day waitlist mortality were identified in derivation group and provided risk scores to divide patients into risk groups. Score system was applied to validation group to check its applicability.

Results.

Risk factors for waitlist mortality in Status 1A included life support, performance status, severe coagulopathy, severe hypo or hypernatremia, and grade 3–4 encephalopathy. Risk factors in MELD ≥40 included higher MELD scores (≥45), age, sex, race, life support, and encephalopathy. On comparing 7- and 28-day mortality, both were higher in Status 1A and MELD ≥40 high-risk groups compared with low-risk groups in the derivation group (P < 0.001). Probability of transplantation was lowest for high-risk MELD ≥40 patients compared with all other groups (P < 0.001). These findings were reproduced in the validation set. Our proposed risk stratification system also showed acceptable 1-year graft and patient survival in high-risk groups.

Conclusions.

Our risk scoring system for extremely ill liver transplant candidates successfully stratified risk of waitlist mortality. Waitlist outcomes might be improved by modifications involving categorization of patients based on the presence/absence of risk factors.
Equally Interchangeable? How Sex and Gender Affect Transplantation
Authors: Melk Anette , Babitsch Birgit , Borchert-Mörlins Bianca , Claas Frans , Dipchand Anne I. , Eifert Sandra , Eiz-Vesper Britta , Epping Jelena , Falk Christine S. , Foster Bethany , Geyer Siegfried , Gjertson David , Greer Mark , Haubitz Marion , Lau Ashley , Maecker-Kolhoff Britta , Memaran Nima , Messner Hans A. , Ostendorf Karen , Samuel Undine , Schmidt Bernhard M.W. , Tullius Stefan G. , West Lori , Wong Germaine , Zimmermann Tanja , Berenguer Marina
Published: February 2019

Organ transplantation as an option to overcome end-stage diseases is common in countries with advanced healthcare systems and is increasingly provided in emerging and developing countries. A review of the literature points to sex- and gender-based inequity in the field with differences reported at each step of the transplant process, including access to a transplantation waiting list, access to transplantation once waitlisted, as well as outcome after transplantation. In this review, we summarize the data regarding sex- and gender-based disparity in adult and pediatric kidney, liver, lung, heart, and hematopoietic stem cell transplantation and argue that there are not only biological but also psychological and socioeconomic issues that contribute to disparity in the outcome, as well as an inequitable access to transplantation for women and girls. Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure equity and efficiency of the organ allocation system. In the spirit of equity and equality, the authors call for recognition of these inequities and the development of policies that have the potential to ensure that girls and women have equitable access to transplantation.
Regulatory T-cell Number in Peripheral Blood at 1 Year Posttransplant as Predictor of Long-term Kidney Graft Survival
Authors: San Segundo David , Galván-Espinoza Luis H. , Rodrigo Emilio , Irure Juan , Ruiz Juan C. , Fernández-Fresnedo Gema , Riesco Laura , Bada Jairo , Belmar Lara , Lopez-Hoyos Marcos
Published: February 2019

Background

Regulatory T (Treg) cells play a role in limiting kidney transplant rejection and can potentially promote long-term transplant tolerance. There are no large prospective studies demonstrating the utility of peripheral blood Treg cells as biomarkers for long-term graft outcome in kidney transplantation. The aim of our study was to analyze the influence of the absolute number of peripheral blood Treg cells after transplantation on long-term death-censored graft survival.

Methods

We monitored the absolute numbers of Treg cells by flow cytometry in nonfrozen samples of peripheral blood in 133 kidney transplant recipients, who were prospectively followed up to 2 years after transplantation. Death-censored graft survival was determined retrospectively in January 2017.

Results

The mean time of clinical follow-up was 7.4 ± 2.9 years and 24.1% patients suffered death-censored graft loss (DCGL). Patients with high Treg cells 1 year after transplantation and above the median value (14.57 cells/mm3), showed better death-censored graft survival (5-year survival, 92.5% vs 81.4%, Log-rankP= .030). One-year Treg cells showed a receiver operating characteristic - area under curve of 63.1% (95% confidence interval, 52.9–73.2%,P= 0.026) for predicting DCGL. After multivariate Cox regression analysis, an increased number of peripheral blood Treg cells was a protective factor for DCGL (hazard ratio, 0.961, 95% confidence interval, 0.924–0.998,P= 0.041), irrespectively of 1-year proteinuria and renal function.

Conclusions

Peripheral blood absolute numbers of Treg cells 1 year after kidney transplantation predict a better long-term graft outcome and may be used as prognostic biomarkers.
Clinical Outcomes in Patients Taking Inhaled Loxapine, Haloperidol, or Ziprasidone in the Emergency Department
Authors: McDowell Marc , Nitti Kara , Kulstad Erik , Cirone Michael , Shah Riddhi , Rochford Daniel , Walsh Richard , Hesse Kathleen
Published: February 2019

Objectives

Our objective was to compare outcomes of discharge disposition, need for additional medications, and restraint use for patients who received inhaled loxapine compared with patients receiving traditional antipsychotic drugs in the emergency department (ED).

Methods

A retrospective chart review was conducted on all patients who presented to the ED with agitation and received antipsychotic therapy, including loxapine, ziprasidone, or haloperidol from December 1, 2014, through October 31, 2016.

Results

The mean time from physician assignment to medical clearance was 7.9 hours for patients treated with inhaled loxapine versus 10.3 hours for controls (P < 0.01). Those who received inhaled loxapine were given significantly less benzodiazepines as additional rescue medications as compared with other antipsychotic medications (P < 0.01, 35.2% vs 65.1%). Additionally, restraints were utilized less frequently in the loxapine group (P < 0.01, 1.8% vs 19.8%).

Conclusions

Treating patients with agitation due to psychotic episodes in an ED setting with inhaled loxapine versus haloperidol or ziprasidone was associated with significantly improved treatment outcomes, suggesting that inhaled loxapine may be a more effective and rapid treatment option.
Multifocal Stroke From Ozone Gas Emboli
Authors: Freund Paul R. , Alshafai Laila , Margolin Edward A.
Published: February 2019

A 34-year-old man with chronic neck pain was treated with regular cervical paravertebral ozone injections. After his last injection, he experienced a syncopal episode and, upon awakening, was found to have ataxia, aphasia, hemiparesis, and left sixth nerve palsy. Computed tomographic angiography demonstrated intra-arterial gas in the right vertebral artery; multiple posterior circulation infarcts were seen on brain MRI. This case illustrates the potential dangers of paravertebral injections of ozone.
p130Cas contributes to cellular mechanosensing and force exertion
Authors: van Hoorn Hedde , Donato Dominique M. , Balcioglu H. Emrah , Danen Erik H. , Schmidt Thomas
Published: February 2019

Cell survival, differentiation, and migration are all dependent on the cell’s interaction with its external environment. In addition to chemical cues, cells react to their physical environment, particularly the stiffness of the substrate. In order for cells to react to these elements, they must make use of cellular machinery to signal changes in their microenvironment. One such proposed machinery is the protein p130Cas, which has been shown to regulate focal adhesion turnover, actin dynamics, and cell migration. Here we show that p130Cas localizes to focal adhesions depending on substrate stiffness and subsequently modulates cellular force exertion. We compared on substrates of tunable stiffness knock-out CAS-/-cells to cells re-expressing either the full-length p130Cas or a mutant lacking the focal adhesion targeting domains. On polyacrylamide gels, we observed that p130Cas prevented focal adhesion formation at low stiffness. On structured micro-pillar arrays, p130Cas preferentially localized to sites of force exertion when the apparent Young’s modulus of the substrate was higher than E = 47 kPa. Stiffness-dependent localization of p130Cas coincided with slower, but increased force exertion for the full-length p130Cas. Cas localization to focal adhesions preceded force build-up by three minutes, suggesting a coordinating role for p130Cas in the cellular mechanoresponse. Thus, p130Cas appears to relay mechanosensory information in the cell through its ability to tune force exertion at the focal adhesion.
A wrappable microwire electrode for awake, chronic interfacing with small diameter autonomic peripheral nerves
Authors: Falcone Jessica D. , Liu Tristan , Goldman Laura , Pogue David D. , Straka Malgorzata , Rieth Loren , Bouton Chad E. , Sohal Harbaljit S.
Published: February 2019

Bioelectronic medicine requires the ability to monitor and modulate nerve activity in awake patients over time. The vagus nerve is a promising stimulation target, and preclinical models often use mice. However, an awake, chronic mouse vagus nerve interface has yet to be demonstrated. Here, we developed a functional wrappable microwire electrode to chronically interface with the small diameter mouse cervical vagus nerve (∼100 μm). In an acute setting, the wrappable microwire had similar recording performance to commercially available electrodes. A chronic, awake mouse model was then developed to record spontaneous compound action potentials (CAPs). Viable signal-to-noise ratios (SNRs) were obtained from the wrappable microwires between 30 and 60 days (n = 8). Weekly impedance measurements showed no correlation between SNR or time. The wrappable microwires successfully interfaced with small diameter nerves and has been validated in a chronic, awake preclinical model, which can better facilitate clinical translation for bioelectronic medicine.
Connectomic identification and three-dimensional color tuning of S-OFF midget ganglion cells in the primate retina
Authors: Wool Lauren E , Packer Orin S , Zaidi Qasim , Dacey Dennis M
Published: February 2019

In the trichromatic primate retina, the ‘midget’ retinal ganglion cell is the classical substrate for red-green color signaling, with a circuitry that enables antagonistic responses between long (L)- and medium (M)-wavelength sensitive cone inputs. Previous physiological studies show that some OFF midget ganglion cells may receive sparse input from short (S)-wavelength sensitive cones, but the effect of S-cone inputs on the chromatic tuning properties of such cells has been unexplored. Moreover, anatomical evidence for a synaptic pathway from S cones to OFF midget ganglion cells through OFF-midget bipolar cells remains ambiguous. In this study we address both questions for the macaque monkey retina. First, we used serial block-face electron microscopy (SBEM) to show that every S-cone in the parafoveal retina synapses principally with a single OFF-midget bipolar cell which in turn forms a private-line connection with an OFF midget ganglion cell. Second, we used patch electrophysiology to characterize the chromatic tuning of OFF midget ganglion cells in the near peripheral retina that receive combined input from L, M and S cones. These ‘S-OFF’ midget cells have a characteristic S-cone spatial signature, but demonstrate heterogeneous color properties due to variable strength of L, M, and S cone input across the receptive field. Together these findings strongly support the hypothesis that the OFF midget pathway is the major conduit for S-OFF signals in primate retina, and redefines the pathway as a chromatically complex substrate that encodes color signals beyond the classically recognized L vs. M and S vs. L+M cardinal mechanisms.

Significance statement

The first step of color processing in the visual pathway of primates occurs when signals from short- (S), middle- (M) and long- (L) wavelength sensitive cone types interact antagonistically within the retinal circuitry to create color-opponent pathways. The midget (L vs. M or ‘red-green’) and small bistratified (S vs. L+M, or ‘blue-yellow’) appear to provide the physiological origin of the cardinal axes of human color vision. Here we confirm the presence of an additional S-OFF midget circuit in the macaque monkey fovea with scanning block-face electron microscopy (SBEM) and show physiologically that a subpopulation of S-OFF midget cells combine S, L and M cone inputs along non-cardinal directions of color space, expanding the retinal role in color coding.
Contrasting patterns of ERK activation in the tail of the striatum in response to aversive and rewarding signals
Authors: Gangarossa Giuseppe , Castell Laia , Castro Liliana , Tarot Pauline , Veyrunes Frederic , Vincent Pierre , Bertaso Federica , Valjent Emmanuel
Published: February 2019

The caudal part of the striatum, also named the tail of the striatum (TS), defines a fourth striatal domain. Determining whether rewarding, aversive and salient stimuli regulate the activity of striatal spiny projections neurons (SPNs) of the TS is therefore of a paramount importance to understand its functions, which remain largely elusive. Taking advantage of genetically encoded biosensors (AKAR3) to record PKA signals and by analyzing the distribution of D1R-and D2R/A2aR-SPNs in the TS, we characterized three evolutionary highly conserved subterritories: a D2R/A2aR-lacking area, a D1R/D2-SPNs-enriched and an D1R/D2R-intermingled area. The analysis of ERK phosphorylation in these TS subterritories in response to distinct appetitive, aversive and pharmacological stimuli revealed that SPNs of the TS are not recruited by stimuli triggering innate or learned avoidance responses, fasting, satiety or palatable signals. In contrast, D1R-SPNs of the intermingled and D2R/A2AR-lacking areas are strongly activated by both direct stimulation of D1R and psychostimulant drugs (d-amphetamine, cocaine, MDMA or methylphenidate), but not by hallucinogens. Finally, a similar pattern of ERK activation was observed by blocking selectively dopamine reuptake. Together, our results reveal that the caudal TS might participate in the processing of specific reward signals.
Allele-specific transcript abundance: A pilot study in healthy centenarians
Authors: Tindale Lauren C. , Thiessen Nina , Leach Stephen , Brooks-Wilson Angela R.
Published: February 2019

The genetic basis of healthy aging and longevity remains largely unexplained. One hypothesis as to why long-lived individuals do not appear to have a lower number of common-complex disease variants, is that despite carrying risk variants, they express disease-linked alleles at a lower level than the wild-type alleles. Allele-specific abundance (ASA) is the different transcript abundance of the two haplotypes of a diploid individual. We sequenced the transcriptomes of four healthy centenarians and four mid-life controls. CIBERSORT was used to estimate blood cell fractions: neutrophils were the most abundant source of RNA, followed by CD8+ T cells, resting NK cells, and monocytes. ASA variants were more common in non-coding than coding regions. Centenarians and controls had a comparable distribution of ASA variants by predicted effect, and we did not observe an overall bias in expression towards major or minor alleles. Immune pathways were most highly represented among the gene set that showed ASA. Although we found evidence of ASA in disease-associated genes and transcription factors, we did not observe any differences in the pattern of expression between centenarians and controls in this small pilot study.
Ultra-thin fluorocarbon foils optimise multiscale imaging of three-dimensional native and optically cleared specimens
Authors: Hötte Katharina , Koch Michael , Hof Lotta , Tuppi Marcel , Moreth Till , Stelzer Ernst H. K. , Pampaloni Francesco
Published: February 2019

In three-dimensional light microscopy, the heterogeneity of the optical density in a specimen ultimately limits the achievable penetration depth and hence the three-dimensional resolution. The most direct approach to reduce aberrations, improve the contrast, and achieve an optimal resolution is minimizing the impact of changes of the refractive index along an optical path. Many light sheet fluorescence microscopes operate with a large chamber that contains an aqueous immersion medium and an inner specimen holder that contains the specimen embedded in a possibly entirely different non-aqueous medium. In order to minimize the impact of the specimen holder on the optical quality, we use multi-facetted cuvettes fabricated with vacuum-formed ultra-thin fluorocarbon (FEP) foils The ultra-thin FEP-foil cuvettes have a wall thickness of about 12 µm. They are resilient to fluidic exchanges, durable, mechanically stable and yet flexible.

We confirm the improved imaging performance of ultra-thin FEP-foil cuvettes with excellent quality images of whole organs, thick tissue sections and dense organoid clusters. The cuvettes outperform many other sample-mounting techniques in terms of full separation of the specimen from the immersion medium, compatibility with aqueous and organic clearing media, quick specimen mounting without hydrogel embedding, as well as their applicability for multiple-view imaging and automated segmentation. Additionally, we show that ultra-thin FEP foil cuvettes are suitable for seeding and growing organoids over a time period of at least ten days. The ultra-thin cuvettes allow the fixation and staining of the specimens inside the holder, preserving the delicate morphology of e.g. fragile, mono-layered three-dimensional organoids.
Where do our graduates go? A toolkit for retrospective and ongoing career outcomes data collection for biomedical PhD students and postdoctoral scholars
Authors: Silva Elizabeth A. , Mejía Alicia B. , Watkins Elizabeth S.
Published: February 2019

Universities are at long last undertaking efforts to collect and disseminate information about student career outcomes, after decades of calls to action. Organizations such as Rescuing Biomedical Research and Future of Research brought this issue to the forefront of graduate education, and the second Future of Biomedical Graduate and Postdoctoral Training conference (FOBGAPT2) featured the collection of career outcomes data in its final recommendations, published in this journal (Hitchcock et al., 2017). More recently, 26 institutions assembled as the Coalition for Next Generation Life Science, committing to ongoing collection and dissemination of career data for both graduate and postdoc alumni. A few individual institutions have shared snapshots of the data in peer-reviewed publications (Mathur et al., 2018; Silva, des Jarlais, Lindstaedt, Rotman, Watkins, 2016) and on websites. As more and more institutions take up this call to action, they will now be looking for tools, protocols, and best practices for ongoing career outcomes data collection, management, and dissemination. Here, we describe UCSF's experiences in conducting a retrospective study, and in institutionalizing a methodology for annual data collection and dissemination. We describe and share all tools we have developed, and we provide calculations of the time and resources required to accomplish both retrospective studies and annual updates. We also include broader recommendations for implementation at your own institutions, increasing the feasibility of this endeavor.
High prevalence of precocious menarche in Puerto Barrios, Guatemala
Authors: Torres-González Edmundo , López Griselda , Trabert Britton , Lou Hong , Guerra Sarita Polo , Orozco Anali , Garland Lisa , Florez-Vargas Oscar , Castillo Miriam , Argueta Victor , Gharzouzi Eduardo , Dean Michael , Orozco Roberto
Published: February 2019

Background

Age of menarche is variable between women with a median age of 14 years old worldwide, and averages ranging from 12-13 years old in developed countries to 15-16 years old in low and middle-income countries. Precocious menarche, occurring before age 11, is rare, with a prevalence of 1.4 to 2.3% in most worldwide populations. Precocious menarche is poorly understood but is associated with early puberty and is a risk factor for pre-teen birth. In studying HPV prevalence in Latin America, we identified a community with a very high rate of precocious menarche.

Objective(s)

Describe the patterns of precocious menarche in Guatemala.

Study Design

Reproductive histories were collected from 3385 cancer-free women at the time of routine Pap smear from 4 sites in Guatemala including hospitals in Guatemala City and Puerto Barrios, Izabal. Statistical analyses included determination of the age-specific prevalence of menarche and linear regression to determine the effect of year of birth, study site, number of births and miscarriages, on the age at menarche.

Results

Compared with a low prevalence of precocious menarche observed in Guatemala City (3.1%, 88/2834), we observed a high prevalence of precocious menarche in the city of Puerto Barrios, Izabal, Guatemala (88%, 486/551). We observed a high prevalence of precocious menarche in Puerto Barrios across all age groups. In contrast in Guatemala City, the median age at menarche declined from the age of 14 in 50-60-year-old women to 13 in women under 40 years of age. Hospital records show that the occurrence of both miscarriage and pregnancy under age 14 is substantially higher in Izabal. In addition, the main public hospital in Puerto Barrios accounts for a high fraction of the early pregnancies and miscarriages seen in Guatemala.

Conclusions

In Puerto Barrios, Izabal, Guatemala, the prevalence of menarche before age 11 is dramatically elevated compared to Guatemala City and substantially higher than other worldwide populations. We observed precocious menarche in Puerto Barrios in all age groups examined, indicating that this condition has been common for decades. This finding is supported by the comparatively higher occurrence of early pregnancy and miscarriage in Puerto Barrios compared with Guatemala City. The cause is unknown, but precocious menarche is associated with adverse reproductive outcome in young women and warrants further investigation.
A NMF-based approach to discover overlooked differentially expressed gene regions from single-cell RNA-seq data
Authors: Matsumoto Hirotaka , Hayashi Tetsutaro , Ozaki Haruka , Tsuyuzaki Koki , Umeda Mana , Iida Tsuyoshi , Nakamura Masaya , Okano Hideyuki , Nikaido Itoshi
Published: February 2019

Single-cell RNA sequencing has enabled researchers to quantify the transcriptomes of individual cells, infer cell types, and investigate differential expression among cell types, which will lead to a better understanding of the regulatory mechanisms of cell states. Transcript diversity caused by phenomena such as aberrant splicing events have been revealed, and differential expression of previously unannotated transcripts might be overlooked by annotation-based analyses.

Accordingly, we have developed an approach to discover overlooked differentially expressed (DE) gene regions that complements annotation-based methods. We applied our algorithm to two datasets and discovered several intriguing DE transcripts, including a transcript related to the modulation of neural stem/progenitor cell differentiation.
GEMME: a simple and fast global epistatic model predicting mutational effects
Authors: Laine Elodie , Karami Yasaman , Carbone Alessandra
Published: February 2019

Abstracts

The systematic and accurate description of protein mutational landscapes is a question of utmost importance in biology, bioengineering and medicine. Recent progress has been achieved by leveraging on the increasing wealth of genomic data and by modeling inter-site dependencies within biological sequences. However, state-of-the-art methods require numerous highly variable sequences and remain time consuming. Here, we present GEMME (www.lcqb.upmc.fr/GEMME), a method that overcomes these limitations by explicitly modeling the evolutionary history of natural sequences. This allows accounting for all positions in a sequence when estimating the effect of a given mutation. Assessed against 41 experimental high-throughput mutational scans, GEMME overall performs similarly or better than existing methods and runs faster by several orders of magnitude. It greatly improves predictions for viral sequences and, more generally, for very conserved families. It uses only a few biologically meaningful and interpretable parameters, while existing methods work with hundreds of thousands of parameters.
Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia
Authors: Gilbertson Tom , Humphries Mark , Steele J. Douglas
Published: February 2019

In monogenetic generalized forms of dystonia,in vitroneurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico-striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico-striatal synaptic plasticity contributes to abnormal reward-learning behavior in patients with focal dystonia. Forty patients and forty controls performed a reward-gain and loss-avoidance reversal learning task. Participant’s behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico-striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesised receptor specific abnormalities of cortico-striatal long term potentiation (LTP) and Long Term Depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post-reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient’s motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient’s behavior, suggesting excessive D2 cortico-striatal synaptic depotentiation could underpin biased reward learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioural correlate of D2 specific abnormalities in cortico-striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward-learning behavior in these patients.
Whole Brain Polarity Regime Dynamics are Significantly Disrupted in Schizophrenia and Correlate Strongly with Network Connectivity Measures
Authors: Miller Robyn L. , Pearlson Godfrey , Calhoun Vince D.
Published: February 2019

From a large clinical blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) study, we report several interrelated findings involving transient supra-network brainwide states characterized by a saturation phenomenon we are referring to as “polarization.” These are whole-brain states in which the voxelwise-normalized BOLD (vnBOLD) activation of a large proportion of voxels is simultaneously either very high or very low. The presence of such states during a resting-state fMRI (rs-fMRI) scan is significantly anti-correlated with diagnosed schizophrenia, significantly anti-correlated with connectivity between subcortical networks and auditory, visual and sensorimotor networks and also significantly anti-correlated with contemporaneous occupancy of transient functional network connectivity states featuring broad disconnectivity or strong inhibitory connections between the default mode and other networks. Conversely, the presence of highly polarized vn-BOLD states is significantly correlated with connectivity strength between auditory, visual and sensorimotor networks and with contemporaneous occupancy of transient whole-brain patterns of strongly modularized network connectivity and diffuse hyperconnectivity. Despite their consistency with well-documented effects of schizophrenia on static and time-varying functional network connectivity, the observed relationships between polarization and network connectivity are with very few exceptions unmediated by schizophrenia diagnosis. We also find that the spatial distribution of voxels most likely to contribute to the highly polarized states (polarity participation maps (PPMs)) differs with a high degree of statistical significance between schizophrenia patients and healthy controls. Finally, we report evidence suggesting the process by which the most polarized states are achieved, i.e. the ways that strongly polarized voxel regions extend, merge and recede also differs significantly between patient and control populations. Many differences observed between patients and controls are echoed within the patient population itself in the effect patterns of positive symptomology (e.g. hallucinations, delusions, grandiosity and other positive symptoms of schizophrenia). Our findings highlight a particular whole-brain spatiotemporal BOLD activation phenomenon that differs markedly between healthy subjects and schizophrenia patients, one that also strongly informs time-resolved network connectivity patterns that are associated with this serious clinical disorder.
Transition scale-spaces: A computational theory for the discretized entorhinal cortex
Authors: Waniek Nicolai
Published: February 2019

Goal-directed spatial navigation is fundamental for mobile animals and is generally attributed to Place Cells (PCs) and Grid Cells (GCs) of the Hippocampus. It was proposed recently that GCs optimally encode transitions in spatiotemporal sequences. However, a single scale of transitions exhibits unfavorable runtimes when planning long sequences. This issue is approached by observing a relationship to binary search and data structures to optimally accelerate it. Then, this insight is extended to biologically plausible neural representations. The resultant data structure is a scale-space that learns approximate transitions and has an optimal scale-increment of between subsequent scales. Also, the results generalize beyond navigation and, thus, describe a general-purpose cortical data structure. Applied to navigation, it resembles multi-resolution path planning, a technique widely deployed in mobile robotics. In addition, the scale-space can be used to find short-cuts, shown in a simulated Morris water maze experiment. Finally, the results provoke a novel understanding of Theta Phase Precession (TPP).
Percentage of Foveal versus Total Macular Geographic Atrophy as a Predictor of Visual Acuity in Age-related Macular Degeneration
Authors: Bagheri Saghar , Lains Ines , Silverman Rebecca , Kim Ivana , Eliott Dean , Silva Rufino , Miller John , Husain Deeba , Miller Joan W , Saad Leonide , Vavvas Demetrios
Published: February 2019

Objectives

To investigate the relationship between visual acuity (VA), total area of geographic atrophy (GA) and percentage of foveal GA.

Methods

Multicenter, retrospective cross-sectional study of patients with GA due to age-related macular degeneration. Demographics, VA, fundus autofluorescence (FAF) and optical coherence tomography (OCT) images were collected. Using FAF images aided by OCT, foveal sparing status, GA pattern, total GA size, and percentage of GA covering the foveal area - area within a 1.5 mm diameter circle centered on the fovea centralis - were assessed. Univariable and multiple linear regression analyses were performed.

Results

54 eyes (mean age 78.7 ±7.7 (SD), 60.0% female) were studied. Mean VA was 0.8 ± 0.6 logMAR, mean total GA 8.8 ± 6.7 mm2 and mean percentage of foveal GA was 71.5 ± 30.9%. Of all assessed eyes, 48.2% (n = 26) presented with multifocal GA, and 18.5% (n = 10) had foveal sparing. Multiple regression analysis revealed that, controlling for age and GA pattern, the percentage of foveal GA presented a statistically significant association with VA (ß = 0.41, P = 0.004). No significant associations were observed with mean total GA size, while controlling for the same variables (ß = 0.010, P = 0.440).

Conclusion

Percentage of foveal GA was significantly associated with VA impairment, while the same was not verified for total GA area. These findings suggest that percentage of foveal GA may represent a more useful tool for assessing the impact of GA on VA. Further validation is needed in larger cohorts.
Isolates from colonic spirochaetosis in humans show high genomic divergence and carry potential pathogenic features but are not detected by 16S amplicon sequencing using standard primers for the human microbiota
Authors: Thorell Kaisa , Inganäs Linn , Backhans Annette , Agréus Lars , Öst Åke , Walker Marjorie , Talley Nicholas J , Kjellström Lars , Andreasson Anna , Engstrand Lars
Published: February 2019

Colonic spirochaetosis, diagnosed based on the striking appearance in histological sections, still has an obscure clinical relevance and only few bacterial isolates from this condition have been characterized to date. In a randomized, population-based study in Stockholm, Sweden, 745 healthy individuals underwent colonoscopy with biopsy sampling. In these individuals, 17 (2.3 %) had colonic spirochaetosis, which was associated with eosinophilic infiltration and a three-fold increased risk for irritable bowel syndrome (IBS). We aimed to culture the bacteria and perform whole genome sequencing of the isolates from this unique representative population sample. From 14 out of 17 individuals with spirochaetosis we successfully isolated, cultured and performed whole genome sequencing of in total 17 isolates including theBrachyspira aalborgitype strain 513AT. Also, 16S analysis of the mucosa-associated microbiota was performed in the cases and non-spirochaetosis controls.

This is the first report of whole genome analysis of clinical isolates from individuals with colonic spirochaetosis. We found one isolate to be of the speciesBrachyspira pilosicoliand all remaining isolates were of the speciesBrachyspira aalborgi. Besides displaying extensive genetic heterogeneity, the isolates harboured several mucin-degrading enzymes and other virulence-associated genes that could confer a pathogenic potential in the human colon. We also showed that 16S amplicon sequencing using standard primers for human microbiota studies fail to detectBrachyspiradue to primer incompatibility. This failure to detect colonic spirochaetosis should be taken into consideration in project design and interpretation of gastrointestinal tract microbiota in population-based and clinical settings.