bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex, Age, Race/Ethnicity, Veteran Status, and the Likelihood of Reporting Cardiovascular Conditions in the National Health Interview Survey
Authors: Hinojosa Ramon
Published: April 2019

Background

This study explores the likelihood of reporting the presence of cardiovascular health conditions in the National Health Interview Survey, with a focus on the moderating effects of veteran status, race/ethnicity, age, sex, and functional status.

Method

Data from the 2012–2015 National Health Interview Survey examine 5 cardiovascular health conditions/risk factors (hypertension, coronary heart disease, heart conditions, stroke, and heart attack).

Results

Age, sex, and functional status moderate the relationship between veteran status and cardiovascular conditions. Veterans who are younger (veteran × age) have a higher risk of reporting 1 cardiovascular condition compared with veterans who are older (relative risk [RR], 0.99; 95% confidence interval [CI], 0.99–0.99). Veterans with functional limitations (veteran × functional status) are at a lower risk of reporting 3 or more cardiovascular conditions compared with veterans with no functional limitations (RR, 0.73; 95% CI, 0.56–0.95). Interaction variables in the model (veteran × sex) show that female veterans had a higher risk than did female non-veterans of reporting 3 or more cardiovascular conditions compared with male veterans versus male non-veterans (RR, 0.71; 95% CI, 0.53–0.95). Race/ethnicity does not moderate the likelihood of reporting cardiovascular disease conditions in this sample.

Conclusion

This study demonstrates that previous military service is linked to the reporting of cardiovascular disease conditions by using nationally representative data to examine the moderating effects of veteran status on the relationship between race/ethnicity, sex, functional status, and age and cardiovascular disease for veterans living in the general US population. The findings suggest a waning healthy soldier effect for the youngest American veterans and indicate that female veterans' cardiovascular health is at greatest risk.
Targeting Peripheral Vascular Pulsatility in Heart Failure Patients with Continuous-Flow Left Ventricular Assist Devices: The Impact of Pump Speed
Authors: Hydren Jay R. , Kithas Andrew C. , Park Soung Hun , Wever-Pinzon Omar , Selzman Craig H. , Perry William , Vargas Camila A. S. , Stehlik Josef , Drakos Stavros G. , Richardson Russell S.
Published: April 2019

Current continuous-flow left ventricular assist devices (LVADs) decrease peripheral vascular pulsatility, which may contribute to side effects such as bleeding and thrombotic events. However, the actual impact of manipulating LVAD pump speed, revolutions per minute (rpm), on peripheral (brachial) pulsatility index (brachial PI), in patients with heart failure implanted with a HeartWare (HVAD) or HeartMateII (HMII) LVAD is unknown. Therefore, blood velocities (Doppler ultrasound) in the brachial artery were recorded and brachial PI calculated across rpm manipulations which spanned the acceptable clinical outpatient range: 360 rpm (HVAD, n = 10) and 1200 rpm (HMII, n = 10). Left ventricular assist device-derived PIs were also recorded: HVAD maximal blood flow (HVAD
Vmax), HVAD minimum blood flow (HVAD
Vmin), and HMII PI (HMIIPI). Brachial PI changed significantly with rpm manipulations, from 2.3 ± 0.6 to 4.1 ± 0.8 (HVAD) and from 1.8 ± 0.5 to 3.6 ± 1.0 (HMII). Multilevel linear modeling with random intercepts revealed a 180 rpm decrease of the HVAD resulted in a 0.9 ± 0.1 (37 ± 4%, d = 2.65) increase in brachial PI and a 600 rpm decrease in the HMII resulted in a 0.8 ± 0.1 (38 ± 3%, d = 4.66) increase. Furthermore, a reduction in rpm resulted in a 20.0 ± 0.3% power savings, and a reduction in device reported blood flow of 9 ± 1%. Brachial PI was linearly related to HVAD
Vmax, HVAD
Vmin, their difference (R
2 = 0.42, R
2 = 0.65, and R
2 = 0.54, respectively), and HMIIPI (R
2 = 0.86). Manipulating LVAD pump speed, within a clinically acceptable outpatient range, resulted in a significant change in brachial PI, which was reflected by pump indices, documenting the potential for LVAD pump speed manipulations to improve LVAD outcomes.
Acute renal impairment in older adults treated with percutaneous coronary intervention for ST-segment elevation myocardial infarction
Authors: Khoury Shafik , Margolis Gilad , Rozenbaum Zach , Rozenfeld Keren-Lee , Keren Gad , Shacham Yacov
Published: April 2019

Background

Elderly individuals ( ≥ 75 years) constitute an increasing proportion of patients presenting with myocardial infarction treated with primary percutaneous coronary intervention (PCI), but only limited data are available regarding the incidence and prognostic implications of acute kidney injury (AKI) in this group of patients.

Objective

To evaluate the incidence and prognostic implications of AKI in older adults ( ≥ 75 years) with ST-segment elevation myocardial infarction (STEMI) treated with primary PCI.

Patients and methods

A retrospective cohort, observational, single-center study of consecutive 416 older patients with STEMI (≥ 75 years) treated with primary PCI between January 2008 and August 2017 was conducted. AKI was defined as an increase of at least 0.3 mg/dl in serum creatinine within 48 h following admission.

Results

A total of 96/416 (23%) patients developed AKI. The occurrence of AKI was associated with adverse in-hospital outcomes, higher 30 days (25 vs. 6%; P < 0.001), and long-term mortality (46 vs. 17%; hazard ratio: 3.2; 95% confidence interval: 2.1–4.7; P < 0.001). Among patients with AKI, 46/96 (48%) demonstrated recovery of renal function at hospital discharge. Lack of renal function recovery at discharge (50/96 patients; 52%) was associated with the occurrence of new or progression of baseline chronic kidney disease.

Conclusion

Among older patients with STEMI undergoing primary PCI, AKI is a frequent complication associated with adverse renal short-term and long-term outcomes.
Evaluation of bone health in patients with adrenal tumors
Authors: Athimulam Shobana , Bancos Irina
Published: April 2019

Purpose of review

Adrenal tumors occur in 5% of population with higher prevalence in elderly. Patients with adrenal tumors present with overt hormonal excess in up to 15% of cases, and mild autonomous cortisol secretion in 30–40% of cases. Overt Cushing syndrome, mild autonomous cortisol secretion, pheochromocytoma, and primary aldosteronism have been associated with higher cardiovascular morbidity and mortality. Increasing experimental and clinical evidence also suggests that adrenal hormone excess is detrimental to bone health. This review aims to discuss the effect of cortisol, aldosterone, and catecholamine excess on bone metabolism, secondary osteoporosis, and fragility fractures.

Recent findings

Several studies have reported that patients with hormonally active adrenal tumors demonstrate increased prevalence of fragility fractures incongruous to bone density scan findings. The utility of dual absorptiometry X-ray (DXA) in diagnosing secondary osteoporosis is unclear in patients with cortisol, aldosterone, and catecholamine excess. Trabecular bone score and bone turn over markers could serve as potential diagnostic tools in assessment of severity of bone disease in patients with hormonally active adrenal tumors.

Adrenalectomy is the mainstay of therapy in patients with overt hormone production. Appropriate case detection strategies to identify patients at risk of fragility fractures are needed in patients not treated with adrenalectomy, such as bilateral primary aldosteronism and mild autonomous cortisol secretion.
Improved outcomes with surgery compared to radiofrequency ablation in the treatment of resectable hepatocellular carcinoma
Authors: Ruff Samantha M. , Khader Adam , Conte Charles , Kadison Alan , Sullivan James , Wang John , Zaidi Raza , Deutsch Gary B.
Published: April 2019

Background

While overall cancer incidence and mortality have decreased over the last decade, hepatocellular carcinoma (HCC) cases have increased sharply.

Objective

This study set out to evaluate the utility of surgery for resectable single tumor HCC in this setting.

Patients and methods

This study analyzed the National Cancer Database, selecting all patients with a histological diagnosis of HCC and an isolated tumor (≤5 cm) treated with radiofrequency ablation (RFA) or surgical resection.

Results

A total of 7821 patients were identified for this study. In the patients with a single tumor up to 3 cm, 40% had a surgical resection and 60% had RFA. In the group with a tumor 3.01–5 cm, 62% had a surgical resection and 38% had RFA. Patients with a single tumor up to 5 cm had a 3-year survival of 60% after resection compared to 42% with RFA. When the patients were split into those with a tumor up to 3 cm or a tumor 3.01–5 cm, there was a survival benefit in the surgical resection cohort.

Conclusion

Surgical resection may be underutilized in the USA for resectable HCC, especially in patients with a tumor up to 3 cm.
Pediatric lung transplantation: supply and demand
Authors: Benoit Tobias M. , Benden Christian
Published: April 2019

Purpose of review

Lung transplantation has become an accepted therapy in infants, children, and adolescents suffering from end-stage lung diseases, an impaired quality of life and reduced life expectancy. The aim of this review is to highlight specific aspects of pediatric lung transplantation and to give an update on recent findings.

Recent findings

Currently, over 100 lung transplant procedures are performed in children annually worldwide. Long-term success is limited by availability of donor organs and waitlist mortality pretransplant, and an increased infection risk because of immunosuppression, and most importantly late complications, such as chronic lung allograft dysfunction, medication nonadherence, and transition intricacies.

Specific aspects of pediatric lung transplantation will be reviewed and an update on most recent developments in the management of pediatric lung transplant recipients given.
The clinical impact of donor-specific antibodies on antibody-mediated rejection and long-term prognosis after heart transplantation
Authors: Su Jennifer A. , Baxter-Lowe Lee Ann , Kantor Paul F. , Szmuszkovicz Jacqueline R. , Menteer JonDavid
Published: April 2019

Purpose of review

Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation.

Recent findings

The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality. Importantly, different DSA vary in clinical significance. DSA capable of activating the complement cascade portend a higher risk of developing AMR. human leukocyte antigen class I and class II antigens are expressed differently within the heart, and so, clinical manifestations of class I and class II DSA vary accordingly. Further, compared with class I, class II DSA carry an increased risk of graft loss and mortality. When comparing preexisting DSA with formation of de-novo DSA, de-novo DSA are associated with worse outcome.

DSAs are generally associated worse long-term prognosis after heart transplantation but vary in their clinical significance. Recognition of specific risk profiles is essential for guiding posttransplant antibody management.
Innovative Collaborative Partnerships to Conduct Multisite Research
Authors: Swartwout Ellen , El-Zein Ashley , Deyo Patsy , Grant Peggy , Fogle Maureen , Laughon Deborah , Goodwin Denise
Published: April 2019

Multisite nursing research can be a challenging endeavor. A unique partnership between 5 clinical sites and a national research center of a healthcare technology organization led to the successful implementation of a multisite study. Strategies for success, obstacles encountered, benefits, implications for the Magnet® journey, and leadership are discussed.
Describing Nurse Manager Role Preparation and Competency: Findings From a National Study
Authors: Warshawsky Nora , Cramer Emily
Published: April 2019

OBJECTIVE

The aim of this study was to describe the role preparation and competency development of nurse managers.

BACKGROUND

Approximately 70 000 nurses are retiring annually. This represents a significant loss of nursing leadership wisdom. Few systematic studies of nurse manager role preparation and competency development have been conducted.

METHODS

An electronic survey was completed by a national sample of 647 nurse managers managing 964 patient care units in 54 hospitals.

RESULTS

Findings suggest that nurse managers rate themselves as competent for the 1st 6 years as a nurse manager. They begin to reach proficiency by year 7. Experience had the strongest association with nurse manager competence, followed by graduate leadership education.

CONCLUSIONS

Nurse executives need to evaluate the bench strength of their nursing leadership talent pool. They need to develop policies and strategies that promote nurse manager competence.
Early Recognition and Treatment of Acute Disseminated Encephalomyelitis in Pediatrics
Authors: George Tikku , Basin Alice , Avva Usha , Taylor Molly , Muhammed Jibran , Ogedegbe Chinwe
Published: April 2019

Objective

Our aim is to emphasize the varied presentation of acute disseminated encephalomyelitis (ADEM) to help health care professionals improve recognition of the disease in a timely manner, thereby allowing for the selection of an appropriate treatment regimen. Therefore, this may avoid neurocognitive consequences and the ultimate fatality of the patient.

Patients and Methods

This is a retrospective case series involving 7 cases of children presenting to the Pediatric Emergency Department of Hackensack University Medical Center who were ultimately diagnosed with ADEM.

Results

In many of the cases, a preceding viral-like illness with nonspecific symptomatology made it difficult to accurately establish an initial diagnosis. Ultimately, the neurologic symptoms spontaneously resolved or improved with administration of high-dose steroids.

Conclusions

Children presenting to the emergency department with nonspecific symptoms associated with any neurological deficits should undergo further investigation using magnetic resonance imaging and lumbar puncture to rule out rare yet possibly fatal diseases such as ADEM.
ART in HIV-Positive Persons With Low Pretreatment Viremia: Results From the START Trial
Authors: Sereti Irini , Gulick Roy M. , Krishnan Sonya , Migueles Stephen A. , Palfreeman Adrian , Touzeau-Römer Veronique , Belloso Waldo H. , Emery Sean , Law Matthew G. ,   for the INSIGHT START Study Group
Published: April 2019

Background:

The benefit of immediate antiretroviral therapy (ART) at CD4 >500 cells/μL was established in the Strategic Timing of Antiretroviral Treatment (START) study. The benefits and risks of immediate ART in participants with low pretreatment viremia, including virologic suppressors, were further assessed.

Setting:

Randomized prospective international study.

Methods:

START participants with enrollment viremia <3000 c/mL were included. We compared clinical outcomes (grade 4 adverse events, hospitalizations, or death), plasma viremia, CD4 counts, and changes in biomarkers in immediate versus deferred ART groups.

Results:

Participants (N = 1134 including 93 with viremia ≤50 c/mL) had a median age of 37 years, 40% were women, and median CD4 was 713 cells/µL. Ninety-seven percent in the immediate and 29% in the deferred arm initiated ART at a median of 6 and 699 days, respectively. Clinical outcomes were experienced in 64 versus 61 patients in immediate and deferred arms (hazard ratio 1.10, 95% confidence interval: 0.77 to 1.56). The CD4 count difference was 125 cells/µL at 12 and 235 cells/µL at 36 months higher in the immediate versus deferred groups. D-dimer and VCAM levels decreased, and C-reactive protein increased, in the immediate arm at month 8. No significant changes in CD4 counts or biomarkers were observed in persons who maintained spontaneous virologic suppression.

Conclusions:

START participants with low enrollment viremia experienced higher CD4 counts, greater proportion with suppressed viremia, and decreases in D-dimer levels on immediate ART despite the lack of difference in serious clinical outcomes. These data support immediate ART in people with low viremia, although equipoise remains for suppressors.
Metabolic immunomodulation of macrophage functional plasticity in nonhealing wounds
Authors: Anders Catherine B. , Lawton Tyler M.W. , Ammons Mary Cloud B.
Published: April 2019

Purpose of review

Despite modern advances in medicine, nonhealing wounds are the number one cause of nontraumatic, lower-limb amputation. Nonhealing wounds are characterized by a healing process stalled between inflammation and tissue remodel/repair, a stage characterized by a shift in macrophage functional phenotype. Characterization of diversity in macrophage functional phenotype in wounds and metabolic contributions to macrophage polarization are discussed.

Recent findings

Macrophage functional diversity in phenotype has recently evolved from duality (classically activated, pro-inflammatory M1 and alternatively activated, anti-inflammatory M2) to include an additional four alternately activated subphenotypes (M2a, M2b, M2c and M2d). Metabolic pathway utilization shifts characterize macrophage polarization with resulting metabolic and immune outcomes impacting host–pathogen interactions during wound healing.

Recognition of the key role macrophage diversity plays in wound healing, along with better characterization of diverse macrophage phenotypes, will inform our understanding of pathogenicity in wound healing. Comprehensive profiling of the metabolism regulating macrophage polarization and host–pathogen interaction creates opportunity of discovery for innovative new diagnostics and therapeutics for treating nonhealing wounds.
Single-Institution, Multidisciplinary Experience of Soft Tissue Sarcomas in the Chest Wall
Authors: Kuwahara Hiroaki , Salo Juho , Nevala Riikka , Tukiainen Erkki
Published: April 2019

Introduction

We report our single-institution, multidisciplinary experience of nearly 20 years of working on chest wall soft tissue sarcoma cases. The aim of this study was to evaluate clinical outcomes in patients with chest wall soft tissue sarcoma.

Materials and Methods

A retrospective review of 49 surgically treated patients with chest wall soft tissue sarcoma was conducted from 1997 to 2015.

Results

The median age of the patients was 57.0 years. There were 19 full-thickness and 30 partial-thickness resections. Reconstruction was warranted in 37 cases. Sarcomas were high grade in 31 (63.3%) and low grade in 18 (36.7%) cases. Local recurrence developed in 8 and metastasis in 9 patients. No 30-day mortality occurred. By the end of the study period, 35 patients were alive and 14 had died. The 1-, 5-, and 10-year survival rates were 93.8%, 76.0%, and 71.6%, whereas the overall recurrence-free rates were 84.4%, 70.7%, and 70.7% respectively. Favorable prognostic variables for survival included age <50 years and radical treatment (resection with wide margin or resection with marginal margin and adjuvant radiotherapy). Patients who had undergone nonradical treatment had a 3.1-fold lower chance of survival than did those who had undergone radical treatment (95% confidence interval, 0.96–10.12; P = 0.06).

Conclusions

Our study suggests that surgical resection with wide margins should continue to be the mainstay for patients with chest wall sarcoma. Even extensive chest wall resections and reconstructions are safe. If wide margins are not achieved, (neo)adjuvant radiotherapy should be considered to improve local control.
Patient Behaviors and Characteristics Related to Weight Regain After Roux-en-Y Gastric Bypass
Authors: King Wendy C. , Belle Steven H. , Hinerman Amanda S. , Mitchell James E. , Steffen Kristine J. , Courcoulas Anita P.
Published: April 2019

Objective:

To identify patient behaviors and characteristics related to weight regain after Roux-en-Y gastric bypass surgery (RYGB).

Background:

There is considerable variation in the magnitude of weight regain after RYGB, highlighting the importance of patient-level factors.

Methods:

A prospective cohort study of adults who underwent bariatric surgery in 6 US cities between 2006 and 2009 included presurgery, and 6-month and annual assessments for up to 7 years. Of 1573 eligible participants, 1278 (81%) with adequate follow-up were included (80% female, median age 46 years, median body mass index 46 kg/m2). Percentage of maximum weight lost was calculated each year after weight nadir.

Results:

Weight was measured a median of 8 (25th–75th percentile, 7–8) times over a median of 6.6 (25th–75th percentile, 5.9–7.0) years. β coefficients, that is, the mean weight regain, compared with the reference, and 95% confidence interval, are reported. Postsurgery behaviors independently associated with weight regain were: sedentary time [2.9% (1.2–4.7), for highest vs lowest quartile], eating fast food [0.5% (0.2–0.7) per meal/wk], eating when feeling full [2.9% (1.2–4.5)], eating continuously [1.6% (0.1–3.1)], binge eating and loss-of-control eating [8.0% (5.1–11.0) for binge eating; 1.6 (−0.1 to 3.3) for loss of control, vs neither], and weighing oneself <weekly [4.2% (2.9–5.4)]. Postsurgery characteristics independently associated with greater weight regain included: younger age, venous edema, poorer physical function, and more depressive symptoms.

Conclusion:

Several behaviors and characteristics associated with greater weight regain were identified, which inform integrated healthcare approaches to patient care and identify high-risk patients to improve long-term weight loss maintenance after RYGB.
The Cost of Postoperative Complications and Economic Validation of the Comprehensive Complication Index
Authors: de la Plaza Llamas Roberto , Hidalgo Vega Álvaro , Latorre Fragua Raquel A. , López Marcano Aylhín J. , Medina Velasco Aníbal A. , Díaz Candelas Daniel A. , García Gil José M. , Ramia Ángel José M.
Published: April 2019

Objective:

To validate the Comprehensive Complication Index (CCI) via an assessment of its relation to postoperative costs.

Background:

The CCI summarizes all the postoperative complications graded by the Clavien-Dindo classification (CDC) on a numerical scale. Its relation to hospital costs has not been validated to date.

Methods:

Prospective observational cohort study, including all patients undergoing surgery at a general surgery service during the 1-year study period. All complications graded with the CDC and CCI and related to the initial admission, or until discharge if the patient was readmitted within 90 days of surgery, were included. The surgeries were classified according to their Operative Severity Score (OSS) and in 4 groups of homogeneous surgeries. All postoperative costs were recorded.

Results:

In all, 1850 patients were included, of whom 513 presented complications (27.7%). The CDC and the CCI were moderately to strongly correlated with overall postoperative costs (OPCs) in all OSS groups (r
s = 0.444–0.810 vs 0.445–0.820; P < 0.001), homogeneous surgeries (r
s = 0.364–0.802 vs 0.364–0.813; P < 0.001), prolongation of postoperative stay (r
s = 0.802 vs 0.830; P < 0.001), and initial operating room costs (r
s = 0.448 vs 0.451; P < 0.001). This correlation was higher in emergency surgery. With higher CDC grades, the OPC tended to increase an upward trend. In the multivariate analysis, CDC, CCI, age, and duration of surgery were all associated with OPC (P < 0.001).

Conclusions:

In our environment, the CCI presented associations with OPC. This demonstration of its economic validity enhances its clinical validity.
The connectome is necessary but not sufficient for the spread of alpha-synuclein pathology in rats
Authors: Oliveira Miguel A.P. , Arreckx Sylvain , Di Monte Donato , Preciat German A. , Ulusoy Ayse , Fleming Ronan M.T.
Published: April 2019

Certain neuronal populations are selectively vulnerable to alpha-synuclein pathology in Parkinson’s Disease, yet the reasons for this selectivity are unclear. Pathology affects neuronal populations that are anatomically connected although the contribution of neuronal connectivity remains to be quantitatively explored. Herein, we simulate the contribution of the connectome alone to the spread of arbitrary aggregates using a computational model of temporal spread within an abstract representation of the mouse mesoscale connectome. Our simulations are compared with the neuron-to-neuron spread of alpha-synuclein that has been observed with in vivo spreading experiments in rats. We find that neuronal connectivity appears to be compatible with the spreading pattern of alpha-synuclein pathology however, it may be per se insufficient to determine the anatomical pattern of protein spreading observed in experimental animals, suggesting a role of selective vulnerability of neuronal pathways to alpha-synuclein diffusion, accumulation and pathology.

Graphical abstract
RICOPILI: Rapid Imputation for COnsortias PIpeLIne
Authors: Lam Max , Awasthi Swapnil , Watson Hunna J. , Goldstein Jackie , Panagiotaropoulou Georgia , Trubetskoy Vassily , Karlsson Robert , Frei Oleksander , Fan Chun-Chieh , De Witte Ward , Mota Nina R. , Mullins Niamh , Skarabis Nora , Huang Hailiang , Neale Benjamin , Daly Mark , Mattheissen Manuel , Walters Raymond , Ripke Stephan
Published: April 2019

Motivation

Genome-wide association study (GWAS) analyses, at sufficient sample sizes and power, have successfully revealed biological insights for several complex traits. RICOPILI, an open sourced Perl-based pipeline was developed to address the challenges of rapidly processing large scale multi-cohort GWAS studies including quality control, imputation and downstream analyses. The pipeline is computationally efficient with portability to a wide range of high-performance computing (HPC) environments.

RICOPILI was created as the Psychiatric Genomics Consortium (PGC) pipeline for GWAS and has been adopted by other users. The pipeline features i) technical and genomic quality control in case-control and trio cohorts ii) genome-wide phasing and imputation iv) association analysis v) meta-analysis vi) polygenic risk scoring and vii) replication analysis. Notably, a major differentiator from other GWAS pipelines, RICOPILI leverages on automated parallelization and cluster job management approaches for rapid production of imputed genome-wide data. A comprehensive meta-analysis of simulated GWAS data has been incorporated demonstrating each step of the pipeline. This includes all of the associated visualization plots, to allow ease of data interpretation and manuscript preparation. Simulated GWAS datasets are also packaged with the pipeline for user training tutorials and developer work.

Availability and Implementation

RICOPILI has a flexible architecture to allow for ongoing development and incorporation of newer available algorithms and is adaptable to various HPC environments (QSUB, BSUB, SLURM and others). Specific links for genomic resources are either directly provided in this paper or via tutorials and external links. The central location hosting scripts and tutorials is found at this URL:https://sites.google.com/a/broadinstitute.org/RICOPILI/home

Contact

sripke@broadinstitute.org

Supplementary information

Supplementary data are available.
Molecular archaeology of the human brain
Authors: Kaczanowska Joanna , Ganglberger Florian , Galik Bence , Hess Andreas , Moodley Yoshan , Bühler Katja , Haubensak Wulf
Published: April 2019

Mapping the origin of human cognitive traits typically relies on comparing behavioral or neuroanatomical features in human phylogeny. However, such studies rely on inferences from comparative relationships and do not incorporate neurogenetic information, as these approaches are restricted to experimentally accessible species. Here, we fused evolutionary genomics with human functional neuroanatomy to reconstruct the neurogenetic evolution of human brain functions more directly and comprehensively. Projecting genome-wide selection pressure (dN/dS ratios) in sets of chronologically ordered mammalian species onto the human brain reference space unmasked spatial patterns of cumulative neurogenetic selection and co-evolving brain networks from task-evoked functional MRI and functional neuroanatomy. Importantly, this evolutionary atlas allowed imputing functional features to archaic brains from extinct hominin genomes. These data suggest accelerated neurogenetic selection for language and verbal communication across all hominin lineages. In addition, the predictions identified strategic thought and decision making as the dominant traits that may have separated anatomically modern humans (AMH) from archaic hominins.
Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain
Authors: Svensson Jonas E , Schain Martin , Plavén-Sigray Pontus , Cervenka Simon , Tiger Mikael , Nord Magdalena , Halldin Christer , Farde Lars , Lundberg Johan
Published: April 2019

[11C]raclopride is a well established PET tracer for the quantification of dopamine 2/3 receptors (D2/3R) in the striatum. Outside of the striatum the receptor density is up to two orders of magnitude lower. In contrast to striatal binding, the characteristics of extrastriatal [11C]raclopride binding quantification has not been thoroughly described. Still, binding data for e.g., neocortex is frequently reported in the scientific literature. Here we evaluate the validity and reliability of extrastriatal [11C]raclopride binding quantification. Two sets of healthy control subjects were examined with HRRT and [11C]raclopride: i) To assess the validity of extrastriatal [11C]raclopride binding estimates, eleven subjects were examined at baseline and after dosing with quetiapine, a D2/3R antagonist. ii) To assess test-retest repeatability, nine subjects were examined twice. Non displaceable binding potential (BPND) was quantified using the simplified reference tissue model. Quetiapine dosing was associated with decrease in [11C]raclopride BPND in temporal cortex (18±17% occupancy) and thalamus (20±17%), but not in frontal cortex. Extrastriatal occupancy was lower than in putamen (51±4%). The mean absolute variation was 4-7% in the striatal regions, 17% in thalamus, and 13-59% in cortical regions. Our data indicate that [11C]raclopride PET is not a suitable tool for D2/3R binding quantification in extrastriatal regions.
Largest Complete Mitochondrial Genome of a Gymnosperm, Sitka Spruce (Picea sitchensis), Indicates Complex Physical Structure
Authors: Jackman Shaun D. , Coombe Lauren , Warren René L. , Kirk Heather , Trinh Eva , McLeod Tina , Pleasance Stephen , Pandoh Pawan , Zhao Yongjun , Coope Robin J. , Bousquet Jean , Bohlmann Joerg , Jones Steven J. M. , Birol Inanc
Published: April 2019

Plant mitochondrial genomes vary widely in size. Although many plant mitochondrial genomes have been sequenced and assembled, the vast majority are of angiosperms, and few are of gymnosperms. Most plant mitochondrial genomes are smaller than a megabase, with a few notable exceptions. We have sequenced and assembled the 5.5 Mbp mitochondrial genome of Sitka spruce (Picea sitchensis), the largest complete mitochondrial genome of a gymnosperm. We sequenced the whole genome using Oxford Nanopore MinION, and then identified contigs of mitochondrial origin assembled from these long reads. The assembly graph shows a multipartite genome structure, composed of one smaller 168 kbp circular segment of DNA, and a larger 5.4 Mbp component with a branching structure. The assembly graph gives insight into a putative complex physical genome structure, and its branching points may represent active sites of recombination.
Integrated phylogenomic analyses reveal recurrent ancestral large-scale duplication events in mosses
Authors: Gao Bei , Chen Moxian , Li Xiaoshuang , Liang Yuqing , Zhang Daoyuan , Wood Andrew J. , Oliver Melvin J. , Zhang Jianhua
Published: April 2019

Mosses (Bryophyta) are a key group occupying important phylogenetic position for understanding land plant (embryophyte) evolution. The class Bryopsida represents the most diversified lineage and contains more than 95% of the modern mosses, whereas the other classes are by nature species-poor. The phylogeny of mosses remains elusive at present.

Recurrent whole genome duplications have shaped the evolution trajectory of angiosperms, but little is known about the genome evolutionary history in mosses. It remains to be answered if there existed a historical genome duplication event associated with the species radiation of class Bryopsida.

Here, the high-confidence moss phylogeny was generated covering major moss lineages. Two episodes of ancient genomic duplication events were elucidated by phylogenomic analyses, one in the ancestry of all mosses and another before the separation of the Bryopsida, Polytrichopsida and Tetraphidopsida, with estimated ages of the gene duplications clustered around 329 and 182 million year ago, respectively.

The third episode of polyploidy event (termed ψ) was tightly associated with the early diversification of Bryopsida with an estimated age of ~87 million years. By scrutinizing the phylogenetic timing of duplicated syntelogs in Physcomitrella patens, the WGD1 and WGD2 events were confidently re-recognized as the ψ event and the Funarioideae duplication event (~65 mya), respectively. Together, our findings unveiled four episodes of polyploidy events in the evolutionary past of Physcomitrella patens.
Direct measurement of X-ray induced heating of microcrystals
Authors: Warren Anna J , Axford Danny , Owen Robin L
Published: April 2019

Temperature control is a key aspect of macromolecular crystallography, with the technique of cryocooling routinely used to mitigate X-ray induced damage. Beam induced heating could cause the temperature of crystals to rise above the glass transition temperature, greatly increasing the rate of damage. X-ray induced heating of ruby crystals 20-40 microns in size has been quantified non-invasively by monitoring the emission wavelengths of X-ray induced fluorescence during exposure to the X-ray beam. For beamsizes and dose-rates typically used in macromolecular crystallography the temperature rises are of order 20 K. The temperature changes observed are compared with models in the literature and can be used as a validation tool for future models.

Synopsis

X-ray induced heating of micro-crystals is quantified through the temperature-dependent shift in X-ray induced fluorescence from ruby crystals.
ORF Capture-Seq: a versatile method for targeted identification of full-length isoforms
Authors: Sheynkman Gloria M. , Tuttle Katharine S. , Tseng Elizabeth , Underwood Jason G. , Yu Liang , Dong Da , Smith Melissa L. , Sebra Robert , Hao Tong , Calderwood Michael A. , Hill David E. , Vidal Marc
Published: April 2019

Most human protein-coding genes are expressed as multiple isoforms. This in turn greatly expands the functional repertoire of the encoded proteome. While at least one reliable open reading frame (ORF) model has been assigned for every gene, the majority of alternative isoforms remains uncharacterized experimentally. This is primarily due to: i) vast differences of overall levels between different isoforms expressed from common genes, and ii) the difficulty of obtaining contiguous full-length ORF sequences. Here, we present ORF Capture-Seq (OCS), a flexible and cost-effective method that addresses both challenges for targeted full-length isoform sequencing applications using collections of cloned ORFs as probes. As proof-of-concept, we show that an OCS pipeline focused on genes coding for transcription factors increases isoform detection by an order of magnitude, compared to unenriched sample. In short, OCS enables rapid discovery of isoforms from custom-selected genes and will allow mapping of the full set of human isoforms at reasonable cost.
Endogenous TDP-43 prevents retrotransposons activation through Dicer-2 activity and the RNA silencing machinery in Drosophila neurons
Authors: Romano Giulia , Klima Raffaella , Feiguin Fabian
Published: April 2019

The aberrant expression of retrotransposable elements (RTEs) was observed in different neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a terminal disorder characterized by functional alterations in the small RNA-binding protein TDP-43, suggesting that these events might be connected. Using genome wide gene expression profiles, we detected RTEs highly upregulated in TDP-43-null Drosophila heads while, the genetic rescue of TDP-43 function reverted these modifications. Furthermore, we found that TDP-43 modulates the small interfering RNA (siRNA) silencing machinery responsible for RTEs repression. Molecularly, we observed that TDP-43 regulates the expression levels of Dicer-2 by direct protein-mRNA interactionsin vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposons activation and revert the neurodegeneration in TDP-43-null Drosophila motoneurons. Our results, describe a novel physiological role of endogenous TDP-43 in the prevention of RTEs-induced neurodegeneration through the modulation of Dicer-2 activity and the siRNA pathway.
Magnetic Resonance Fingerprinting with Combined Gradient- and Spin-echo Echo-planar Imaging: Simultaneous Estimation of T1, T2 and T2* with integrated-B1 Correction
Authors: Khajehim Mahdi , Christen Thomas , Chen J. Jean
Published: April 2019

Purpose

To introduce a novel magnetic-resonance fingerprinting (MRF) framework with single-shot echo-planar imaging (EPI) readout to simultaneously estimate tissue T2, T1 and T2*, and integrate B1 correction.

Methods

Spin-echo EPI is combined with gradient-echo EPI to achieve T2 estimation as well as T1 and T2* quantification. In the dictionary matching step, the GE-EPI data segment provides estimates of tissue T1 and T2* with additional B1 information, which are then incorporated into the T2-matching step that uses the SE-EPI data segment. In this way, biases in T2 and T2* estimates do not affect each other.

Results

An excellent correspondence was found between our T1, T2, and T2* estimates and results obtained from standard approaches in both phantom and human scans. In the phantom scan, a linear relationship with R2>0.96 was found for all parameter estimates. The maximum error in the T2 estimate was found to be below 6%. In the in-vivo scan, similar contrast was noted between MRF and standard approaches, and values found in a small region of interest (ROI) located in the grey matter (GM) were in line with previous measurements (T2MRF=88±7ms vs T2Ref=89±11ms, T1MRF=1153±154ms vs T1Ref=1122±52ms, T2*MRF=56±4ms vs T2*Ref=53±3ms).

Conclusion

Adding a spin echo data segment to EPI based MRF allows accurate and robust measurements of T2, T1 and T2* relaxation times. This MRF framework is easier to implement than spiral-based MRF. It doesn’t suffer from undersampling artifacts and seems to require a smaller dictionary size that can fasten the reconstruction process.
A Two-Component System that Modulates Cyclic-di-GMP Metabolism PromotesLegionella pneumophilaDifferentiation and Viability in Low-Nutrient Conditions
Authors: Hughes Elisa D. , Byrne Brenda G. , Swanson Michele S.
Published: April 2019

During its life cycle, the environmental pathogenLegionella pneumophilaalternates between a replicative and a transmissive cell type when cultured in broth, macrophages, or amoebae. Within a protozoan host,L. pneumophilafurther differentiates into the hardy cell type known as the Mature Infectious Form (MIF). The second messenger cyclic-di-GMP coordinates lifestyle changes in many bacterial species, but its role in theL. pneumophilalife cycle is less understood. Using anin vitrobroth culture model that approximates the intracellular transition from the replicative to transmissive form, here we investigate the contribution toL. pneumophiladifferentiation of a two-component system (TCS) that regulates cyclic-di-GMP metabolism. The TCS is encoded bylpg0278-lpg0277and is co-transcribed withlpg0279, which encodes a protein upregulated in MIF cells. Using agfp-reporter, we demonstrate that the promoter for this operon is RpoS-dependent and induced in nutrient-limiting conditions that do not support replication. The response regulator of the TCS (Lpg0277) is a bifunctional enzyme that both synthesizes and degrades cyclic-di-GMP. Using a panel of site-directed point mutants, we show that cyclic-di-GMP synthesis mediated by a conserved GGDEF domain promotes growth arrest of replicativeL. pneumophila, production of pigment and poly-3-hydroxybutyrate storage granules, and viability in nutrient-limiting conditions. Genetic epistasis tests predict that the MIF protein Lpg0279 acts upstream of the TCS as a negative regulator. Thus,L. pneumophilais equipped with a regulatory network in which cyclic-di-GMP stimulates the switch from a replicative to a resilient state equipped to survive in low-nutrient environments.

IMPORTANCE

Although an intracellular pathogen,L. pneumophilahas developed mechanisms to ensure long-term survival in low-nutrient aqueous conditions. Eradication ofL. pneumophilafrom contaminated water supplies has proven challenging, as outbreaks have been traced to previously remediated systems. Understanding the genetic determinants that supportL. pneumophilapersistence in low-nutrient environments can inform design of remediation methods. Here we characterize a genetic locus that encodes a two-component signaling system (lpg0278-lpg0277) and a putative regulator protein (lpg0279) that modulates production of the messenger molecule cyclic-di-GMP. We show that this locus promotes bothL. pneumophilacell differentiation and survival in nutrient-limiting conditions, thus advancing our understanding of the mechanisms that contribute toL. pneumophilaenvironmental resilience.
Genomic Analysis of Emerging Florfenicol-Resistant Campylobacter coli Isolated from the Intestinal Cecal Contents of Cattle in the United States
Authors: Zhao Shaohua , Mukherjee Sampa , Hsu Chih-Hao , Young Shenia , Li Cong , Tate Heather , Morales Cesar A. , Haro Jovita , Thitaram Sutawee , Tillman Glenn E. , Dessai Uday , McDermott Patrick
Published: April 2019

Objective

Genomic analyses were performed on florfenicol resistant (FFNR) Campylobacter coli (C. coli) isolated from cattle and the cfr(C) gene-associated multi-drug resistance (MDR) plasmid was characterized.

Methods

Sixteen FFNRC. coli isolates recovered between 2013-2018 from beef cattle were sequenced using MiSeq. Genomes and plasmids were closed for three of the isolates using the PacBio® system. Single nucleotide polymorphisms (SNPs) across the genome and the structures of MDR plasmids were investigated. Conjugation experiments were performed to determine the transferability of cfr(C) associated MDR plasmids. The spectrum of resistance encoded by the cfr(C) gene was further investigated by agar dilution antimicrobial susceptibility testing.

Results

All 16 FFNR isolates were MDR and exhibited co-resistance to ciprofloxacin, nalidixic acid, clindamycin and tetracycline. All isolates shared the same resistance genotype, carrying aph(3’)-III, hph, ∆aadE (truncated), blaOXA-61, cfr(C), and tet(O) genes plus a mutation of GyrA T86I. The cfr(C), aph(3’)-III, hph ∆aadE, and tet(O) genes were co-located on transferable MDR plasmids with size 48-50 kb. These plasmids showed high sequence homology with the pTet plasmid, and carried several Campylobacter virulence genes, including virB2, virB4, virB5, VirB6, virB7, virB8, virb9, virB10, virB11 and virD4. The cfr(C) gene conferred resistance to florfenicol (8-32 µg/ml), clindamycin (512-1,024 µg/ml), linezolid (128-512 µg/ml), and tiamulin (1,024 µg/ml). Phylogenetic analysis showed SNP differences ranging from 11-2,248 among the 16 isolates.

Conclusions

The results showed that the cfr(C) gene located in the conjugative pTet MDR/virulence plasmid is present in diverse strains, where it confers high levels of resistance to several antimicrobials, including linezolid, a critical drug for treating Gram positive bacterial infections in humans. This study highlights the power of genomic antimicrobial resistance surveillance to uncover the intricacies of transmissible co-resistance and provides information that is needed for accurate risk assessment and mitigation strategies.
Spatio-temporal analysis of human preimplantation development reveals dynamics of epiblast and trophectoderm
Authors: Meistermann Dimitri , Loubersac Sophie , Reignier Arnaud , Firmin Julie , Campion Valentin Francois , Kilens Stéphanie , Lelièvre Yohann , Lammers Jenna , Feyeux Magalie , Hulin Phillipe , Nedellec Steven , Bretin Betty , Covin Simon , Castel Gael , Bihouée Audrey , Soumillon Magali , Mikkelsen Tarjei , Barrière Paul , Bourdon Jérémie , Fréour Thomas , David Laurent
Published: April 2019

Recent technological advances such as single-cell RNAseq1-3and CRISPR-CAS9-mediated knock-out4have allowed an unprecedented access into processes orchestrating human preimplantation development5. However, the sequence of events which occur during human preimplantation development are still unknown. In particular, timing of first human lineage specification, the process by which the morula cells acquire a specific fate, remains elusive. Here, we present a human preimplantation development model based on transcriptomic pseudotime modelling of scRNAseq biologically validated by spatial information and precise time-lapse staging. In contrast to mouse, we show that trophectoderm (TE) / inner cell mass (ICM) lineage specification in human is only detectable at the transcriptomic level at the blastocyst stage, just prior to expansion. We validated the expression profile of novel markers enabling precise staging of human preimplantation embryos, such as IFI16 which highlights establishment of epiblast (EPI) and NR2F2 which appears at the transition from specified to mature TE. Strikingly, mature TE cells arise from the polar side, just after specification, supporting a model of polar TE cells driving TE maturation. Altogether, our study unravels the first lineage specification event in the human embryo and provides a browsable resource for mapping spatio-temporal events underlying human lineage specification.
Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) ofM. tuberculosis
Authors: Tam Benjamin , Sherf Dror , Cohen Shira , Eisdorfer Sarah Adi , Perez Moshe , Soffer Adam , Vilenchik Dan , Akabayov Sabine Ruth , Wagner Gerhard , Akabayov Barak
Published: April 2019

M. tuberculosis(Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of theMtbribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50values, which were significantly improved over standard antibiotic drugs.