bluuebunny/crossref_metadata_2025 huggingface dataset:
Sociodemographic Characteristics as Determinants and Physical Performance Measures as Correlates of Falls Among Malaysian Community-Dwelling Older Adults
Authors: Singh Devinder Kaur Ajit , Samah Zunaidah Abu , Shahar Suzana , Omar Mohd Azahadi , Shaharudin Muhammad Iqbal , Chin Ai-Vyrn
Published: April 2019

There is limited information regarding combined sociodemographic data and physical performance measures as determinants and correlates of falls among community-dwelling older adults. In this study, we aimed to identify whether sociodemographic data and physical performance measures are significant determinants and correlates for falls in community-dwelling older adults. Three hundred twenty-five Malaysian community-dwelling older adults (145 men and 180 women), aged 60 to 89 (M = 67.64, SD = 5.56) years, were recruited through multistage random samplings for this prospective study (with 6 months' follow-up). Binary logistic regression analysis was performed on the sociodemographic data and physical performance measures to determine the determinants and correlates of falls among these participants. The Physiological Profile Assessment (PPA) was the only significant (P < .05) physical performance measure that correlated with falls. The Timed Up and Go (TUG) Test and education levels were significant correlates and determinants of falls in this population, with the absence of PPA in the model. The PPA is the best physical performance measure correlate of falls among Malaysian community-dwelling older adults. However, when the PPA is not available, the TUG Test, although a simple performance tool, may be used to predict falls among community-dwelling older adults.
Comparison of Functional Outcomes Between Elderly and Young Patients With Traumatic Brain Injury in a Subacute Rehabilitation Unit
Authors: Kim Doo Young , Kim Min-Hyun , Pyun Sung-Bom
Published: April 2019

Objectives:

To compare the clinical characteristics and outcomes between elderly and young patients with traumatic brain injury (TBI) in a subacute rehabilitation unit.

Subjects and Methods:

Ninety-two TBI patients who had been admitted to a rehabilitation unit from January 2010 to July 2017 were included for analysis and categorized into elderly and young TBI patient groups. A retrospective analysis was performed to compare the clinical characteristics and functional outcomes of the 2 groups at admission and discharge. The main measures included the Glasgow Coma Scale (GCS), Mini-Mental State Examination (MMSE), Berg Balance Scale (BBS), Modified Barthel Index (MBI), and Glasgow Outcome Scale (GOS).

Results:

The most common cause of injury was fall, and subdural hematoma was more common in the elderly group. Although initial GCS scores were similar between both groups, BBS and MBI scores at admission were significantly lower in elderly patients. At discharge, the MMSE, BBS, and MBI scores were significantly better in the young TBI group. However, the amount of functional improvement (Δ) in MMSE, BBS, and MBI scores during admission and the home discharge rate were similar in both groups (P > .05).

Conclusion:

Although the initial injury severity was similar in both groups, the functional outcome of cognition, balance, and activities of daily living at discharge was better in the young TBI group. However, the amount of functional improvement was similar after rehabilitation, regardless of age.
Caring for an “Old” Young Person in a Geriatric Rehabilitation Setting
Authors: Klein Jennifer , Huang James
Published: April 2019

We report a case of a 29-year-old man with a rare condition, Coats plus syndrome, who was admitted to the geriatric rehabilitation unit due to his frailty and complex health issues. This case illustrates the potential benefit of admitting younger patients onto geriatric rehabilitation units, as this team has specialized skills that can engage young frail patients with complex care needs as partners in their own care decisions, helping them live in the present, adjust to changing circumstances, maximize their quality of life, and optimize positive experiences in the health care setting.
Effects of Aerobic Exercise on Electrophysiological Features of Diabetic Peripheral Neuropathy
Authors: Azizi Sirous , Najafi Sharif , Rezasoltani Zahra , Sanati Ehsan , Zamani Nahid , Dadarkhah Afsaneh
Published: April 2019

Objective:

To investigate electrophysiological effects of exercise on peripheral neuropathy in patients with type 2 diabetes mellitus.

Methods:

Thirty-five patients (21 women) with diabetic peripheral neuropathy were included with mean (SD) age of 56.9 (6.2) years. We performed electrophysiological studies, and after 8 weeks of exercise, reevaluated the participants.

Results:

Sural sensory nerve (P < .001) and tibial compound muscle (P = .001) action potential increased, while F-wave (P = .024) and nerve conduction velocity (P = .001) decreased significantly. Conduction velocity for deep peroneal nerve showed a significant increase (P = .001).

Conclusion:

Aerobic exercise improves electrophysiological features and should be considered in the therapy of diabetic peripheral neuropathy.
Pharmacologic Management of Acute Migraines in the Emergency Department
Authors: Jesani Jennifer , Simerson Darlie
Published: April 2019

Migraine headaches account for approximately 1.2 million emergency department (ED) visits annually. Despite the prevalence of this condition, there is little consensus on the best pharmacotherapeutic interventions to use in the ED setting. Guidelines published by the American Headache Society and the Canadian Headache Society offer some direction to ED providers but are not widely utilized. This article reviews the best evidence behind some of the medications frequently used to treat acute migraines in the ED setting, including dopamine receptor antagonists, serotonin receptor agonists, anti-inflammatory medications, opioids, magnesium, valproate, and propofol. The evaluation of patients presenting to the ED with an acute headache, the diagnostic criteria for migraines, and implications for advanced practice are also discussed.
Appropriateness Criteria for Neuroimaging of Adult Headache Patients in the Emergency Department
Authors: Heetderks-Fong Elizabeth
Published: April 2019

The American College of Radiology (ACR) developed Appropriateness Criteria (ACR-AC) for diagnostic imaging to reduce overuse and promote high-yield, cost-effective, evidence-based decision-making. For adult headaches, there are 16 variants with specific imaging recommendations. Headache accounts for 4.5% of emergency department (ED) visits, and 61% are chronic. Imaging for headaches has increased in the past 2 decades, with intracranial pathology diagnoses going down. Evidence suggests that there is poor knowledge of the ACR-AC among advanced practice nurses (APNs) and nonradiologist physicians. The ACR-AC recommendations were examined using the Health Care Cost and Utilization Project State Emergency Department Data (HCUP SEDD) from Maryland in 2013. Imaging proportions were examined, as well as differences between residency program hospitals and hospitals that have APNs in the ED. Of the 11,109 chronic headache visits, a quarter underwent computed tomography ([CT]; 26.9%) and 3.6% underwent magnetic resonance imaging (MRI); the ACR-AC does not recommend use of either of these in patients with chronic headache. There were significant practice differences related to hospital teaching and whether APNs were employed in the ED or not. For patients with posttraumatic headache, there were no significant differences in practice. Computed tomography was used in 76.4% of posttraumatic headache visits. It is unknown whether the ACR-AC are being used in the ED, and there is variability in following the recommendations. Posttraumatic headache protocol is well established in the ED, but chronic headache continues to be a problem in imaging overuse despite recommendations. Radiological education, including the ACR-AC, as well as radiation dosing and exposure information should be part of APN, physician, and registered nurse education, as well as continuing education. Continuing education is critical for adherence to the ACR-AC, as the recommendations are complex and continuously evolving. In addition, to minimize overuse of CT in headaches, the ACR-AC should be integrated into clinical decision support to promote best imaging practices.
Utilizing Ultrasound-Guided Femoral Nerve Blocks and Fascia Iliaca Compartment Blocks for Proximal Femur Fractures in the Emergency Department
Authors: Nagel Emily Marie , Gantioque Raymund , Taira Taku
Published: April 2019

Proximal femur fractures (PFF) are one of the many common injuries that present to the emergency department (ED). The current practice for pain management utilizes systemic opioid analgesics. The use of opioids is an excellent analgesic choice, but they carry a significant burden for potential adverse effects. It is vital that providers have a variety of approaches to acute pain control. The use of femoral nerve blocks (FNBs) and fascia iliaca compartment blocks (FICB) are an alternative method of pain control in the ED. They have advantages over systemic opiates in that they do not require hemodynamic monitoring, have less adverse effects, and more importantly they induce rapid pain control with longer duration than systemic analgesics (Cross & Warkentine, 2016). This manuscript examines a review of literature and identifies the efficacy, patient safety, indications, contraindications, patient satisfaction, and ultrasound-guided FNB and FICB techniques.
Pretransplant Donor-specific IFNγ ELISPOT as a Predictor of Graft Rejection: A Diagnostic Test Accuracy Meta-analysis
Authors: Montero Nuria , Farouk Samira , Gandolfini Ilaria , Crespo Elena , Jarque Marta , Meneghini Maria , Torija Alba , Maggiore Umberto , Cravedi Paolo , Bestard Oriol
Published: April 2019

Background.

Pretransplant interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) has been proposed as a tool to quantify alloreactive memory T cells and estimate the risk of acute rejection (AR) after kidney transplantation, but studies have been inconclusive so far. We performed a meta-analysis to evaluate the association between pretransplant IFN-γ ELISPOT and AR and assess its predictive accuracy at the individual level.

Methods.

We estimated the pooled summary of odds ratio for AR and the joined sensitivity and specificity for predicting AR using random-effects and hierarchical summary receiver-operating characteristic models. We used meta-regression models with the Monte Carlo permutation method to adjust for multiple tests to explain sensitivity and specificity heterogeneity across studies. The meta-analytic estimates of sensitivity and specificity were used to calculate positive and negative predictive values across studies.

Results.

The analysis included 12 studies and 1181 patients. IFN-γ ELISPOT was significantly associated with increased AR risk (odds ratio: 3.29; 95% confidence interval (CI), 2.34-4.60); hierarchical summary receiver operating characteristic jointly estimated sensitivity and specificity values were 64.9% (95% CI, 53.7%-74.6%) and 65.8% (95% CI, 57.4%-73.5%), respectively, with moderate heterogeneity across studies. After adjusting for multiple testing, meta-regression models showed that thymoglobulin induction, recipient black ethnicity, living versus deceased donors, and geographical location did not affect sensitivity or specificity. Because of the varying AR incidence of the studies, positive and negative predictive values ranged between 16%–60% and 70%–95%, respectively.

Conclusions.

Pretransplant IFN-γ ELISPOT is significantly associated with increased risk of AR but provides suboptimal predictive ability at an individual level. Prospective randomized clinical trials are warranted.
Impact of Cold Ischemia Time on Outcomes of Deceased Donor Kidney Transplantation: An Analysis of a National Registry
Authors: Peters-Sengers Hessel , Houtzager Julia H.E. , Idu Mirza M. , Heemskerk Martin B.A. , van Heurn Ernst L.W. , Homan van der Heide Jaap J. , Kers Jesper , Berger Stefan P. , van Gulik Thomas M. , Bemelman Frederike J.
Published: April 2019

Background.

Cold ischemia time (CIT) is known to impact kidney graft survival rates. We compare the impact of CIT on graft failure and mortality in circulatory death versus brain death donor kidneys and how it relates to donor age.

Methods.

We used the prospective Dutch Organ Transplantation Registry to include 2153 adult recipients of brain death (n = 1266) and circulatory death (n = 887) donor kidneys after static cold storage from transplants performed between 2005 and 2012. CIT was modeled nonlinearly with splines. Associations and interactions between CIT, donor type, donor age, 5-year (death-censored) graft survival, and mortality were evaluated.

Results.

The median CIT was 16.2 hours (interquartile range 12.8–20), ranging from 3.4 to 44.7 hours for brain death and 4.7 to 46.6 hours for circulatory death donor kidneys. At >12 hours of CIT, we observed an increased risk of graft failure in kidneys donated after circulatory death versus after brain death. This risk rose significantly at >22 hours of CIT (hazard ratio 1.45; 95% confidence interval, 1.01-2.49;P= 0.043). Kidneys that came from 60-year-old circulatory death donors demonstrated elevated hazard risk at 19 hours of CIT, a shorter timeline than that for kidneys that came from brain death donors of the same age (hazard ratio 1.33; 95% confidence interval, 1.00-1.78;P= 0.045). The additional harmful effects of increased CIT in kidneys from circulatory-death donors were also found for death-censored graft failure but did not affect mortality rates in any significant way.

Conclusions.

The findings support the hypothesis that prolonged cold ischemia is more harmful for circulatory death donor kidneys that have already been subjected to a permissible period of warm ischemia. Efforts should be made to reduce CIT, especially for older circulatory death donor kidneys.
Selective Recruitment of Large Lower Lobe Atelectasis on Donor Back Table in Rejected Donor Lungs
Authors: Okamoto Toshihiro , Niikawa Hiromichi , Wheeler David , Ayyat Kamal S. , Basem Soliman , Itoda Yoshifumi , Sunagawa Gengo , Farver Carol F. , McCurry Kenneth R.
Published: April 2019

Background.

Large atelectatic areas in donor lungs are frequently resistant to standard recruitment maneuvers, producing a tenaciously low PO2/FiO2 ratio. The aim of this study is to investigate the optimal protocol for the recruitment of large atelectatic areas in the context of ex vivo lung perfusion (EVLP).

Methods.

Seventeen rejected lungs with large lower lobe atelectasis (≥40%) were divided into 2 groups: manual resuscitation (n = 5) and selective recruitment (n = 12). Transplant suitability was then evaluated in cellular EVLP. In the manual resuscitation group, following bronchoscopy, if the conventional recruitment maneuver was not successful, a bagging technique was utilized to resolve atelectasis in EVLP. In the selective recruitment group, a pediatric endotracheal tube was introduced to the lower lobe bronchus on the back table of the donor hospital. Selective recruitment of the lower lobe was accomplished while keeping peak inspiratory pressure <30 cm H2O for 30 seconds.

Results.

The average atelectasis size and lung weight in 17 donor lungs was 75.4 ± 20.6% and 960 ± 221 g, respectively. There were no significant differences between the 2 groups in all donor variables, except cold ischemic time (P = 0.001, 5.2 ± 0.5 versus 6.4 ± 0.7 hours). The selective recruitment group was associated with better transplant suitability (P = 0.035, 75% versus 20%), better PO2/FiO2 ratio (P = 0.186, 324 ± 89 versus 258 ± 87 mm Hg), lower lung weight (P = 0.057, 997.9 ± 229.2 versus 1377.2 ± 452.9 g), and better pathological score (P < 0.05, 1.0 ± 1.3 versus 2.8 ± 0.8) than the manual resuscitation group.

Conclusion.

A selective recruitment procedure is a safe and effective method of eliminating large atelectasis before EVLP.
Risk of Corneal Graft Rejection After High-risk Keratoplasty Following Fine-needle Vessel Coagulation of Corneal Neovascularization Combined With Bevacizumab: A Pilot Study
Authors: Hos Deniz , Le Viet Nhat Hung , Hellmich Martin , Siebelmann Sebastian , Roters Sigrid , Bachmann Bjoern O. , Cursiefen Claus
Published: April 2019

Background.

Corneal neovascularization is considered an important risk factor for allograft rejection after corneal transplantation (keratoplasty). Therefore, the aim of this study was to determine whether preoperative reduction of corneal neovascularization by fine-needle thermal cauterization combined with bevacizumab reduces the incidence of allograft rejection after subsequent high-risk keratoplasty.

Methods.

In this interventional uncontrolled clinical pilot study, 31 eyes of 31 patients with corneal neovascularization in at least one corneal quadrant were included. All eyes were treated by fine-needle thermal cauterization of corneal vessels and subconjunctival injection of bevacizumab. Both treatments were repeated in the cases of visible reperfusion of occluded vessels. Afterward, penetrating keratoplasty was performed. When corneal neovascularization was present on the day of keratoplasty, additional vessel cauterization and injection of bevacizumab was performed. Patients were then followed to determine the incidence of allograft rejection.

Results.

In 18 eyes, vessel cauterization with bevacizumab injection was performed once before keratoplasty, whereas 13 eyes required retreatment before keratoplasty. No complications were observed. In 23 eyes, corneal neovascularization was present on the day of keratoplasty due to reperfusion of previously occluded vessels and simultaneous vessel cauterization with bevacizumab injection was performed. During follow-up (mean: 560 days; range: 59–1095 days), 4 graft rejection episodes in 4 eyes were observed. Estimated probabilities of corneal graft survival were 92.9% after 1 year (number at risk: 23), 78.4% after 2 years (number at risk: 9), and 78.4% after 3 years (number at risk: 3).

Conclusions.

Our initial results indicate that angioregressive treatment of pathological corneal vessels by fine-needle thermal cauterization combined with subconjunctival injection of bevacizumab before high-risk keratoplasty seems to result in graft survival rates comparable to survival rates seen in normal-risk keratoplasty. The findings of our pilot study warrant further controlled clinical trials with longer follow-up in a larger patient cohort.
Dementia With Lewy Bodies
Authors: Vergouw Leonie J.M. , Marler Luca P. , van de Berg Wilma D.J. , Rozemuller Annemieke J.M. , de Jong Frank Jan
Published: April 2019

Diagnosing dementia with Lewy bodies (DLB) is challenging as symptoms are heterogenous and not specific to the disease. Here we present a clinicopathologic series of false-positive DLB cases. Patients were enrolled retrospectively from the Netherlands Brain Bank when they met the clinical criteria of probable DLB, but with a pathologic diagnosis other than DLB or Parkinson’s disease dementia. Twenty-two false-positive cases were selected. Alzheimer disease with or without copathology was the most common (64%) pathologic diagnosis. Other pathologic diagnoses, such as frontotemporal dementia, multiple-system atrophy, Creutzfeldt-Jakob disease, and autoimmune encephalitis, were also encountered. Atypical clinical signs for DLB were present in almost half of the cases and could be a trigger to consider other diagnoses than DLB. Additional diagnostic examinations, feedback of pathologic diagnosis, and the creation of a set of clinical features that are indicative of other conditions, could reduce the amount of false-positive DLB cases.
Psychiatric Symptoms in Patients With Dementia
Authors: Riedel Oliver , Klotsche Jens , Pisa Federica E.
Published: April 2019

Purpose:

Neuropsychiatric symptoms (NPS) are common in Alzheimer Disease (AD). Treatment could be optimized by supplementing the clinician’s impression of a patient with information from the caregiver. Yet the agreement between caregivers and physicians on the presence of NPS in patients with AD is understudied.

Methods:

Data were obtained from a 2-staged survey in neurology outpatient offices. At stage 1, patients (n=403) were documented by their physicians, including an assessment on the presence of NPS. At stage 2, patients’ CGs (n=171) were asked about the presence of NPS in the patients, based on questions from the Neuropsychiatric Inventory. Caregivers were screened for depression with the Depression Screening Questionnaire.

Patients:

The study sample comprised patients with mild or moderate AD.

Results:

NPS frequency varied between 52.6% [95% confidence interval (CI), 44.9%-60.3%] and 67.2% (95% CI, 59.7%-74.2%, reported by CGs) and 34.2% (95% CI, 26.8%-42.1%) and 50.9% (95% CI, 42.9%-58.9%, reported by physicians). Apathy, depression, aggression, and irritability occurred most frequently according to both sources. κ values were lowest for euphoria (κ=0.03; 95% CI, −0.08 to 0.25), and highest for depression (κ=0.26; 95% CI, 0.11-0.43). CG depression was associated with an increased probability (odds ratio=2.9; 95% CI, 1.2-6.7) of disagreement between caregivers and physicians on the patient’s mental status.

Conclusion:

NPS, though very prevalent in dementia patients, are perceived differently by caregivers and physicians. This divergence increases depending on the psychological health of caregivers.
Corpus callosum metrics predict severity of visuospatial and neuromotor dysfunctions in ARID1B mutations with Coffin–Siris syndrome
Authors: Demily Caroline , Duwime Charlyne , Lopez Clémence , Hemimou Cherhazad , Poisson Alice , Plasse Julien , Robert Matthieu P. , Dénier Charlotte , Rossi Massimiliano , Franck Nicolas , Besmond Claude , Barcia Giulia , Boddaert Nathalie , Munnich Arnold , Vaivre-Douret Laurence
Published: April 2019

ARID1B mutations in Coffin–Siris syndrome are a cause of intellectual disability (0.5–1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman’s rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin–Siris syndrome.
BioBankRead: Data pre-processing in Python for UKBiobank clinical data
Authors: Schneider-Luftman D. , Crum W. R.
Published: April 2019

Motivation

UKBiobank collects health-related data from 500,000 volunteers and is widely used by medical researchers. However, the data is supplied in a custom compressed format and its preparation for analysis is cumbersome and time-consuming. This Python package automates the extraction of selected UKBiobank data, for easy integration in an analysis pipeline.

Features

The functions provided within this Python package reduce the number of steps, as well as human and computational time, required for extraction and preparation of the data for analysis. It is executable through command line, is easily installed on any platform and requires no prior knowledge of Python.

Application

BiobankRead is used for an analysis of dietary lifestyles and cardio-vascular outcomes. A large range of dietary, phenotypical, lifestyle and vascular outcomes is extracted and pre-processed. Significant associations are found between non-meat-eating and lower blood pressure / reduced risk of hypertension.

Availability

The Python package BiobankRead is freely available under the GNU General Public License (version 3 or later). It can be downloaded from GitHub (https://github.com/saphir746/BiobankRead-Bash), where example scripts and detailed instructions are also available.
Connectal Coding: Discovering the Structures Linking Cognitive Phenotypes to Individual Histories
Authors: Vogelstein Joshua T. , Bridgeford Eric W. , Pedigo Benjamin D. , Chung Jaewon , Levin Keith , Mensh Brett , Priebe Carey E.
Published: April 2019

Cognitive phenotypes characterize our memories, beliefs, skills, and preferences, and arise from our ancestral, developmental, and experiential histories. These histories are written into our brain structure through the building and modification of various brain circuits. Connectal coding, by way of analogy with neural coding, is the art, study, and practice of identifying the network structures that link cognitive phenomena to individual histories. We propose a formal statistical framework for connectal coding and demonstrate its utility in several applications spanning experimental modalities and phylogeny.
Reducing malaria burden and accelerating elimination with long-lasting systemic insecticides: a modeling study of three potential use cases
Authors: Selvaraj Prashanth , Suresh Joshua , Wenger Edward A. , Bever Caitlin A. , Gerardin Jaline
Published: April 2019

Background

While bednets and insecticide spraying have had significant impact on malaria burden in many endemic regions, outdoor vector feeding and insecticide resistance may ultimately limit their contribution to elimination and control campaigns. Complementary vector control methods such as endectocides or systemic insecticides are therefore generating much interest. Here we explore the conditions under which long-lasting systemic insecticides would have a substantial impact on transmission and burden.

Methods

Hypothetical long-lasting systemic insecticides with effective durations ranging from 14 days to 90 days are simulated using an individual-based mathematical model of malaria transmission. The impact of systemic insecticides when used to complement existing vector control and drug campaigns is evaluated in three settings – a highly seasonal high-transmission setting, a near-elimination setting with seasonal travel to a high-risk area, and a near-elimination setting in southern Africa.

Results

At 60% coverage, a single round of long-lasting systemic insecticide with effective duration of at least 60 days, distributed at the start of the season alongside a seasonal malaria chemoprevention campaign in a high-transmission setting, results in further burden reduction of 30-90% depending on the sub-populations targeted. In a near-elimination setting where transmission is sustained by seasonal travel to a high-risk area, targeting high-risk travelers with systemic insecticide with effective duration of at least 30 days can result in likely elimination even if intervention coverage is as low as 50%. In near-elimination settings with robust vector control, the addition of a 14-day systemic insecticide alongside an antimalarial in mass drug administration (MDA) campaigns can decrease the necessary MDA coverage from about 85% to the more easily achievable 65%.

Conclusions

While further research into the safety profile of systemic insecticides is necessary before deployment, we find that long-lasting systemic insecticides can play a critical role in reducing burden or eliminating malaria in a range of contexts with different target populations, existing malaria control methods, and transmission intensities.
Coordinated circadian timing through the integration of local inputs in Arabidopsis thaliana
Authors: Greenwood Mark , Domijan Mirela , Gould Peter D. , Hall Anthony J.W. , Locke James C.W.
Published: April 2019

Every plant cell has a genetic circuit, the circadian clock, that times key processes to the day-night cycle. These clocks are aligned to the day-night cycle by multiple environmental signals that vary across the plant. How does the plant integrate clock rhythms, both within and between organs, to ensure coordinated timing? To address this question, we examined the clock at the sub-tissue level across Arabidopsis thaliana seedlings under multiple environmental conditions and genetic backgrounds. Our results show that the clock runs at different speeds (periods) in each organ, which causes the clock to peak at different times across the plant in both constant environmental conditions and light-dark cycles. Closer examination reveals that spatial waves of clock gene expression propagate both within and between organs. Using a combination of modeling and experiment, we reveal that these spatial waves are the result of the period differences between organs and local coupling, rather than long distance signaling. With further experiments we show that the endogenous period differences, and thus the spatial waves, are caused by the organ specificity of inputs into the clock. We demonstrate this by modulating periods using light and metabolic signals, as well as with genetic perturbations. Our results reveal that plant clocks are set locally by organ specific inputs, but coordinated globally via spatial waves of clock gene expression.
Strong self-regulation and widespread facilitative interactions in phytoplankton communities
Authors: Picoche Coralie , Barraquand Frédéric
Published: April 2019

The persistence of phytoplanktonic diversity in spite of competition for basic resources has long been a source of wonder and inspiration to ecologists. To sort out, among the many coexistence mechanisms suggested by theory and experiments, which ones actually maintain diversity in natural ecosystems, long-term field studies are paramount.

We analysed a large dataset of phytoplankton abundance time series using dynamic, multivariate autoregressive models. Phytoplankton was counted and identified down to the genus level, every two weeks over twenty years, at ten sites along the French coastline. Multivariate autoregressive models allowed to estimate biotic interaction networks, while also accounting for abiotic variables that may drive part of the phytoplankton fluctuations. We then analysed the ratio of intra-to inter-taxa interactions (measuring self-regulation, itself a measure of niche differentiation), the frequency of negative vs positive interactions, and how stability metrics (both at the network and genus level) relate to network complexity and genus self-regulation or abundance.

We showed that a strong self-regulation, with competition strength within a taxon (genus) an order of magnitude higher than between taxa, was present in all phytoplanktonic interaction networks. This much stronger intragenus competition suggests that niche differentiation - rather than neutrality - is commonplace in phytoplankton. Furthermore, interaction networks were dominated by positive net effects between phytoplanktonic taxa (on average, more than 50% of interactions were positive). While network stability (sensuresilience) was unrelated to complexity measures, we unveiled links between self-regulation, intergenus interaction strengths and abundance. The less common taxa tend to be more strongly self-regulated and can therefore maintain in spite of competition with more abundant ones.

Synthesis: We demonstrate that strong niche differentiation, widespread facilitation between phytoplanktonic taxa and stabilizing covariances between interaction strengths should be common features of coexisting phytoplankton communities in the field. These are structural properties that we can expect to emerge from plausible mechanistic models of phytoplankton communities. We discuss mechanisms, such as predation or restricted microscale movement, that are consistent with these findings, which paves the way for further research.
RST1 and RIPR connect the cytosolic RNA exosome to the Ski complex inArabidopsis
Authors: Lange Heike , Ndecky Simon Y. A. , Gomez-Diaz Carlos , Pflieger David , Butel Nicolas , Zumsteg Julie , Kuhn Lauriane , Piermaria Christina , Chicher Johana , Christie Michael , Karaaslan Ezgi S. , Lang Patricia L. M. , Weigel Detlef , Vaucheret Hervé , Hammann Philippe , Gagliardi Dominique
Published: April 2019

The RNA exosome is a key 3’-5’ exoribonuclease with an evolutionarily conserved structure and function. Its cytosolic functions require the co-factors SKI7 and the Ski complex. Here we demonstrate by co-purification experiments that the ARM repeat protein RESURRECTION1 (RST1) and RST1 INTERACTING PROTEIN (RIPR) connect the cytosolicArabidopsisRNA exosome to the Ski complex.rst1andriprmutants accumulate RNA quality control siRNAs (rqc-siRNAs) produced by the post-transcriptional gene silencing (PTGS) machinery when mRNA degradation is compromised. The small RNA populations observed inrst1andriprmutants are also detected in mutants lacking the RRP45B/CER7 core exosome subunit. Thus, molecular and genetic evidence supports a physical and functional link between RST1, RIPR and the RNA exosome. Our data reveal the existence of additional cytosolic exosome co-factors besides the known SKI subunits. RST1 is not restricted to plants, as homologues with a similar domain architecture but unknown function exist in animals, including humans.
A neural system that represents the association of odors with rewarded outcomes and promotes behavioral engagement
Authors: Gadziola Marie A. , Stetzik Lucas A. , Wright Katherine N. , Milton Adrianna J. , Arakawa Keiko , del Mar Cortijo María , Wesson Daniel W.
Published: April 2019

Learning strengthens the strong emotional and behavioral responses odors are well known for eliciting. Presumably subserving this, several brain regions display experience-dependent plasticity during odor learning, yet the specific cellular systems involved and the actual influence of these systems on odor-directed behavior are less understood. Here we investigated the transformation of odor information throughout the association of odors with rewards and also sought to link those neural systems with displays of reinforcement-based task engagement. First, we investigated the representation of odor-reward associations within two areas recipient of dense olfactory bulb input, the posterior piriform cortex (pPCX) and olfactory tubercle (OT), using simultaneous multi-site electrophysiological recordings from mice engaged in a reward-based olfactory learning task. As expected, neurons in both regions represented conditioned odors and did so with similar information content, yet both the proportion of neurons recruited by conditioned rewarded odors and the magnitudes and durations of their responses were greater in the OT. Using fiber photometry, we found that OT D1-type dopamine receptor expressing neurons flexibly represent odors based upon reward associations. In both the recordings and imaging, statistically meaningful changes in activity occurred soon after odor onset. Finally, using optogenetics we show that OT D1-receptor expressing neurons strongly influence behavior to promote task engagement. Together our results contribute to a model whereby OT D1 neurons support odor-guided motivated behaviors.
An open interface in the pre-80S ribosome coordinated by ribosome assembly factors Tsr1 and Dim1 enables temporal regulation of Fap7
Authors: Rai Jay , Parker Melissa D. , Huang Haina , Choy Stefan , Ghalei Homa , Johnson Matthew C. , Karbstein Katrin , Stroupe M. Elizabeth
Published: April 2019

During their maturation, nascent 40S subunits enter a translation-like quality control cycle, where they are joined by mature 60S subunits to form 80S-like ribosomes. While these assembly intermediates are essential for maturation and quality control, how they form, and how their structure promotes quality control remains unknown. To address these questions, we determined the structure of an 80S-like ribosome assembly intermediate to an overall resolution of 3.4 Å. The structure, validated by biochemical data, resolves a large body of previously paradoxical data and illustrates how assembly and translation factors cooperate to promote the formation of an interface that lacks many mature subunit contacts but is stabilized by the universally conserved Dim1. We also show how Tsr1 enables this interface by blocking the canonical binding of eIF5B to 40S subunits, while maintaining its binding to 60S. The structure also shows how this interface leads to unfolding of the platform, which allows for temporal regulation of the ATPase Fap7, thus linking 40S maturation to quality-control during ribosome assembly.
A Large-scale Study Reveals 24 hour Operational Rhythms in Hospital Treatment
Authors: Ruben Marc D. , Francey Lauren J. , Guo Yuping , Wu Gang , Cooper Edward B. , Shah Amy S. , Hogenesch John B. , Smith David F.
Published: April 2019

Hospitals operate 24 hours a day, and it is assumed that critical decisions occur continuously around the clock. However, many aspects of hospital operation occur at particular times of day, including medical team rounding and shift changes. It is unclear if this impacts patient care, as an empirical account of 24 h treatment patterns is lacking. We analyzed the daily distribution of ~120K doses of 12 separate drugs in 1,486 inpatients at a major children’s hospital in the U.S. Treatment orders and administration were strongly time-of-day-dependent, marked by distinct morning time surges and overnight lulls. These 24 h rhythms in treatment were remarkably consistent across drugs, diagnoses, and hospital units. In sum, nearly one-third of all 116,975 orders for treatment were placed between 8 AM and 12 PM. This rhythm in hospital medicine coincided with medical team rounding time, not necessarily immediate medical need. Lastly, we show that the clinical response to hydralazine, an acute antihypertensive, is dosing time-dependent and greatest at night, when the fewest doses were administered. The prevailing dogma is that hospital treatment is administered as needed regardless of time of day. Our findings challenge this notion and reveal a potential operational barrier to best clinical care.

SIGNIFICANCE STATEMENT

The order and administration of hospital treatment was characterized by morning time surges and overnight lulls, regardless of drug type, diagnosis or care unit. As the first large-scale account of 24 h rhythms in hospital medicine, this study identifies a potential operational barrier to best clinical care. Critical clinical decisions should be made around the clock; pain, infection, hypertensive crisis, and other conditions do not occur selectively in the morning. Systemic bias in the timing of medicine is also at odds with circadian biology, which can influence when certain treatments are most effective or safe. Prevailing dogma is that hospital treatment is administered as needed regardless of time of day. Our findings challenge this notion and suggest that time of day in hospital operations deserves further consideration.
Loss of function in the autism and learning disabilities associated gene Nf1 disrupts corticocortical and corticostriatal functional connectivity in human and mouse
Authors: Shofty Ben , Bergmann Eyal , Zur Gil , Asleh Jad , Bosak Noam , Kavushansky Alexandra , Castellanos F. Xavier , Ben-Sira Liat , Packer Roger J. , Vezina Gilbert L. , Constantini Shlomi , Acosta Maria T. , Kahn Itamar
Published: April 2019

Children with the autosomal dominant single gene disorder, neurofibromatosis type 1 (NF1), display multiple structural and functional changes in the central nervous system, resulting in neuropsychological cognitive abnormalities. Here we assessed the pathological functional organization that may underlie the behavioral impairments in NF1 using resting-state functional connectivity MRI. Coherent spontaneous fluctuations in the fMRI signal across the entire brain were used to interrogate the pattern of functional organization of corticocortical and corticostriatal networks in both NF1 pediatric patients and mice with a heterozygous mutation in the Nf1 gene (Nf1+/-). Children with NF1 demonstrated abnormal organization of cortical association networks and altered posterior-anterior functional connectivity in the default network. Examining the contribution of the striatum revealed that corticostriatal functional connectivity was altered. NF1 children demonstrated reduced functional connectivity between striatum and the frontoparietal network and increased striatal functional connectivity with the limbic network. Awake passive mouse functional connectivity MRI in Nf1+/- mice similarly revealed reduced posterior-anterior connectivity along the cingulate cortex as well as disrupted corticostriatal connectivity. The striatum of Nf1+/- mice showed increased functional connectivity to somatomotor and frontal cortices and decreased functional connectivity to the auditory cortex. Collectively, these results demonstrate similar alterations across species, suggesting that NF1 pathogenesis is linked to striatal dysfunction and disrupted corticocortical connectivity in the default network.
Multifactorial pathways facilitate resilience among kindergarteners at risk for dyslexia: A longitudinal behavioral and neuroimaging study
Authors: Zuk Jennifer , Dunstan Jade , Norton Elizabeth , Yu Xi , Ozernov-Palchik Ola , Wang Yingying , Hogan Tiffany P. , Gabrieli John D. E. , Gaab Nadine
Published: April 2019

Recent efforts have focused on screening methods to identify children at risk for dyslexia as early as preschool/kindergarten. Unfortunately, while low sensitivity leads to under-identification of at-risk children, low specificity can lead to over-identification, resulting in inaccurate allocation of limited educational resources. The present study focused on children identified as at-risk in kindergarten who donotsubsequently develop dyslexia to specify factors associated with better reading outcomes among at-risk children. Early screening was conducted in kindergarten and a subset of children was tracked longitudinally until second grade. Potential protective factors were evaluated at cognitive-linguistic, environmental, and neural levels. Relative to at-risk kindergarteners who subsequently developed dyslexia, those who did not were characterized by significantly higher socioeconomic status (SES), speech production accuracy, and microstructure of the posterior right-hemispheric superior longitudinal fasciculus (SLF). A positive association between microstructure of the right SLF and subsequent decoding skills was found to be specific to at-risk children and not observed among typical controls. Among at-risk children, several kindergarten-age factors were found to significantly contribute to the prediction of subsequent decoding skills: microstructure of the posterior right SLF, age, gender, SES, and phonological awareness. These findings suggest that putative compensatory mechanisms are already present by the start of kindergarten. The right SLF, in conjunction with the cognitive-linguistic and socioeconomic factors identified, may play an important role in facilitating reading development among at-risk children. This study has important implications for approaches to early screening, and assessment strategies for at-risk children.
Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus
Authors: Yang Jie E. , Rossignol Evan D. , Chang Deborah , Zaia Joseph , Forrester Isaac , Saulsbery Holly , Nicastro Daniela , Jackson William T. , Bullitt Esther
Published: April 2019

Enteroviruses support cell-to-cell viral transmission prior to their canonical lytic spread of virus. Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, and picornaviruses in general, transport multiple virionsen blocvia infectious extracellular vesicles secreted from host cells. Using biochemical and biophysical methods we identify multiple components in these secreted vesicles, including PV virions; positive and negative-sense viral RNA; essential viral replication proteins; ribosomal and regulatory cellular RNAs; and numerous host cell proteins, such as regulators of cellular metabolism and structural remodeling. Using cryo-electron tomography, we visualize the near-native three-dimensional architecture of secreted infectious extracellular vesicles containing both virions and a unique mat-like structure. Based on our biochemical data (western blot, RNA-Seq, and mass spectrometry), these mat-like structures are expected to be comprised of unencapsidated RNA and proteins. Our data show that, prior to cell lysis, non-enveloped viruses are secreted within infectious vesicles that also transport viral and host RNAs and proteins.

Importance

The family of picornaviridae is comprised of small positive-sense RNA viruses, many of which are significant human pathogens. Picornaviruses exploit secreted extracellular vesicles for cell-to-cell viral transmission without cell lysis, and poliovirus serves as a model system for picornaviruses that are not protected by a surrounding membrane (non-enveloped viruses). The structure and contents of these vesicles secreted by virus-infected cells are described here. In addition to mature virions, these vesicles carry negative-sense, ‘template’ viral RNA and essential replication proteins, as well as cellular resources from the host. Their complex contents may comprise an enhanced virulence factor for propagation of infection, and understanding their structure and function is helping elucidate the mechanism by which extracellular vesicles contribute to the spread of non-enveloped virus infection.
Estimating individuals’ genetic and non-genetic effects underlying infectious disease transmission from temporal epidemic data
Authors: Pooley Christopher M. , Marion Glenn , Bishop Stephen C. , Bailey Richard I. , Doeschl-Wilson Andrea B.
Published: April 2019

Individuals differ widely in their contribution to the spread of infection within and across populations. Three key epidemiological host traits affect infectious disease spread: susceptibility (propensity to acquire infection), infectivity (propensity to transmit infection to others) and recoverability (propensity to recover quickly). Interventions aiming to reduce disease spread may target improvement in any one of these traits, but the necessary statistical methods for obtaining risk estimates are lacking. In this paper we introduce a novel software tool calledSIRE(standing for “Susceptibility, Infectivity and Recoverability Estimation”), which allows simultaneous estimation of the genetic effect of a single nucleotide polymorphism (SNP), as well as non-genetic influences on these three unobservable host traits. SIRE implements a flexible Bayesian algorithm which accommodates a wide range of disease surveillance data comprising any combination of recorded individual infection and/or recovery times, or disease status measurements. Different genetic and non-genetic regulations and data scenarios (representing realistic recording schemes) were simulated to validate SIRE and to assess their impact on the precision, accuracy and bias of parameter estimates. This analysis revealed that with few exceptions, SIRE provides unbiased, accurate parameter estimates associated with all three host traits. For most scenarios, SNP effects associated with recoverability can be estimated with highest precision, followed by susceptibility. For infectivity, many epidemics with few individuals give substantially more statistical power to identify SNP effects than the reverse. Importantly, precise estimates of SNP and other effects could be obtained even in the case of incomplete, censored and relatively infrequent measurements of individuals’ infection or survival status, albeit requiring more individuals to yield equivalent precision. SIRE represents a new tool for analysing a wide range of experimental and field disease data with the aim of discovering and validating SNPs and other factors controlling infectious disease transmission.