bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Organ Dysfunction Scores and Functional Outcomes Following Pediatric Critical Illness*
Authors: Matics Travis J. , Pinto Neethi P. , Sanchez-Pinto L. Nelson
Published: May 2019

Objectives:

Short-term and long-term morbidity and mortality are common following pediatric critical illness. Severe organ dysfunction is associated with significant in-hospital mortality in critically ill children; however, the performance of pediatric organ dysfunction scores as predictors of functional outcomes after critical illness has not been previously assessed.

Design:

Secondary analysis of a prospective observational cohort.

Setting:

A multidisciplinary, tertiary, academic PICU.

Patients:

Patients less than or equal to 18 years old admitted between June 2012 and August 2012.

Interventions:

None.

Measurements and Main Results:

The maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during admission were calculated. The Functional Status Scale score was obtained at baseline, 6 months and 3 years following discharge. New morbidity was defined as a change in Functional Status Scale greater than or equal to 3 points from baseline. The performance of organ dysfunction scores at discriminating new morbidity or mortality at 6 months and 3 years was measured using the area under the curve. Seventy-three patients met inclusion criteria. Fourteen percent had new morbidity or mortality at 6 months and 23% at 3 years. The performance of the maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores at discriminating new morbidity or mortality was excellent at 6 months (areas under the curves 0.9 and 0.88, respectively) and good at 3 years (0.82 and 0.79, respectively).

Conclusions:

Severity of organ dysfunction is associated with longitudinal change in functional status and short-term and long-term development of new morbidity and mortality. Maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during critical illness have good to excellent performance at predicting new morbidity or mortality up to 3 years after critical illness. Use of these pediatric organ dysfunction scores may be helpful for prognostication of longitudinal functional outcomes in critically ill children.
UnBeelievable
Authors: Chi Simon , Le Jacqueline
Published: May 2019

There are numerous case studies describing myocarditis and cardiac events in adults after insect envenomation. To our knowledge, there are no similar cases documented in children. We report a unique case of a 14-year-old adolescent boy who developed acute myocarditis after a bee sting. The pathophysiology involving envenomation and myocarditis remains poorly understood.
Time Course and Recovery of the Movements of Hyoid Bone and Thyroid Cartilage During Swallowing in a Patient With Sarcopenic Dysphagia
Authors: Nakayama Enri , Tohara Haruka , Sato Mitsuyasu , Hino Haruka , Sakai Mayu , Nagashima Yuki , Kimura Masanori , Watanabe Mao , Ooshima Masako
Published: May 2019

Sarcopenia is known to adversely affect swallowing function. In this report, we describe the treatment progress of an older patient with dysphagia caused by sarcopenia and the analysis results from videofluorographic examination images. An 89-yr-old man who had been hospitalized for lumbar fracture experienced lower back pain and thus had his oral intake reduced. After transfer to a rehabilitation hospital, he developed aspiration pneumonia and then sarcopenia with low nutrition and low activity. At the beginning of intervention, he aspirated food paste, but he recovered sufficiently to be able to ingest a normal meal via a nutritional approach combined with rehabilitation at the time of discharge. During this process, the maximum amounts of displacements and maximum moving velocities of his hyoid bone and thyroid cartilage during swallowing of moderately thick water were improved. Adequate nutrition intake and training for hyoid muscles are considered effective for the patient with sarcopenic dysphagia. It was concluded that measuring the maximum displacements and moving velocities of the hyoid bone and thyroid cartilage during swallowing in patients with sarcopenic dysphagia was an effective way to monitor their improvement.
Time Effect of Intra-articular Injection With Triamcinolone Hexacetonide and Its Correlations
Authors: Rocha Roberta Hora , Natour Jamil , dos Santos Rita M. , Furtado Rita Nely Vilar
Published: May 2019

Objective

The aim of the study was to assess the time effect of intra-articular injection with triamcinolone hexacetonide in rheumatic patients.

Design

A prospective case-control study with patients submitted to one intra-articular injection with triamcinolone hexacetonide. Patients were followed monthly (12 mos) for pain and swelling.

Results

Two hundred sixty-two joints were assessed in 158 patients with mean ± SD age of 60 ± 13.7 yrs. Remission was observed at 3, 6, and 12 mos in 142 (54.19%), 111 (42.36%), and 105 (40.07%) joints, respectively. The mean ± SD time effect were 8 ± 4.0 mos; 8.4 ± 3.9 for rheumatoid arthritis patients and 6.9 ± 4.0 for osteoarthritis patients (P = 0.012) and 10.4 ± 2.7 mos for small, 7.7 ± 4.1 for medium, and 6.8 ± 4.0 for large joints. The joints were divided into two groups: long-term group (time effect of intra-articular injection longer than 6 mos) and short-term group. The following are the variables associated (P < 0.05) with long-term group: rheumatoid arthritis, small and medium-sized joints, female sex, lower pain and swelling visual analog scale scores, and use of leflunomide. The following are the variables associated with short-term group: receiving only one intra-articular injection, hypertension, diabetes mellitus, and biological therapy.

Conclusions

The mean ± SD time effect of intra-articular injection with triamcinolone hexacetonide was 8.0 ± 4.0 mos. The associated predictors were rheumatoid arthritis, small and medium joints, lower pain/swelling visual analog scale scores, and use of leflunomide.
Extending Visit Intervals for Clinically Stable Patients on Antiretroviral Therapy: Multicohort Analysis of HIV Programs in Southern Africa
Authors: Haas Andreas D. , Johnson Leigh F. , Grimsrud Anna , Ford Nathan , Mugglin Catarina , Fox Matthew P. , Euvrard Jonathan , van Lettow Monique , Prozesky Hans , Sikazwe Izukanji , Chimbetete Cleophas , Hobbins Michael , Kunzekwenyika Cordelia , Egger Matthias ,   for IeDEA Southern Africa
Published: May 2019

Background:

The World Health Organization recommends differentiated antiretroviral therapy (ART) delivery with longer visit intervals for clinically stable patients. We examined time trends in visit frequency and associations between criteria for clinical stability and visit frequency in ART programs in Southern Africa.

Methods:

We included adults on ART from 4 programs with viral-load monitoring, 2 programs with CD4 monitoring, and 4 programs with clinical monitoring of ART. We classified patients as clinically stable based on virological (viral load <1000 copies/mL), immunological (CD4 >200 cells/µL), or clinical (no current tuberculosis) criteria. We used Poisson regression and survival models to examine associations between criteria for clinical stability and the rate of clinic visits.

Results:

We included 180,837 patients. There were trends toward fewer visits in more recent years and with longer ART duration. In all ART programs, clinically stable patients were seen less frequently than patients receiving failing ART, but the strength of the association varied. Adjusted incidence rate ratios comparing visit rates for stable patients with patients on failing ART were 0.82 (95% confidence interval: 0.73 to 0.90) for patients classified based on the virological criterion, 0.81 (0.69 to 0.93) for patients classified based on the clinical criterion, and 0.90 (0.85 to 0.96) for patients classified based on the immunological criterion for stability.

Conclusion:

Differences in visit rates between stable patients and patients failing ART were variable and modest overall. Larger differences were seen in programs using virological criteria for clinical stability than in programs using immunological criteria. Greater access to routine viral-load monitoring may increase scale-up of differentiated ART delivery.
Increased PSMA Expression in Castration-Resistant Prostate Cancer Metastases 3 Months After Initiation of Enzalutamide Indicated by 18F-DCFPyL PET/CT
Authors: Wondergem Maurits , van der Zant Friso , Broos Wouter , Knol Remco
Published: May 2019

Radioisotope-labeled prostate-specific membrane antigen PET/CT is increasingly used for detection of prostate cancer most often in the setting of biochemical recurrence or in primary staging. This report shows increased PSMA expression in lymph node metastases 3 months after initiation of enzalutamide for castration-resistant prostate cancer, whereas lymph node volume and serum prostate-specific antigen decreases over time. This case demonstrates that increasing 18F-DCFPyL uptake after initiation of androgen deprivation therapy should not be confused with disease progression.
Early-Stage Supraglottic “In Situ” Squamous Cell Carcinoma of the Larynx Incidentally Detected by 18F-Fluorocholine PET/CT
Authors: Mangili Stefano Attilio , Rizzardi Nicola , Illuminati Sonia , Bnà Claudio , Savelli Giordano
Published: May 2019

18F-fluorocholine (18F-FCH) PET/CT is widely used to study patients affected by prostate cancer. Despite its specificity, however, 18F-FCH may be taken up by other neoplasms such as multiple myeloma, lymphomas, lung, bladder, and colon cancer; brain tumors; and renal and hepatocellular carcinoma. This is due to its ability to evaluate the cell proliferation, which is typical of neoplastic cells. While this behavior may be an opportunity to image more neoplasms, on the other hand it could represent a source of error in the evaluation of the images. Here we present the case of a laryngeal squamous cell carcinoma detected by 18F-FCH.
Brain Lymphoma on 99mTc-TRODAT-1 SPECT
Authors: Chiu Chen-Kai , Sun Shung-Shung , Kao Chia-Hung , Wu Yu-Chin , Hsieh Te-Chun
Published: May 2019

99mTc-TRODAT-1, as a tropane-derived compound with highly selective binding to the dopamine transporter, has been extensively used as an in vivo biomarker to evaluate parkinsonism. There have been few reports indicating various etiologies about extrastriatal findings on the 99mTc-TRODAT-1 SPECT. We herein present an interesting case about the incidental discovery of brain lymphoma with increasing uptake of 99mTc-TRODAT-1.
The Use of Finite Element Method Analysis for Modeling Different Osteotomy Patterns and Biomechanical Analysis of Craniosynostosis Correction
Authors: Augello Marcello , Maurer Manfred M. , Berg-Boerner Isabelle , Zeilhofer Hans-Florian , Cattin Philippe , Juergens Philipp
Published: May 2019

Purpose:

Several post-processing algorithms for 3D visualization of the skull in craniosynostosis with their specific advantages and disadvantages have been already described. The Finite Element Method (FEM) described herein can also be used to evaluate the efficacy of the cutting patterns with respect to an increase in the projected surface area under assumed uniform loading of the manipulated and cut bone segments.

Methods:

The FEM analysis was performed. Starting with the classic cranial osteotomies for bifrontal craniotomy and orbital bandeau a virtually mirroring of the unaffected triangular shaped frontal bone was performed to achieve a cup-shaped sphere of constant thickness of 2.5 mm with a radius of 65 mm. Mechanical properties required for the analysis were Young's modulus of 340 MPa and Poisson's ratio of 0.22. Four different cutting patterns from straight to curved geometries have been projected onto the inner surface of the sphere with a cutting depth set to 2/3rds of the shell thickness. The necessary force for the deformation, the resulting tensions and the volume loss due to the osteotomy pattern were measured.

Results:

Better outcomes were realized with pattern D. The necessary force was 73.6% smaller than the control group with 66N. Best stress distribution was achieved. Curved cutting patterns led to the highest peak of stress and thus to a higher risk of fracture. Straight bone cuts parallel to the corners or to the thighs of the sphere provided a better distribution of stresses with a small area with high stress. Additionally, also with pattern D a surface increase of 20.7% higher than reference was registered.

Conclusion:

As a proof of concept for different cutting geometries for skull molding in the correction of craniosynostosis, this computational model shows that depending of the cutting pattern different biomechanical behavior is achieved.
Surgical, Speech, and Audiologic Outcomes in Patients With Orofacial Cleft and Van der Woude Syndrome
Authors: Kitchin Spencer , Grames Lynn , Naidoo Sybill D. , Skolnick Gary , Schoenborn Alyssa , Snyder-Warwick Alison , Patel Kamlesh
Published: May 2019

Objective:

The purpose of this study was to investigate the surgical, speech, and audiologic outcomes in patients with Van der Woude syndrome (VWS) and compare them to patients with nonsyndromic cleft palate with or without cleft lip (NS-CP ± L) treated at the same institution.

Design:

Retrospective chart review.

Setting:

A single children's hospital at a major academic institution.

Patients:

The records of 18 patients with VWS who had been treated at a single institution from 1989 to 2017 have been retrospectively examined. Thirty-eight patients with NS-CP ± L who were also treated at the same institution during that same time frame were selected to closely match sex and date of birth.

Main Outcome Measures:

Demographic, clinical, surgical, and speech pathology data were gathered from medical charts.

Result:

By age 4, 88% of subjects with VWS and 76% of subjects with NS-CP ± L (P = 0.732) had been, or were actively involved in, speech therapy. By age 10, 100% of remaining subjects with VWS and 58% of remaining subjects with NS-CP ± L remained involved in speech therapy (P = 0.027).

About 33% of patients with VWS and 16% of patients with NS-CP ± L had a secondary procedure for velopharyngeal dysfunction (VPD) (P = 0.171).

Conclusion:

The VWS group had more than twice the rate of secondary procedures for VPD repair, and a higher rate of continuing involvement for speech therapy at age 10. No differences were found in the rate of participation in speech therapy at or by age 4.
Admission Leukocyte Count is Associated with Late Cardiogenic Shock Development and All-Cause 30-Day Mortality in Patients with St-Elevation Myocardial Infarction
Authors: Klein Anika , Wiberg Sebastian , Hassager Christian , Winther-Jensen Matilde , Frikke-Schmidt Ruth , Bang Lia Evi , Lindholm Matias Greve , Holmvang Lene , Moeller-Helgestad Ole , Ravn Hanne Berg , Jensen Lisette Okkels , Kjaergaard Jesper , Moeller Jacob Eifer , Frydland Martin
Published: May 2019

Background:

Thirty-day mortality in ST-elevation myocardial infarction (STEMI) patients is primarily driven by cardiogenic shock (CS). High neutrophil counts and high neutrophil/lymphocyte ratios (NLR) have previously been associated with mortality in STEMI patients; however, there is only sparse knowledge regarding their association with CS.

Purpose:

We sought to assess the associations between neutrophil count and NLR with the development of CS as well as 30-day mortality in STEMI patients.

Methods:

Patients admitted with STEMI at two tertiary Heart Centres throughout 1 year were included in the study and stratified into quartiles according to the level of leukocyte count upon admission. The primary endpoint was development of CS both before (early CS) and after leaving the catheterization laboratory (late CS). The secondary endpoint was all-cause 30-day mortality.

Results:

A total of 1,892 STEMI patients were included, whereof 194 (10%) developed CS while 122 (6.4%) died within 30 days. Patients in the highest quartile of neutrophils (OR: 2.54; 95% CI: 1.40–4.60; P = 0.002) and NLR (OR: 3.64; 95% CI: 2.02–6.54; P<0.0001) were at increased risk of developing late CS compared with patients in the lower quartiles, whereas there was no risk difference across quartiles regarding development of early CS. Both biomarkers correlated strongly to an increased 30-day mortality (plogrank<0.0001) and, moreover, a high level of neutrophils was independently associated with 30-day mortality (HR: 1.95; 95% CI: 1.25–3.03; P = 0.003).

Conclusion:

High levels of neutrophils and a high NLR upon admission for STEMI were independently associated with an increased risk of developing late CS and, additionally, both biomarkers showed association to 30-day mortality.
Stressors in Midlife and Risk of Dementia
Authors: Gilsanz Paola , Quesenberry Charles P. , Mayeda Elizabeth Rose , Glymour M. Maria , Farias Sarah T. , Whitmer Rachel A.
Published: May 2019

Background:

Posttraumatic stress disorder is associated with increased dementia risk but less is known about stress because of everyday problems in diverse populations.

Methods:

A total of 9605 health care plan members who provided information regarding midlife stressors in 1972 to 1973 (ages, 40 to 55 y) were followed for dementia diagnosis between 1996 and 2017. Cox proportional hazard models evaluated associations between midlife stressors and dementia adjusting for demographics and lifecourse health indicators.

Results:

Reporting at least 1 midlife stressor was associated with 17% greater dementia risk [hazard ratio (HR), 1.17; 95% confidence interval (CI),1.07-1.27] versus 0 midlife stressors and 26% increased risk among those with less than equal to high school education (HR, 1.26; 95% CI,1.09-1.44) adjusting for demographics. Compared with whites without stressors, whites with ≥1 stressor had 13% greater dementia risk (HR, 1.13; 95% CI, 1.02-1.24), blacks without stressors 19% greater risk (HR, 1.19; 95% CI,1.08-1.32), and blacks with ≥1 stressors 47% greater risk (HR, 1.47; 95% CI,1.27-1.69) in fully adjusted models. Resource problems were associated with 20% greater risk (HR, 1.20; 95% CI, 1.01-1.42) than interpersonal problems.

Conclusion:

Reporting ≥1 serious midlife stressor was associated with elevated dementia risk, especially stressors related to resources problems and for those with less than equal to high school education. Everyday stressors can impact brain health over the long term and may contribute to racial inequities in dementia rates, though education can be a mitigating factor.
Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion
Authors: Johnston Jessica M , Angyal Adrienn , Bauer Robert C , Hamby Stephen , Suvarna S Kim , Baidžajevas Kajus , Hegedus Zoltan , Dear T Neil , Turner Martin ,   The Cardiogenics Consortium, Wilson Heather L , Goodall Alison H , Rader Daniel J , Shoulders Carol C , Francis Sheila E , Kiss-Toth Endre
Published: May 2019

Macrophages drive atherosclerotic plaque progression and rupture, hence attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.
LFPy – multimodal modeling of extracellular neuronal recordings in Python
Authors: Hagen Espen , Næss Solveig , Ness Torbjørn V. , Einevoll Gaute T.
Published: May 2019

1.

LFPy is an open-source tool for calculating brain signals such as extracellular potentials and magnetic signals from simulated activity in multicompartment neuron models, ranging from single cells to large neuronal networks. The tool is provided as a Python package, and relies on the NEURON simulation environment.
Psychotic symptoms in 16p11.2 copy number variant carriers
Authors: Jutla Amandeep , Turner J. Blake , Snyder LeeAnne Green , Chung Wendy K. , Veenstra-VanderWeele Jeremy
Published: May 2019

16p11.2 copy number variation (CNV) is implicated in neurodevelopmental disorders, with the duplication and deletion associated with autism spectrum disorder (ASD) and the duplication associated with schizophrenia (SCZ). The 16p11.2 CNV may therefore provide insight into the relationship between ASD and SCZ, distinct disorders that co-occur at an elevated rate and are difficult to distinguish from each other and from common co-occurring diagnoses such as obsessive compulsive disorder (OCD), itself a potential risk factor for SCZ. As psychotic symptoms are core to SCZ but distinct from ASD, we sought to examine their predictors in a population (n = 546) of 16p11.2 CNV carriers and their noncarrier siblings recruited by the Simons Variation in Individuals Project. We hypothesized that psychotic symptoms would be most common in duplication carriers followed by deletion carriers and noncarriers, that an ASD diagnosis would predict psychotic symptoms among CNV carriers, and that OCD symptoms would predict psychotic symptoms among all participants. Using data collected across multiple measures, we identified 19 participants with psychotic symptoms. Logistic regression models adjusting for biological sex, age, and IQ found that 16p11.2 duplication and ASD diagnosis predicted psychotic symptom presence. Our findings suggest that the association between 16p11.2 duplication and psychotic symptoms is independent of ASD diagnosis and that ASD diagnosis and psychotic symptoms may be associated in 16p11.2 CNV carriers.

Lay Summary

Either deletion or duplication at chromosome 16p11.2 raises the risk of autism spectrum disorder, and duplication, but not deletion, has been reported in schizophrenia. In a sample of 16p11.2 deletion and duplication carriers, we found that having the duplication or having an autism diagnosis may increase the risk of psychosis, a key feature of schizophrenia.
Optimizing systemic insecticide use to improve malaria control
Authors: Meredith Hannah R. , Furuya-Kanamori Luis , Yakob Laith
Published: May 2019

Long lasting insecticidal nets and indoor residual sprays have significantly reduced the burden of malaria. However, several hurdles remain before elimination can be achieved: mosquito vectors have developed resistance to public health insecticides, including pyrethroids, and have altered their biting behaviour to avoid these indoor control tools. Systemic insecticides, drugs applied directly to blood-hosts to kill mosquitoes that take a blood meal, offer a promising vector control option. To date, most studies focus on repurposing ivermectin, a drug used extensively to treat river blindness. There is concern that over-dependence on a single drug will inevitably repeat past experiences with the rapid spread of pyrethroid resistance in malaria vectors. Diversifying the arsenal of systemic insecticides used for mass drug administration would improve this strategy’s sustainability. Here, a review was conducted to identify systemic insecticide candidates and consolidate their pharmacokinetic/pharmacodynamic properties. The impact of alternative integrated vector control options and different dosing regimens on malaria transmission reduction are illustrated through a mathematical model simulation. The review identified drugs from four classes commonly used in livestock and companion animals: avermectics, milbemycins, isoxazolines, and spinosyns. Simulations predicted that isoxazoline and spinosyn drugs were promising candidates for mass drug administration, as they were predicted to need less frequent application than avermectins and milbemycins to maintain mosquitocidal blood concentrations. These findings will provide a guide for investigating and applying different systemic insecticides to achieve better mosquito control strategies.

Significance

The widespread use of long lasting insecticidal nets (LLINs) and indoor residual spray has selected for mosquitoes that are resistant to pyrethroids or avoid exposure by feeding outdoors or on livestock. Systemic insecticides, drugs that render a host’s blood toxic to feeding mosquitoes, could be an effective control strategy for mosquitoes with pyrethroid resistance and/or outdoor feeding tendencies. Here, a number of existing systemic insecticide candidates are identified and their pharmacokinetic properties in different drug-host-route scenarios consolidated. These data were used to parameterise a mathematical model that illustrated the projected gains achievable in malaria control programmes already employing LLINs. The findings provide a guide for investigating and applying different systemic insecticides to improve mosquito control strategies and reduce malaria transmission.
Dopamine replacement remediates risk aversion in Parkinson’s disease in a value-independent manner
Authors: Cherkasova Mariya V. , Corrow Jeffrey C. , Taylor Alisdair , Yeung Shanna C. , Stubbs Jacob L. , McKeown Martin J. , Appel-Cresswell Silke , Stoessl A. Jon , Barton Jason J. S.
Published: May 2019

Introduction

Clinical evidence suggests that Parkinson’s Disease (PD) patients are risk averse. Dopaminergic therapy has been reported to increase risk tolerance, but the underlying mechanisms are unclear. Some studies have suggested an amplification of subjective reward value, consistent with the role of dopamine in reward value coding. Others have reported value-independent risk enhancement. We evaluated the value-dependence of the effects of PD and its therapy on risk using tasks designed to sensitively measure risk over a wide range of expected values.

Method

36 patients with idiopathic PD receiving levodopa monotherapy and 36 healthy matched controls performed two behavioural economic tasks aimed at quantifying 1) risk tolerance/ aversion in the gain frame and 2) valuation of potential gains relative to losses. PD patients performed the tasks on and off their usual dose of levodopa in randomized order; controls performed the same tasks twice.

Results

Relative to the controls, unmedicated PD patients showed significant value-independent risk aversion in the gain frame, which was normalized by levodopa. PD patients did not differ from controls in their valuation of gains relative to losses. However, across both tasks and regardless of medication, choices of the patients were more determined by expected values of the prospects than those of controls.

Conclusion

Dopamine deficiency in PD was associated with risk aversion, and levodopa promoted riskier choice in a value-independent manner. PD patients also showed an increased sensitivity to expected value, which was independent of levodopa and does not appear to result directly from dopamine deficiency.
Sonogenetic modulation of cellular activities using an engineered auditory-sensing protein
Authors: Huang Yao-Shen , Fan Ching-Hsiang , Hsu Ning , Wu Chun-Yao , Chang Chu-Yuan , Hong Shi-Rong , Chang Ya-Chu , Wu Anthony Yan-Tang , Guo Vanessa , Chiang Yueh-Chen , Hsu Wei-Chia , Chiu Nai-Hua , Chen Linyi , Lai Charles Pin-Kuang , Yeh Chih-Kuang , Lin Yu-Chun
Published: May 2019

Biomolecules that respond to different external stimuli enable the remote control of genetically modified cells. Chemogenetics and optogenetics, two tools that can control cellular activities via synthetic chemicals or photons, respectively, have been widely used to elucidate underlying physiological processes. These methods are, however, very invasive, have poor penetrability, or low spatiotemporal precision, attributes that hinder their use in therapeutic applications. We report herein a sonogenetic approach that can manipulate target cell activities by focused ultrasound stimulation. This system requires an ultrasound-responsive protein derived from an engineered auditory-sensing protein prestin. Heterogeneous expression of mouse prestin containing two parallel amino acid substitutions, N7T and N308S, that frequently exist in prestins from echolocating species endowed transfected mammalian cells with the ability to sense ultrasound. An ultrasound pulse of low frequency and low pressure efficiently evoked cellular calcium responses after transfecting with prestin(N7T, N308S). Moreover, pulsed ultrasound can also non-invasively stimulate target neurons expressing prestin(N7T, N308S) in deep regions of mice brains. Our study delineates how an engineered auditory-sensing protein can cause mammalian cells to sense ultrasound stimulation. Moreover, owing to the great penetration of low-frequency ultrasound (∼400 mm in depth), our sonogenetic tools will serve as new strategies for non-invasive therapy in deep tissues of large animals like primates.
Associations between EEG functional brain connectivity and a cognitive reserve proxy in healthy older adults
Authors: Moezzi Bahar , Lavrencic Louise M. , Goldsworthy Mitchell R. , Coussens Scott , Keage Hannah A.D.
Published: May 2019

Cognitive reserve is a concept that explains individual differences in vulnerability to cognitive impairment due to age and dementia-related brain changes. Mechanisms underlying the cognitive reserve effect are poorly understood. We investigated associations between a comprehensive cognitive reserve proxy (Lifetime Experiences Questionnaire/LEQ) and functional connectivity of the prefrontal cortex across the whole scalp, covarying for the level of current cognitive functioning (Addenbrookes Cognitive Examination Revised/ACE-R), using multiblock parallel and orthogonalized partial least squares regression. EEG data were collected from 34 healthy older adults (63 to 83 years) in eyes-open and eyes-closed resting-states, and during 0-back and 1-back tasks. Functional connectivity was estimated using imaginary coherence in the theta and alpha frequency bands, as these bands have been heavily implicated in cognitive ageing, attention and executive function. We found three clusters of electrodes where the absolute values of the regression coefficient were above threshold when covarying for ACE-R: (1) a cluster approximating the right frontocentral region during the eyes-open condition in the theta band with seed electrodes approximating the left prefrontal cortex with positive associations of medium effect size; (2) a cluster approximating the right parietotemporal region during the 0-back task in the theta band with seed electrodes approximating the right prefrontal cortex with negative associations of medium to large effect sizes; and (3) a cluster approximating the occipitoparietal region in the eyes-closed condition in the alpha band with seed electrodes approximating the left prefrontal cortex with negative associations of medium effect size. These relationships between a cognitive reserve proxy and functional connectivity, within key networks and frequency bands associated with attention and executive function, may reflect greater neural capacity and efficiency.
Population structure of Apodemus flavicollis and comparison to Apodemus sylvaticus in northern Poland based on RAD-seq
Authors: Cerezo Maria Luisa Martin , Kucka Marek , Zub Karol , Chan Yingguang Frank , Bryk Jarosław
Published: May 2019

Background

Mice of the genus Apodemus are one the most common mammals in the Palaearctic region. Despite their broad range and long history of ecological observations, there are no whole-genome data available for Apodemus, hindering our ability to further exploit the genus in evolutionary and ecological genomics context.

Results

Here we present results from the double-digest restriction site-associated DNA sequencing (ddRAD-seq) on 72 individuals of A. flavicollis and 10 A. sylvaticus from four populations, sampled across 500 km distance in northern Poland. Our data present clear genetic divergence of the two species, with average p-distance, based on 21377 common loci, of 1.51% and a mutation rate of 0.0011 - 0.0019 substitutions per site per million years. We provide a catalogue of 117 highly divergent loci that enable genetic differentiation of the two species in Poland and to a large degree of 20 unrelated samples from several European countries and Tunisia. We also show evidence of admixture between the three A. flavicollis populations but demonstrate that they have negligible average population structure, with largest pairwise FST < 0.086.

Conclusion

Our study demonstrates the feasibility of ddRAD-seq in Apodemus and provides the first insights into the population genomics of the species.
Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small Cell Lung Cancer
Authors: Chang Han , Sasson Ariella , Srinivasan Sujaya , Golhar Ryan , Greenawalt Danielle M. , Geese William J. , Green George , Zerba Kim , Kirov Stefan , Szustakowski Joseph
Published: May 2019

Introduction

Tumor mutational burden (TMB) has emerged as a clinically relevant biomarker that may be associated with immune checkpoint inhibitor efficacy. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment.

Objective

Here we describe the in-depth evaluation of bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples from a phase 3 clinical trial.

Methods

In the CheckMate 026 clinical trial, TMB was retrospectively assessed in 312 patients with non-small cell lung cancer (58% of the intent-to-treat population) who received first-line nivolumab treatment or standard-of-care chemotherapy. We examined the sensitivity of TMB assessment to bioinformatic filtering methods and assessed concordance between TMB data derived by WES and the FoundationOne®CDx assay.

Results

TMB scores comprising synonymous, indel, frameshift, and nonsense mutations (all mutations) were 3.1-fold higher than data including missense mutations only, but values were highly correlated (Spearman’s r = 0.99). Scores from CheckMate 026 samples including missense mutations only were similar to those generated from data in The Cancer Genome Atlas, but those including all mutations were generally higher. Using databases for germline subtraction (instead of matched controls) showed a trend for race-dependent increases in TMB scores. WES and FoundationOne CDx outputs were highly correlated (Spearman’s r = 0.90).

Conclusions

Parameter variation can impact TMB calculations, highlighting the need for standardization. Encouragingly, differences between assays could be accounted for by empirical calibration, suggesting that reliable TMB assessment across assays, platforms, and centers is achievable.

Key Points

Tumor mutational burden (TMB) is a clinically relevant biomarker for efficacy of immunotherapy in patients with cancer

Variations in TMB assessment parameters can shift the final TMB value. Harmonization and standardization are important to the successful clinical implementation of TMB testing

TMB values assessed by different methods are highly correlated. Harmonization of TMB testing in patients with cancer is therefore achievable
Levels of Representation in a Deep Learning Model of Categorization
Authors: Guest Olivia , Love Bradley C.
Published: May 2019

Deep convolutional neural networks (DCNNs) rival humans in object recognition. The layers (or levels of representation) in DCNNs have been successfully aligned with processing stages along the ventral stream for visual processing. Here, we propose a model of concept learning that uses visual representations from these networks to build memory representations of novel categories, which may rely on the medial temporal lobe (MTL) and medial prefrontal cortex (mPFC). Our approach opens up two possibilities:a) formal investigations can involve photographic stimuli as opposed to stimuli handcrafted and coded by the experimenter;b) model comparison can determine which level of representation within a DCNN a learner is using during categorization decisions. Pursuing the latter point, DCNNs suggest that the shape bias in children relies on representations at more advanced network layers whereas a learner that relied on lower network layers would display a color bias. These results confirm the role of natural statistics in the shape bias (i.e., shape is predictive of category membership) while highlighting that the type of statistics matter, i.e., those from lower or higher levels of representation. We use the same approach to provide evidence that pigeons performing seemingly sophisticated categorization of complex imagery may in fact be relying on representations that are very low-level (i.e., retinotopic). Although complex features, such as shape, relatively predominate at more advanced network layers, even simple features, such as spatial frequency and orientation, are better represented at the more advanced layers, contrary to a standard hierarchical view.
Juvenile hormone interacts with multiple factors to modulate aggression and dominance in groups of orphan bumble bee (Bombus terrestris) workers
Authors: Pandey Atul , Motro Uzi , Bloch Guy
Published: May 2019

Juvenile hormone (JH) is a key regulator of insect development and reproduction. Given that JH commonly affects adult insect fertility, it has been hypothesized to also regulate behaviors such as dominance and aggression that are associated with reproduction. We tested this hypothesis in the bumble beeBombus terrestrisfor which JH has been shown to be the major gonadotropin. We used the allatoxin Precocene-I (P-I) to reduce hemolymph JH titers and replacement therapy with the natural JH to revert this effect. In small orphan groups of workers with similar body size but mixed treatment, P-I treated bees showed lower aggressiveness, oogenesis, and dominance rank compared with control and replacement therapy treated bees. In similar groups in which all bees were treated similarly, there was a clear dominance hierarchy, even in P-I and replacement therapy treatment groups in which the bees showed similar levels of ovarian activation. In a similar experiment in which bees differed in body size, larger bees were more likely to be dominant despite their similar JH treatment and ovarian state. In the last experiment, we show that JH manipulation does not affect dominance rank in groups that had already established a stable dominance hierarchy. These findings solve previous ambiguities concerning whether or not JH affects dominance in bumble bees. JH positively affects dominance, but bees with similar levels of JH can nevertheless establish dominance hierarchies. Thus, multiple factors including JH, body size, and previous experience affect dominance and aggression in social bumble bees.
Mammalian gene expression variability is explained by underlying cell state
Authors: Foreman Robert , Wollman Roy
Published: May 2019

Gene expression variability in mammalian systems plays an important role in physiological and pathophysiological conditions. This variability can come from differential regulation related to cell state (extrinsic) and allele-specific transcriptional bursting (intrinsic). Yet, the relative contribution of these two distinct sources is unknown. Here we exploit the qualitative difference in the patterns of covariance between these two sources to quantify their relative contributions to expression variance in mammalian cells. Using multiplexed error robust RNA fluorescent in situ hybridization (MERFISH) we measured the multivariate gene expression distribution of 150 genes related to Ca2+signaling coupled with the dynamic Ca2+response of live cells to ATP. We show that after controlling for cellular phenotypic states such as size, cell cycle stage, and Ca2+response to ATP, the remaining variability is effectively at the Poisson limit for most genes. These findings demonstrate that the majority of expression variability results from cell state differences and that the contribution of transcriptional bursting is relatively minimal.
RNA polymerase mutations cause cephalosporin resistance in clinicalNeisseria gonorrhoeaeisolates
Authors: Palace Samantha G. , Wang Yi , Rubin Daniel H. F. , Welsh Michael A. , Mortimer Tatum D. , Cole Kevin , Eyre David W. , Walker Suzanne , Grad Yonatan H.
Published: May 2019

IncreasingNeisseria gonorrhoeaeresistance to ceftriaxone, the last antibiotic recommended for empiric gonorrhea treatment, poses an urgent public health threat. However, the genetic basis of reduced susceptibility to ceftriaxone is not completely understood: while most ceftriaxone resistance in clinical isolates is caused by target site mutations inpenA, others lack these mutations. Here, we show thatpenA-independent ceftriaxone resistance has evolved multiple times through distinct mutations inrpoBandrpoD. We identify five mutations in these genes that each increase resistance to ceftriaxone, including one mutation that arose independently in two lineages, and show that clinical isolates from multiple lineages are a single nucleotide change from ceftriaxone resistance. These RNA polymerase mutations result in large-scale transcriptional changes without altering susceptibility to other antibiotics, reducing growth rate, or deranging cell morphology. These results underscore the unexpected diversity of pathways to resistance and the importance of continued surveillance for novel resistance mutations.
Multicellular behavior enables cooperation in microbial cell aggregates
Authors: Ebrahimi Ali , Schwartzman Julia , Cordero Otto X.
Published: May 2019

During the degradation of biological materials such as biopolymers, extracellular enzymes liberate oligosaccharides that act as common goods and become available for all cells in the local neighborhood. This phenomenon can lead to cooperative growth, whereby cell-cell aggregation increases both the per-capita availability of resources and the per cell growth rate. However, aggregation can also have detrimental consequences for growth, as gradients form within aggregates limiting the resource accessibility. We used a computational model to show that high bacterial densities and high enzyme secretion rates restrict cooperation in aggregates larger than 10μm, due to the emergence of polymer and oligomer counter-gradients. We compared these predictions against experiments performed with two well-studied alginate degrading Vibrios, one of which displayed a strong density dependent growth. We observed that both strains can form large aggregates (<50μm), overcoming diffusion limitation by rearranging their internal structure. The non-cooperative, strong enzyme producer formed aggregates with internal channels that allowed exchange between the bulk environment and the aggregate core, whereas the cooperative, weak enzyme producer formed dense aggregates that developed a hollow structure as they grew. These internal structures allowed cells to avoid overcrowded areas near the core, enabling the development of large cell aggregates. Our study shows that bacterial behavior can help overcome competition imposed by resource gradients within cell aggregates.
Using Deep Learning to Annotate the Protein Universe
Authors: Bileschi Maxwell L. , Belanger David , Bryant Drew , Sanderson Theo , Carter Brandon , Sculley D. , DePristo Mark A. , Colwell Lucy J.
Published: May 2019

Understanding the relationship between amino acid sequence and protein function is a long-standing problem in molecular biology with far-reaching scientific implications. Despite six decades of progress, state-of-the-art techniques cannot annotate 1/3 of microbial protein sequences, hampering our ability to exploit sequences collected from diverse organisms. In this paper, we explore an alternative methodology based on deep learning that learns the relationship between unaligned amino acid sequences and their functional annotations across all 17929 families of the Pfam database. Using the Pfam seed sequences we establish rigorous benchmark assessments that use both random and clustered data splits to control for potentially confounding sequence similarities between train and test sequences. Using Pfam full, we report convolutional networks that are significantly more accurate and computationally efficient than BLASTp, while learning sequence features such as structural disorder and transmembrane helices. Our model co-locates sequences from unseen families in embedding space, allowing sequences from novel families to be accurately annotated. These results suggest deep learning models will be a core component of future protein function prediction tools.
Click-PD: A Quantitative Method for Base-Modified Aptamer Discovery
Authors: Gordon Chelsea K. L. , Wu Diana , Feagin Trevor A. , Pusuluri Anusha , Csordas Andrew T. , Eisenstein Michael , Hawker Craig J. , Niu Jia , Soh H. Tom
Published: May 2019

Base-modified aptamers that incorporate non-natural chemical moieties can achieve greatly improved affinity and specificity relative to natural DNA or RNA aptamers. However, conventional methods for generating base-modified aptamers require considerable expertise and resources. In this work, we have accelerated and generalized the process of generating base-modified aptamers by combining a click-chemistry strategy with a fluorescence-activated cell sorting (FACS)-based screening methodology that measures the affinity and specificity of individual aptamers at a throughput of ∼10^7 per hour. Our “click-PD” strategy offers many advantages. First, almost any chemical modification can be introduced with a commercially-available polymerase. Second, click-PD can screen vast numbers of individual aptamers based on quantitative on- and off-target binding measurements to simultaneously achieve high affinity and specificity. Finally, it requires minimal specialized equipment or reagents besides a FACS instrument which is now widely-available. Using click-PD, we generated a boronic acid-modified aptamer with ∼1 μM affinity for epinephrine, a target for which no aptamer has been reported to date. We subsequently generated a mannose-modified aptamer with nanomolar affinity for the lectin concanavalin A (ConA). The strong affinity of both aptamers is fundamentally dependent upon the presence of chemical modifications, and we show that their removal essentially eliminates aptamer binding. Importantly, our ConA aptamer exhibited exceptional specificity, with minimal binding to other structurally-similar lectins. Finally, we show that our aptamer remarkable biological activity. Indeed, to the best of our knowledge, this aptamer is the most potent inhibitor of Con A-mediated hemagglutination reported to date.