bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Prediction Rule for Heterotopic Ossification of the Hip in Patients with Spinal Cord Injury
Authors: Suero Eduardo M. , Meindl Renate , Schildhauer Thomas A. , Citak Mustafa
Published: April 2018

Study Design.

A case-control study; clinical prediction rule.

Objective.

The aim of this study was to construct and internally validate a clinical prediction rule to identify patients at high risk of developing heterotopic ossification (HO) after spinal cord injury (SCI).

Summary of Background Data.

HO after SCI can lead to loss of joint mobility, loss of function, peripheral nerve entrapment, and pressure sores. HO is usually diagnosed on the basis of clinical symptoms, as no laboratory tests are yet available to identify patients with early HO formation. Risk factors include a complete SCI; patient age; spasticity; urinary tract infection (UTI); pneumonia; pelvic trauma; cervical or thoracic injury; and pressure sores.

Methods.

We analyzed a total of 558 patients with SCI, of whom 221 developed HO of the hip. A parametric survival model was fitted to estimate the probability of developing HO of the hip within 3 months of a SCI. Hazard ratios (HRs) calculation, internal validation, calibration, and model reduction were performed over 200 bootstrapped resamples. A risk score for clinical used was developed.

Results.

Risk factors contributing to the risk score were completeness of the injury, age, sex, UTI, spasticity, and pneumonia. The model demonstrated good discrimination (AUC = 0.72). According to the risk score quintiles, the risk of developing HO after SCI was 1.0 for persons with a score of 0 to 17 and increased 2.47-fold for persons with a score of 1 to 21, 4.75-fold for persons with a score of 22 to 27, 6.95-fold for persons with a score of 28 to 31, and 9.23-fold for persons with a score of 32-35.

Conclusion.

The risk score demonstrated good discrimination in predicting the occurrence of HO within 3 months of a SCI. Further development and validation of the model in other populations is warranted.

Level of Evidence: 3
Implication of Biomarker Mutations for Predicting Survival in Patients With Metastatic Lung Cancer to the Spine
Authors: Choi Bryan D. , Shankar Ganesh M. , Sivaganesan Ahilan , Van Beaver Laura A. , Oh Kevin , Shin John H.
Published: April 2018

Study Design.

A retrospective cohort study.

Objective.

We performed a retrospective study of patients treated at our institution over the last 7 years to ascertain whether gene expression signatures in patients with advanced metastatic disease are associated with survival, when the disease has progressed to the spine.

Summary of Background Data.

Spinal metastases are a major cause of morbidity in patients with cancer. Molecular profiling strategies to characterize lung cancer have identified several genetic biomarkers that may lead to more effective prognostication.

Methods.

We queried our institutional database for patients with metastatic lung cancer who underwent treatment for spinal metastases between 2011 and 2017. Genetic mutations in ALK, MET, ROS1, EGFR, and KRAS were chosen a priori for study based on availability by standard SNaPshot Lung Tumor Genotyping Analysis. Survival time was the duration between treatment for spinal metastases and death. Kaplan–Meier methods and the log-rank test were applied to characterize survival data.

Results.

Twenty-six patients met criteria for inclusion. Median survival after surgery was 0.67 years. Median overall survival (OS) after diagnosis was 2.7 years. The presence of molecular abnormalities in patients with spinal metastases was significantly associated with increased OS (HR 0.38, 95% CI 0.12–1.22, P = 0.03).

Conclusion.

Molecular phenotyping may provide prognostic insight in patients undergoing surgery for spinal metastases. This is the first study to demonstrate an association between genetic mutational data and OS in this patient population. It also represents the largest published series of such patients (n = 26) for which genetic mutational data are reported. Future models estimating survival for patients with spinal metastases may be enhanced by incorporation of molecular criteria.

Level of Evidence: 4
Alloknesis and hyperknesis—mechanisms, assessment methodology, and clinical implications of itch sensitization
Authors: Andersen Hjalte Holm , Akiyama Tasuku , Nattkemper Leigh Ann , van Laarhoven Antoinette , Elberling Jesper , Yosipovitch Gil , Arendt-Nielsen Lars
Published: April 2018

Itch and pain share numerous mechanistic similarities. Patients with chronic itch conditions (for instance atopic dermatitis or neuropathic itch) often experience symptoms such as mechanical alloknesis and hyperknesis. These dysesthesias are analogous to the pain-associated phenomena allodynia and hyperalgesia, which are often observed, for example, in neuropathic pain conditions. Mechanical itch dysesthesias represent abnormal sensory states (caused by neuroplastic changes), wherein considerable itch is evoked, for instance by light cutaneous stimuli such as from clothing (alloknesis), or where increased itch is perceived in response to normally itch-evoking stimuli (hyperknesis). These itch sensitization phenomena have been explored in experimental human studies, observed in chronic itch patients, and in animal models of itch. Limited attention has been paid to these sensory phenomena in clinical studies, and it is unknown how they respond to antipruritics. Psychophysical quantitative sensory testing can quantify the presence, severity, and spatial extent of itch dysesthesias in chronic itch patients, providing a proxy measurement of itch sensitization. This review outlines current assessment techniques, knowledge on the mechanisms of mechanical alloknesis and hyperknesis, and presents the diverse results derived from clinical studies exploring the presence of itch dysesthesias in chronic itch patients. A key role of quantitative sensory testing and neuronal sensitization in patients with chronic pain is accepted and used in clinical assessments. However, the precise mechanisms and potential clinical implications of itch sensitization in chronic itch patients remain to be evaluated.
Hybrid Extracorporeal Therapies as a Bridge to Pediatric Liver Transplantation*
Authors: Akcan Arikan Ayse , Srivaths Poyyapakkam , Himes Ryan W. , Tufan Pekkucuksen Naile , Lam Fong , Nguyen Trung , Miloh Tamir , Braun Michael , Goss John , Desai Moreshwar S.
Published: April 2018

Objectives:

Standard intensive care treatment is inadequate to keep children with liver failure alive without catastrophic complications to ensure successful transplant, as accumulation of endogenous protein-bound toxins often lead to hepatic encephalopathy, hepatorenal syndrome, cardiovascular instability, and multiple organ failure. Given paucity of proven treatment modalities for liver failure, blood purification using different extracorporeal treatments as a bridge to transplantation is used, but studies evaluating the safety and efficacy of combination of these therapies, especially in pediatric liver failure, are lacking. We describe our experience at a major tertiary children’s hospital, where a unique hybrid extracorporeal treatment protocol has been instituted and followed for acute liver failure or acute-on-chronic liver failure as a bridge to transplantation. This protocol combines high-flux continuous renal replacement therapy for hyperammonemia, therapeutic plasma exchange for coagulopathy, and albumin-assisted dialysis (molecular adsorbent recirculating system) for hepatic encephalopathy.

Design:

Retrospective observational study.

Setting:

Freestanding tertiary children’s hospital and liver transplant referral center.

Patients:

All patients with acute liver failure/acute-on-chronic liver failure receiving hybrid extracorporeal therapy over 24 months.

Intervention:

Hybdrid extracorporeal therapy.

Measurements and Main Results:

Fifteen children (age 3 yr [0.7–9 yr]; 73% male) with acute liver failure/acute-on-chronic liver failure who were either listed or actively considered for listing and met our protocol criteria were treated with hybrid extracorporeal therapy; 93% were ventilated, and 80% were on vasoactive support. Of these, two patients recovered spontaneously, four died prior to transplant, and nine were successfully transplanted; 90-day survival post orthotopic liver transplant was 100%. Overall survival to hospital discharge was 73%.

Conclusions:

Hybrid extracorporeal therapies can be effectively implemented in pediatric liver failure as a bridge to transplantation. Overall complexity and heavy resource utilization need to be carefully considered in instituting these therapies in suitable candidates.
Practice Change From Intermittent Medication Boluses to Bolusing From a Continuous Infusion in Pediatric Critical Care: A Quality Improvement Project
Authors: Hochstetler Jessica L. , Thompson A. Jill , Ball Natalie M. , Evans Melissa C. , Frame Shaun C. , Haney A. Lauren , Little Amelia K. , O’Donnell Jaime L. , Rickett Bryna M. , Mack Elizabeth H.
Published: April 2018

Objectives:

To determine whether implementing a guideline to bolus medications from continuous infusions in PICUs affects nursing satisfaction, patient safety, central line entries, medication utilization, or cost.

Design:

This is a pre- and postimplementation quality improvement study.

Setting:

An 11-bed ICU and 14-bed cardiac ICU in a university-affiliated children’s hospital.

Patients:

Patients less than 18 years old admitted to the PICU or pediatric cardiac ICU receiving a continuous infusion of dexmedetomidine, midazolam, fentanyl, morphine, vecuronium, or cisatracurium from May 2015 to May 2016, excluding November 2015 (washout period), were eligible for inclusion.

Interventions:

Change in practice from administering bolus doses from an automated dispensing machine to administering bolus medications from continuous infusion in PICUs.

Measurements and Main Results:

Timing studies were conducted pre- and post implementation in 29 and 26 occurrences, respectively. The median time from the decision to give a bolus until it began infusing decreased by 169 seconds (p < 0.01). Nursing satisfaction increased from 19.3% pre- to 100% post implementation. Safety was assessed via barcode scanning compliance, which decreased by 1.4% for patients and 1% for medications, and smart pump limit overrides. The percentage of infusion pump bolus overrides increased as expected, with the majority (99%) of these exceeding soft maximum limits by less than two-fold. Central line entries were unaffected post implementation. To assess medication utilization, a total of 50 patients in each intervention group were selected for retrospective chart review. Daily fentanyl boluses increased from one to three (p = 0.021). However, midazolam infusion dose and fentanyl infusion duration decreased (p = 0.026 and p = 0.005, respectively). Medication utilization was otherwise unchanged post implementation (p > 0.05). Annualized cost avoidance was $124,160.

Conclusions:

Implementation of bolus medications from continuous infusion in PICUs significantly decreased time to begin a bolus dose and increased nursing satisfaction. The practice change also improved medication utilization without negatively impacting patient safety.
Igniting Innovation in Healthcare: A Novel Collaborative Multidisciplinary Approach in a PICU
Authors: Malakooti Marcelo R.
Published: April 2018

Generating innovation in the healthcare setting faces a number of challenges when compared with industry counterparts. More than ever, innovation occupies a critical element for healthcare organizations aspiring toward clinical, research and strategic excellence, although it may not exist as a priority due to a number of barriers. There are several strategies in other industries from which healthcare organizations can borrow, such as using nontraditional methods of problem solving, group ideation, and cross-pollination. As a high-intensity environment facing diverse challenges and conditions, the PICU is primed for building and generating innovation, which can be facilitated by implementing many of these strategies. This article describes an innovation program created to exercise a multidisciplinary approach for generating novel solutions in our PICU. Using nontraditional methods and ideation, this program has generated innovative solutions in an otherwise traditional setting, revealing new opportunities for growth, value generation, and collaboration between healthcare and the community.
Our Surgical Repair for Macrostomia with Two Novel Small Triangular Flaps: Long-Term Follow-Up and Results
Authors: Tsumoto Jumpei , Imai Keisuke , Masuoka Takeshi , Sakahara Daisuke , Kawamoto Koji , Kang Songsu , Komune Hiroyuki
Published: April 2018

The surgical methods for repairing congenital macrostomia should be carefully selected from both functional and aesthetic points of view. The surgical correction of macrostomia results in normal orbicularis oris function and symmetry of the repaired lip. In this article, the authors report their novel technique and the results obtained, assessed retrospectively. Twelve primary cases of macrostomia underwent surgical repair between 1996 and 2013. The age at surgery ranged from 3 to 78 months. The authors’ operative procedure uses two small triangular flaps with a superficial layer of orbicularis muscle to preserve the dynamic action of muscle fibers attached to the skin of the triangular flaps, with suturing across the orbicularis muscle bundles. The optimal length of a medial small triangular flap is 1.5 to 2.0 mm, and the length of a lateral flap is 5 to 8 mm. Evaluation was based on the degree of symmetry of the lips as a ratio of the affected side to the unaffected side, and the scar characteristics. The follow-up period in this retrospective study ranged from 3 to 21 years. The same method was applied to all 12 cases in the reconstruction of a natural appearance and dynamic function of the oral commissure, and the results over several years showed satisfactory outcomes. The authors’ technique is very useful in the primary surgery for macrostomia, as the dynamic action of muscle fibers is preserved, if the muscle is not dissected from the skin in the cleft margin that includes the two medial small triangular flaps.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, V.
Surgeon Volume and the Outcomes of Dupuytren’s Surgery: Results from a Dutch Multicenter Study
Authors: Zhou Chao , Ceyisakar Iris E. , Hovius Steven E. R. , Feitz Reinier , Slijper Harm P. , Lingsma Hester F. , Selles Ruud W.
Published: April 2018

Background:

For many major surgical procedures, the outcomes are better when performed by surgeons with higher procedure volumes. The purpose of this study was to examine the relations between surgeon procedure volume and the outcomes of Dupuytren’s surgery.

Methods:

The authors conducted an observational study from 2011 to 2014 at six dedicated hand surgery practice sites in The Netherlands. Five hundred eighty-eight patients underwent surgery for Dupuytren’s contracture performed by one of the 16 surgeons. The main exposure variable was annual surgeon volume. Outcome measures were the degree of residual contracture, full release rate, and any postoperative adverse event examined within 3 months of surgery.

Results:

Mean annual surgeon volume was 51 among the 16 surgeons(range; 4-86) procedures. The majority of patients had primary disease (79 percent) and underwent open fasciectomy (74 percent). Multivariable regression analyses showed that surgeon volume was linearly related to all three outcomes, and identified no optimal volume threshold. Performing 10 additional procedures annually was independently associated with nearly 0.8 degree less residual contracture (p = 0.002), 9 percent higher odds of attaining a full release (p = 0.037), and 11 percent lower odds of an adverse event (p < 0.001). Nonetheless, patient-related factors had larger impacts on all three clinical outcomes than surgeon volume.

Conclusions:

In this study of practicing hand surgeons, surgeon volume varied widely, and a higher volume was associated with less postoperative residual contracture, higher full release rates, and fewer adverse events. This implies that increasing surgeon’s procedure volume provides an opportunity for improving the outcomes of Dupuytren’s surgery.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Opportunistic Bone Density Measurement on Abdomen and Pelvis Computed Tomography to Predict Fracture Risk in Women Aged 50 to 64 Years Without Osteoporosis Risk Factors
Authors: Fang Jieming , Franconeri Andrea , Boos Johannes , Nimhuircheartaigh Jennifer , Zhang Zheng , Brook Alexander , Brook Olga R.
Published: April 2018

Objective

The aim of this study is to evaluate opportunistic vertebral bone density measurement in abdominal and pelvic computed tomography (CT) to predict future osteoporotic fracture in women aged 50 to 64 years without known osteoporosis risk factors.

Methods

Consecutive female patients 50 to 64 years old without osteoporosis risk factors with 2 CT examinations more than 10 years apart were included. Vertebral height and bone density in each vertebra from T10 to L5 were measured. Vertebral fractures were diagnosed on CT preformed 10 years after the original CT and through online medical records.

Results

Thirty (15%) of 199 patients developed osteoporotic fracture. Bone density was lower in patients who developed fractures compared with those who did not (P< 0.05). Development of osteoporotic fracture of any grade was predicted for patients having bone density less than 180 HU at L4 with sensitivity of 90% (95% confidence interval, 74%–97%) and specificity of 43% (95% confidence interval, 34%–50%).

Conclusions

Opportunistic bone density screening can identify women at elevated risk of developing fractures within 10 years.
Overall Disability Sum Score for Clinical Assessment of Neurological Involvement in Eosinophilic Granulomatosis With Polyangiitis
Authors: Padoan Roberto , Marconato Maddalena , Felicetti Mara , Cinetto Francesco , Cerchiaro Mariachiara , Rizzo Francesca , Marcolongo Renzo , Punzi Leonardo , Agostini Carlo , Schiavon Franco
Published: April 2018

Aim

The aim of this study was to verify the application of Overall Disability Sum Score (ODSS) for standardized clinical assessment of neurological involvement in patients with eosinophilic granulomatosis with polyangiitis (EGPA) and its correlation with treatment response and long-term outcomes.

Methods

Consecutive EGPA patients referred to our tertiary vasculitis center were retrospectively evaluated. Patients' neurological damage and disability were systematically assessed with Vasculitis Damage Index and ODSS.

Results

Fifty EGPA patients were included in the study with a median follow-up of 75 months (9–180 months). Twenty-five (50%) developed peripheral neuropathy, 17 (68%) presented mononeuritis multiplex, whereas 8 (32%) had symmetric polyneuropathy. Patients with neurological involvement were older (56.3 ± 13.4 vs. 44.4 ± 12.1 years,P< 0.0009), more frequently antineutrophil cytoplasmic antibody positive (48% vs. 16%,P= 0.015), and were more likely to have renal involvement (24% vs. 0%,P= 0.022). An early clinical response to therapy was observed within 6 months of treatment, resulting in a significant decrease in ODSS, which fell from the baseline value of 4.2 ± 2.4 to 2.9 ± 1.5 (P= 0.0001), whereas only a slow decreasing pattern was noted over the long-term period. However, all subjects developed neurological impairment and disability despite remission from active vasculitis. Patients with ODSS of greater than 3 at baseline (n = 13 [52%]) retained a higher score at the last examination (P< 0.001), predicting a low therapeutic response. Furthermore, ODSS of greater than 3 was found associated with more neurological relapses (53.8% vs. 0%,P= 0.027).

Conclusion

Overall Disability Sum Score could be a rapid, simple, reliable instrument to evaluate the severity of disability and nerve damage due to neurological involvement caused by vasculitis and to predict, at presentation, improvement and risk of neurological worsening.
Convergent evidence for predispositional effects of brain gray matter volume on alcohol consumption
Authors: Baranger David AA , Demers Catherine H. , Elsayed Nourhan M. , Knodt Annchen R. , Radtke Spenser R. , Desmarais Aline , Agrawal Arpana , Heath Andrew C. , Barch Deanna M. , Squeglia Lindsay M. , Williamson Douglas E. , Hariri Ahmad R. , Bogdan Ryan
Published: April 2018

Background

Alcohol use has been reliably associated with smaller subcortical and cortical regional gray matter volumes (GMVs). Whether these associations reflect shared predisposing risk factors and/or causal consequences of alcohol use remains poorly understood.

Methods

Data came from 3 neuroimaging samples (total n=2,423), spanning childhood/adolescence to middle age, with prospective or family-based data. First, we identified replicable GMV correlates of alcohol use. Next, we used family-based and longitudinal data to test whether these associations may plausibly reflect a predispositional liability for alcohol use, and/or a causal consequence of alcohol use. Finally, we evaluated whether GWAS-defined genomic risk for alcohol consumption is enriched for genes preferentially expressed in regions identified in our neuroimaging analyses, using heritability and gene-set enrichment, and transcriptome-wide association study (TWAS) approaches.

Results

Smaller right dorsolateral prefrontal cortex (DLPFC; i.e., middle and superior frontal gyri) and insula GMVs were associated with increased alcohol use across samples. Family-based and prospective longitudinal data suggest these associations are genetically conferred and that DLPFC GMV prospectively predicts future use and initiation. Genomic risk for alcohol use was enriched in gene-sets preferentially expressed in the DLPFC and associated with differential expression of C16orf93, CWF19L1, and C18orf8 in the DLPFC.

Conclusions

These data suggest that smaller DLPFC and insula GMV plausibly represent predispositional risk factors for, as opposed to consequences of, alcohol use. Alcohol use, particularly when heavy, may potentiate these predispositional risk factors. DLPFC and insula GMV represent promising biomarkers for alcohol consumption liability and related psychiatric and behavioral phenotypes.
Performance of an IAVI-African Network of Clinical Research Laboratories in Standardized ELISpot and Peripheral Blood Mononuclear Cell Processing in Support of HIV Vaccine Clinical Trials
Authors: Langat Robert , Farah Bashir , Indangasi Jackton , Ogola Simon , Omosa-Manyonyi Gloria , Anzala Omu , Bizimana Jean , Tekirya Emmanuel , Ngetsa Caroline , Silwamba Moses , Muyanja Enoch , Chetty Paramesh , Jangano Maureen , Hills Nancy , Gilmour Jill , Dally Len , Cox Josephine H. , Hayes Peter
Published: April 2018

Immunological assays performed in different laboratories participating in multi-centre clinical trials must be standardized in order to generate comparable and reliable data. This entails standardized procedures for sample collection, processing, freezing and storage. The International AIDS Vaccine Initiative (IAVI) partnered with local institutions to establish Good Clinical Laboratory Practice (GCLP)-accredited laboratories to support clinical trials in Africa, Europe and Asia. Here we report on the performance of seven laboratories based in Africa and Europe in the interferon-gamma enzyme-linked immunospot (IFN-γ ELISpot) assay and peripheral blood mononuclear cell (PBMC) processing over four years. Characterized frozen PBMC samples from 48 volunteer blood packs processed at a central laboratory were sent to participating laboratories. For each stimulus, there were 1751 assays performed over four years. 98% of these ELISpot data were within acceptable ranges with low responses to mock stimuli. There were no significant differences in ELISpot responses at five laboratories actively conducting immunological analyses in support of IAVI sponsored clinical trials or HIV research. In a separate study, 1,297 PBMC samples isolated from healthy HIV-1 negative participants in clinical trials of two prophylactic HIV vaccine candidates were analysed for PBMC yield from fresh blood and cell recovery and viability following freezing and thawing. 94 % and 96 % of samples had fresh PBMC viabilities and cell yields within the pre-defined acceptance criteria while for frozen PBMC, 99 % and 96 % of samples had acceptable viabilities and cell recoveries respectively, along with acceptable ELISpot responses in 95%. These findings demonstrate the competency of laboratories across different continents to generate comparable and reliable data in support of clinical trials.

Importance

There is a need for the establishment of an African network of laboratories to support large clinical trials across the continent to support and further the development of vaccine candidates against emerging infectious diseases such as Ebola, Zika and dengue viruses and the continued HIV-1 pandemic. This is particularly true in sub-Saharan Africa where the HIV-1 pandemic is most severe. In this report we have demonstrated by using standardized SOPs, training, equipment and reagents that GCLP-accredited clinical trial laboratories based in Africa and Europe can process clinical trial samples and maintain cell integrity and functionality demonstrated by IFN-γ ELISpot testing, producing comparable and reliable data.
Mice harboring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity.
Authors: Mancini Cecilia , Hoxha Eriola , Iommarini Luisa , Brussino Alessandro , Richter Uwe , Montarolo Francesca , Cagnoli Claudia , Parolisi Roberta , Gondor Morosini Diana Iulia , Nicolo Valentina , Maltecca Francesca , Muratori Luisa , Ronchi Giulia , Geuna Stefano , Arnaboldi Francesca , Donetti Elena , Giorgio Elisa , Cavalieri Simona , Di Gregorio Eleonora , Pozzi Elisa , Ferrero Marta , Riberi Evelise , Casari Giorgio , Altruda Fiorella , Turco Emilia , Gasparre Giuseppe , Battersby Brendan J , Porcelli Anna Maria , Ferrero Enza , Brusco Alfredo , Tempia Filippo
Published: April 2018

Spinocerebellar ataxia 28 is an autosomal dominant neurodegenerative disorder caused by missense mutations affecting the proteolytic domain of AFG3L2, a major component of the mitochondrial m-AAA protease. However, little is known of the underlying pathogenetic mechanisms or how to treat patients with SCA28. Currently available Afg3l2 mutant mice harbour deletions that lead to severe, early-onset neurological phenotypes that do not faithfully reproduce the late-onset and slowly progressing SCA28 phenotype. Here we describe production and detailed analysis of a new knock-in murine model harbouring an Afg3l2 allele carrying the p.Met665Arg patient-derived mutation. Heterozygous mutant mice developed normally but signs of ataxia were detectable by beam test at 18 months. Cerebellar pathology was negative; electrophysiological analysis showed increased spontaneous firing in Purkinje cells from heterozygous mutants with respect to wild-type controls, although not statistically significant. As homozygous mutants died perinatally with evidence of cardiac atrophy, for each genotype we generated mouse embryonic fibroblasts (MEFs) to investigate mitochondrial function. MEFs from mutant mice showed altered mitochondrial bioenergetics, with decreased basal oxygen consumption rate, ATP synthesis and mitochondrial membrane potential. Mitochondrial network formation and morphology was also altered, in line with greatly reduced expression of Opa1 fusogenic protein L-isoforms. The mitochondrial alterations observed in MEFs were also detected in cerebella of 18-month-old heterozygous mutants, suggesting they may be a hallmark of disease. Pharmacological inhibition of de novo mitochondrial protein translation with chloramphenicol caused reversal of mitochondrial morphology in homozygous mutant MEFs, supporting the relevance of mitochondrial proteotoxicity for SCA28 pathogenesis and therapy development.
Improvements to the rice genome annotation through large-scale analysis of RNA-Seq and proteomics datasets
Authors: Ren Zhe , Qi Da , Pugh Nina , Li Kai , Wen Bo , Zhou Ruo , Xu Shaohang , Liu Siqi , Jones Andrew R
Published: April 2018

Rice (Oryza sativa) is one of the most important worldwide crops. The genome has been available for over 10 years and has undergone several rounds of annotation. We created a comprehensive database of transcripts from 29 public RNA sequencing datasets, officially predicted genes from Ensembl plants, and common contaminants in which to search for protein-level evidence. We re-analysed nine publicly accessible rice proteomics datasets. In total, we identified 420K peptide spectrum matches from 47K peptides and 8,187 protein groups. 4168 peptides were initially classed as putative novel peptides (not matching official genes). Following a strict filtration scheme to rule out other possible explanations, we discovered 1,584 high confidence novel peptides. The novel peptides were clustered into 692 genomic loci where our results suggest annotation improvements. 80% of the novel peptides had an ortholog match in the curated protein sequence set from at least one other plant species. For the peptides clustering in intergenic regions (and thus potentially new genes), 101 loci were identified, for which 43 had a high-confidence hit for a protein domain. Our results can be displayed as tracks on the Ensembl genome or other browsers supporting Track Hubs, to support re-annotation of the rice genome.
The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleotide selectivity of PNPs
Authors: Torini Juliana Roberta , Romanello Larissa , Batista Fernanda Aparecida Heleno , Serrão Vitor Hugo Balasco , Faheem Muhammad , Zeraik Ana Eliza , Bird Louise , Nettleship Joanne , Reddivari Yamini , Owens Ray , DeMarco Ricardo , Borges Júlio César , Brandão-Neto José , Pereira Humberto D’Muniz
Published: April 2018

Purine nucleoside phosphorylases (PNPs) play an important role in the blood fluke parasite Schistosoma mansoni as a key enzyme of the purine salvage pathway. Here we present the structural and kinetic characterization of a new PNP isoform from S. mansoni, named as SmPNP2. Screening of different ligands using a thermofluorescence approach indicated cytidine and cytosine as potential ligands. The binding of cytosine was confirmed by isothermal titration calorimetry, with a KD of 27 μM, and kinetic parameters for cytidine catalysis were obtained by ITC resulting in a KM of 76.3 μM. SmPNP2 also displays catalytic activity against inosine and adenosine, making it the first described PNP with robust catalytic activity towards both pyrimidines and purines. Crystallographic structures of SmPNP2 with different ligands were obtained and comparison of these structures with the previously described S. mansoni PNP (SmPNP1) provided clues for the unique capability of SmPNP2 to bind pyrimidines. When compared with the structure of SmPNP1, substitutions in the vicinity of SmPNP2 active site alter the architecture of the nucleoside base binding site allowing an alternative binding mode for nucleosides, with a 180° rotation from the canonical binding mode. The remarkable plasticity of this binding site deepens the understanding of the correlation between structure and nucleotide selectivity, offering new ways to analyses PNP activity.

Author Summary

Schistosoma mansoni is a human parasite dependent on purine salvage for purine bases supply. Purine nucleoside phosphorylase (PNP) is a key enzyme in this pathway. It carries two PNP isoforms, one previously characterized (SmPNP1) and one unknown (SmPNP2). Here we present the crystallographic structure of SmPNP2 and its complex with cytosine, cytidine, ribose-l-phosphate, adenine, hypoxanthine, and tubercidin. Cytidine and cytosine were identified as ligands of SmPNP2 using a thermofluorescence approach. Binding of cytosine was proven by Isothermal Titration Calorimetry (ITC) and cytidine, inosine, and adenosine kinetic parameters were also obtained. Purine bases showed different binding in the active site, rotated 180° from the canonical binding mode. It’s the first report showing a Low Molecular Mass PNP capable of catalyzing both types of nucleotide bases. The SmPNP2 odd behavior sheds a new light on the Schistosoma mansoni’s life cycle metabolic adaptation.
Design of Transcranial Magnetic Stimulation Coils with Optimal Trade-off between Depth, Focality, and Energy
Authors: Gomez Luis J. , Goetz Stefan M. , Peterchev Angel V.
Published: April 2018

Background

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique used for research and clinical applications. Existent TMS coils are limited in their precision of spatial targeting (focality), especially for deeper targets.

Objective

This paper presents a methodology for designing TMS coils to achieve optimal trade-off between the depth and focality of the induced electric field (E-field), as well as the energy required by the coil.

Methods

A multi-objective optimization technique is used for computationally designing TMS coils that achieve optimal trade-offs between stimulation focality, depth, and energy (fdTMS coils). The fdTMS coil winding(s) maximize focality (minimize stimulated volume) while reaching a target at a specified depth and not exceeding predefined peak E-field strength and required coil energy. Spherical and MRI-derived head models are used to compute the fundamental depth–focality trade-off as well as focality–energy trade-offs for specific target depths.

Results

Across stimulation target depths of 1.0–3.4 cm from the brain surface, the stimulated volume can be theoretically decreased by 42%–55% compared to existing TMS coil designs. The stimulated volume of a figure-8 coil can be decreased by 36%, 44%, or 46%, for matched, doubled, or quadrupled energy. For matched focality and energy, the depth of a figure-8 coil can be increased by 22%.

Conclusion

Computational design of TMS coils could enable more selective targeting of the induced E-field. The presented results appear to be the first significant advancement in the depth–focality trade-off of TMS coils since the introduction of the figure-8 coil three decades ago, and likely represent the fundamental physical limit.

DECLARATION OF INTEREST

The fdTMS technology described in this paper is subject to a provisional patent application by Duke University with the authors as inventors. Additionally: L.J.G. is inventor on a patent pertaining to the design of focal multicoil TMS systems. S.M.G. is inventor on patents and patent applications; he has received royalties from Rogue Research, TU Muenchen, and Porsche; furthermore, he has been provided with research support and patent fee reimbursement from Magstim Co. A.V.P. is inventor on patents and patent applications, and has received research and travel support as well as patent royalties from Rogue Research; research and travel support, consulting fees, as well as equipment loan from Tal Medical / Neurex; patent application and research support from Magstim; and equipment loans from MagVenture, all related to technology for transcranial magnetic stimulation.
Fresh Snowfall Microbiology and Chemistry are Driven by Geography in Storm-Tracked Events
Authors: A. S. Honeyman , M.L. Day , J.R. Spear
Published: April 2018

Snowfall is a global phenomenon highly integrated with hydrology and ecology. Forays into studying bioaerosols and their dependence on aeolian movement are largely constrained to either precipitation-independent analyses orin-silicomodels. Though snowpack and glacial microbiological studies have been conducted, little is known about the biological component of meteoric snow. Through culture-independent phylogenetic and geochemical analyses, we show that the geographical location at which snow precipitates determines snowfall’s geochemical and microbiological composition. Storm-tracking, furthermore, can be used as a valuable environmental indicator to trace down what factors are influencing bioaerosols. We estimate annual deposits of up to ~10 kg of bacterial / archaeal biomass per hectare along our study area of the eastern Front Range in Colorado. The dominant kinds of microbiota captured in an analysis of seven snow events at two different locations, one urban, one rural, across the winter of 2016/2017 included phylaProteobacteria,Bacteroidetes,FirmicutesandAcidobacteria, though a multitude of different kinds of organisms were found in both. Taxonomically,Bacteroideteswere more abundant in Golden (urban plain) snow whileProteobacteriawere more common in Sunshine (rural mountain) samples. Chemically, Golden snowfall was positively correlated with some metals and anions. The work also hints at better informing the ‘everything is everywhere’ hypotheses of the microbial world and that atmospheric transport of microbiota is not only common, but is capable of disseminating vast amounts of microbiota of different physiologies and genetics that then affect ecosystems globally. Snowfall, we conclude, is a significant repository of microbiological material with strong implications for both ecosystem genetic flux and general bio-aerosol theory.

Importance

Snowfall is commonplace to the temperate and polar regions of the world. As an interface between the atmosphere, hydrosphere and earth, snow is responsible for high annual deposits of moisture globally, and, can serve as a ‘water bank’ in the form of both permanent snow fields and glaciers. Essential to general ecosystem function, snow can also be considered a transporter of aerosolized material. Given the magnitude of microbiota deposited by snowfall, which we report, it is likely that biological material within snowfall, with its geochemical underpinning— and the associated genetic banks—have significant downstream ecological effects.

Understanding what is contained in snowfall becomes especially urgent in a warming climate where high-impact meteorological and ecological changes are imminent and likely. With climate-induced changes to snowfall patterns, surface ecosystems are likely to be impacted by ensuing changes in microbiota deposition. Thus, the ecosystem function of soils, rock and surface waters are also likely to be impacted; these changes, in turn, greatly influence agriculture, weathering and infrastructure.
Optimum Search Schemes for Approximate String Matching Using Bidirectional FM-Index
Authors: Kianfar Kiavash , Pockrandt Christopher , Torkamandi Bahman , Luo Haochen , Reinert Knut
Published: April 2018

Finding approximate occurrences of a pattern in a text using a full-text index is a central problem in bioinformatics and has been extensively researched. Bidirectional indices have opened new possibilities in this regard allowing the search to start from anywhere within the pattern and extend in both directions. In particular, use of search schemes (partitioning the pattern and searching the pieces in certain orders with given bounds on errors) can yield significant speed-ups. However, finding optimal search schemes is a difficult combinatorial optimization problem.

Here for the first time, we propose a mixed integer program (MIP) capable to solve this optimization problem for Hamming distance with given number of pieces. Our experiments show that the optimal search schemes found by our MIP significantly improve the performance of search in bidirectional FM-index upon previous ad-hoc solutions. For example, approximate matching of 101-bp Illumina reads (with two errors) becomes 35 times faster than standard backtracking. Moreover, despite being performed purely in the index, the running time of search using our optimal schemes (for up to two errors) is comparable to the best state-of-the-art aligners, which benefit from combining search in index with in-text verification using dynamic programming. As a result, we anticipate a full-fledged aligner that employs an intelligent combination of search in the bidirectional FM-index using our optimal search schemes and in-text verification using dynamic programming that will outperform today’s best aligners. The development of such an aligner, called FAMOUS (Fast Approximate string Matching using OptimUm search Schemes), is ongoing as our future work.
Trypanosomes have divergent kinesin-2 proteins that function differentially in IFT, cell division, and motility
Authors: Douglas Robert L. , Haltiwanger Brett M. , Wu Haiming , Jeng Robert L. , Mancuso Joel , Cande W. Zacheus , Welch Matthew D.
Published: April 2018

Trypanosoma brucei, the causative agent of African sleeping sickness, has a flagellum that is crucial for motility, pathogenicity, and viability. In most eukaryotes, the intraflagellar transport (IFT) machinery drives flagellum biogenesis, and anterograde IFT requires kinesin-2 motor proteins. In this study, we investigated the function of the twoT. bruceikinesin-2 proteins, TbKin2a and TbKin2b, in bloodstream form trypanosomes. We found that compared to other kinesin-2 proteins, TbKin2a and TbKin2b show greater variation in neck, stalk, and tail domain sequences. Both kinesins contributed additively to flagellar lengthening. Surprisingly, silencing TbKin2a inhibited cell proliferation, cytokinesis and motility, whereas silencing TbKin2b did not. TbKin2a was localized on the flagellum and colocalized with IFT components near the basal body, consistent with it performing a role in IFT. TbKin2a was also detected on the flagellar attachment zone, a specialized structure in trypanosome cells that connects the flagellum to the cell body. Our results indicate that kinesin-2 proteins in trypanosomes play conserved roles in IFT and exhibit a specialized localization, emphasizing the evolutionary flexibility of motor protein function in an organism with a large complement of kinesins.
New capabilities in high-resolution neutron Larmor diffraction at ORNL
Authors: Li Fankang , Feng Hao , Thaler Alexander N. , Parnell Steven R. , Crow Lowell , Matsuda Masaaki , Ye Feng , Kimura Tsuyoshi , Fernandez-Baca Jaime A. , Pynn Roger
Published: April 2018

Using superconducting magnetic Wollaston prisms, high-resolution neutron Larmor diffraction has been implemented at the High-Flux Isotope Reactor of Oak Ridge National Laboratory (ORNL), Tennesse, USA. This technique allows the inverse relationship between the achievable diffraction resolution and the usable neutron flux to be overcome. Instead of employing physically tilted radio-frequency spin flippers, the method uses magnetic Wollaston prisms which are electromagnetically tuned by changing the field configurations in the device. As implemented, this method can be used to measure lattice-spacing changes induced, for example, by thermal expansion or strain with a resolution of Δd/d ≃ 10−6, and the splitting of sharp Bragg peaks with a resolution of Δd/d = 3 × 10−4. The resolution for discerning a change in the profile of a Bragg peak is Δd/d < 10−5. This is a remarkable degree of precision for a neutron diffractometer as compact as the one used in this implementation. Higher precision could be obtained by implementing this technique in an instrument with a larger footprint. The availability of this technique will provide an alternative when standard neutron diffraction methods fail and will greatly benefit the scientific communities that require high-resolution diffraction measurements.
Toward improved LCC-informed decisions in building management
Authors: Salvado Filipa , Almeida Nuno Marques de , Vale e Azevedo Alvaro
Published: April 2018

Purpose

Stakeholders of the Architecture, Engineering and Construction (AEC) sector require information on the buildings economic performance throughout its life cycle. This information is neither readily available nor always accurate because building management (BM) professionals still face difficulties to fully incorporate the life cycle cost (LCC) concept into their daily practice. The purpose of this paper is to identify and contribute to solving these difficulties.

Design/methodology/approach

This paper provides a background knowledge review and set the ground for a structured research roadmap and a management framework that highlight the links and limitations to be addressed within and between LCC and BM. A six-stage method was used for developing conceptual frameworks targeting six goals: establishing a point of departure; mapping sources of information; literature research; notion deconstruction and conceptual categorization; overview of the applicable background knowledge; and structuring of a framework for LCC-informed decisions in BM.

Findings

Management solutions for the built context are necessarily connected with LCC and BM current concepts such as asset management, project, program and portfolio management, facility management and data management. These management approaches highlight the importance of incorporating life cycle concepts and promote LCC effective application within the AEC sector.

Originality/value

This paper identifies and discusses current limitations on the information availability for the economic performance of buildings throughout its life cycle. This work also identifies LCC-related topics that need to be further explored or addressed by both the scientific community and practitioners to overcome these limitations and facilitate the integration of the LCC concept into BM activities.
A cluster analysis of tourist attractions in Spain
Authors: Lascu Dana-Nicoleta , Manrai Lalita A. , Manrai Ajay K. , Gan Allison
Published: April 2018

Purpose

Natural and cultural tourism are important motivators for international tourism. Spain has impressive tourist attractions that are outstanding on the natural and cultural tourism dimensions. The purpose of this paper is to identify traits of the most attractive destinations in Spain and to understand the relative importance of natural, cultural, and dual (natural and cultural) attractions to target consumers.

Design/methodology/approach

The authors compare the level of tourism in the 17 major regions of Spain and identify the key natural, cultural, and dual attractions using a two-step cluster analysis to ascertain the relative importance of the three types of attractions.

Findings

The findings of the cluster analysis suggest that natural attractions had the highest importance, followed by dual attractions, with cultural attractions having the lowest importance in affecting the level of tourism in a region. The study identified four categories of regions resulting from “high vs low” total number of attractions by “high vs low” levels of tourism (operationalized via the number of tourist-nights). The regions with high levels of tourism were either located in the bodies of water (a group of islands) or on ocean/sea(s) surrounding Spain. The study suggests placing greater emphasis on promoting cultural attractions in Spain.

Practical implications

The findings suggest that there is a need to put more emphasis on promoting the cultural attractions in Spain. Spain is a diverse country with huge potential for tourism from people all over the world, due to its diverse geography and rich history.

Originality/value

To the best of the authors’ knowledge, this is the first study that analyzes 17 regions of Spain in relation to their tourism characteristics, identifying attractions that are not sufficiently leveraged, and suggesting strategies for identifying opportunities for the tourism industry in Spain.