bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8
Authors: Berenguer Jordi , Lagerweij Tonny , Zhao Xi Wen , Dusoswa Sophie , van der Stoop Petra , Westerman Bart , de Gooijer Mark C. , Zoetemelk Marloes , Zomer Anoek , Crommentuijn Matheus H. W. , Wedekind Laurine E. , López‐López Àlan , Giovanazzi Alberta , Bruch‐Oms Marina , van der Meulen‐Muileman Ida H. , Reijmers Rogier M. , van Kuppevelt Toin H. , García‐Vallejo Juan‐Jesús , van Kooyk Yvette , Tannous Bakhos A. , Wesseling Pieter , Koppers‐Lalic Danijela , Vandertop W. Peter , Noske David P. , van Beusechem Victor W. , van Rheenen Jacco , Pegtel D. Michiel , van Tellingen Olaf , Wurdinger Thomas
Published: March 2018

Cancer cells release extracellular vesicles (EVs) that contain functional biomolecules such as RNA and proteins. EVs are transferred to recipient cancer cells and can promote tumour progression and therapy resistance. Through RNAi screening, we identified a novel EV uptake mechanism involving a triple interaction between the chemokine receptor CCR8 on the cells, glycans exposed on EVs and the soluble ligand CCL18. This ligand acts as bridging molecule, connecting EVs to cancer cells. We show that glioblastoma EVs promote cell proliferation and resistance to the alkylating agent temozolomide (TMZ). Using in vitro and in vivo stem‐like glioblastoma models, we demonstrate that EV‐induced phenotypes are neutralised by a small molecule CCR8 inhibitor, R243. Interference with chemokine receptors may offer therapeutic opportunities against EV‐mediated cross‐talk in glioblastoma.
Genome-scale metabolic modeling of responses to polymyxins in Pseudomonas aeruginosa
Authors: Zhu Yan , Czauderna Tobias , Zhao Jinxin , Klapperstueck Matthias , Maifiah Mohd Hafidz Mahamad , Han Mei-Ling , Lu Jing , Sommer Björn , Velkov Tony , Lithgow Trevor , Song Jiangning , Schreiber Falk , Li Jian
Published: March 2018

Background

Pseudomonas aeruginosa often causes multidrug-resistant infections in immunocompromised patients, and polymyxins are often used as the last-line therapy. Alarmingly, resistance to polymyxins has been increasingly reported worldwide recently. To rescue this last-resort class of antibiotics, it is necessary to systematically understand how P. aeruginosa alters its metabolism in response to polymyxin treatment, thereby facilitating the development of effective therapies. To this end, a genome-scale metabolic model (GSMM) was used to analyze bacterial metabolic changes at the systems level.

Findings

A high-quality GSMM iPAO1 was constructed for P. aeruginosa PAO1 for antimicrobial pharmacological research. Model iPAO1 encompasses an additional periplasmic compartment and contains 3022 metabolites, 4265 reactions, and 1458 genes in total. Growth prediction on 190 carbon and 95 nitrogen sources achieved an accuracy of 89.1%, outperforming all reported P. aeruginosa models. Notably, prediction of the essential genes for growth achieved a high accuracy of 87.9%. Metabolic simulation showed that lipid A modifications associated with polymyxin resistance exert a limited impact on bacterial growth and metabolism but remarkably change the physiochemical properties of the outer membrane. Modeling with transcriptomics constraints revealed a broad range of metabolic responses to polymyxin treatment, including reduced biomass synthesis, upregulated amino acid catabolism, induced flux through the tricarboxylic acid cycle, and increased redox turnover.

Conclusions

Overall, iPAO1 represents the most comprehensive GSMM constructed to date for Pseudomonas. It provides a powerful systems pharmacology platform for the elucidation of complex killing mechanisms of antibiotics.
Differential protein expression and post-translational modifications in metronidazole-resistant Giardia duodenalis
Authors: Emery Samantha J , Baker Louise , Ansell Brendan R E , Mirzaei Mehdi , Haynes Paul A , McConville Malcom J , Svärd Staffan G , Jex Aaron R
Published: March 2018

Background

Metronidazole (Mtz) is the frontline drug treatment for multiple anaerobic pathogens, including the gastrointestinal protist, Giardia duodenalis. However, treatment failure is common and linked to in vivo drug resistance. In Giardia, in vitro drug-resistant lines allow controlled experimental interrogation of resistance mechanisms in isogenic cultures. However, resistance-associated changes are inconsistent between lines, phenotypic data are incomplete, and resistance is rarely genetically fixed, highlighted by reversion to sensitivity after drug selection ceases or via passage through the life cycle. Comprehensive quantitative approaches are required to resolve isolate variability, fully define Mtz resistance phenotypes, and explore the role of post-translational modifications therein.

Findings

We performed quantitative proteomics to describe differentially expressed proteins in 3 seminal Mtz-resistant lines compared to their isogenic, Mtz-susceptible, parental line. We also probed changes in post-translational modifications including protein acetylation, methylation, ubiquitination, and phosphorylation via immunoblotting. We quantified more than 1,000 proteins in each genotype, recording substantial genotypic variation in differentially expressed proteins between isotypes. Our data confirm substantial changes in the antioxidant network, glycolysis, and electron transport and indicate links between protein acetylation and Mtz resistance, including cross-resistance to deacetylase inhibitor trichostatin A in Mtz-resistant lines. Finally, we performed the first controlled, longitudinal study of Mtz resistance stability, monitoring lines after cessation of drug selection, revealing isolate-dependent phenotypic plasticity.

Conclusions

Our data demonstrate understanding that Mtz resistance must be broadened to post-transcriptional and post-translational responses and that Mtz resistance is polygenic, driven by isolate-dependent variation, and is correlated with changes in protein acetylation networks.
Characteristics of Combat-Associated Small Bowel Injuries
Authors: Skube Mariya E , Mallery Quinn , Lusczek Elizabeth , Elterman Joel , Spott Mary A , Beilman Greg J
Published: March 2018

Introduction

Although there are multiple studies regarding the management and outcomes of colonic injuries incurred in combat, the literature is limited with regard to small bowel injuries. This study seeks to provide the largest reported review of the characteristics of combat-associated small bowel injuries.

Materials and Methods

The Department of Defense Trauma Registry was queried for U.S. Armed Forces members who sustained hollow viscus injuries in the years 2007–2012 during Operations Enduring Freedom, Iraqi Freedom, and New Dawn. Concomitant injuries, procedures, and complications were delineated. Fisher’s exact test was used to analyze the relationship of bowel injury pattern to rates of repeat laparotomy, fecal diversion, and complications.

Results

One hundred seventy-one service members had small bowel injuries. The mean age was 25.8 ± 6.6 yr with a mean injury severity score of 27.9 ± 12.4. The majority of injuries were penetrating (94.2%, n = 161) as a result of explosive devices (61.4%, n = 105). The median blood transfusion requirement in the first 24 h was 6.0 units (interquartile range 1.0–17.3 units). The most frequent concomitant injuries were large bowel (64.3%, n = 110), pelvic fracture (35.7%, n = 61), and perineal (26.3%, n = 45). Fifty patients (29.2%) had a colostomy, and nine patients (5.3%) had an ileostomy; 62.6% (n = 107) of soldiers underwent more than one laparotomy. The mortality rate was 1.8% (n = 3). The most common complications were pneumonia (15.2%, n = 26), deep vein thrombosis (14.6%, n = 25), and wound infection (14.6%, n = 25). The need for repeat laparotomy and fecal diversion was found to be significantly associated with injury pattern (p = 0.00052 and p < 0.0001, respectively).

Conclusion

We found that two-thirds of service members with small bowel injuries also had a large bowel injury. One-third of the patients required diversion and two-thirds had more than one laparotomy. The pattern of bowel injury significantly affected the need for repeat laparotomy and fecal diversion.
A Spatial Analysis of the Potato Cyst NematodeGlobodera pallidain Idaho
Authors: Contina J. B. , Dandurand L. M. , Knudsen G. R.
Published: March 2018

The potato cyst nematode Globodera pallida is a globally regulated and quarantine potato pest. It was detected for the first time in the United States in the state of Idaho in 2006. A spatial analysis was performed to (i) understand the spatial arrangement of fields infested with G. pallida in southern Idaho using spatial point pattern analysis, and (ii) evaluate the potential threat of G. pallida for entry to new areas using spatial interpolation techniques. Data point locations, cyst numbers and egg viability values for each infested field were collected by USDA-APHIS during 2006 to 2014. Results showed the presence of spatially clustered fields infested with G. pallida (P = 0.003). We determined that the spread of G. pallida grew in diameter from the original center of infestation toward the southwest as an ellipsoidal-shaped cluster. Based on the aggregated spatial pattern of distribution, we determined that G. pallida spread followed a contagion effect scenario, where nearby infested fields contributed to the infestation of new fields, probably through soil contaminated agricultural equipment or tubers. We determined that the presence of G. pallida in southern Idaho is unlikely to be associated with new introductions from outside the state of Idaho. The aggregation pattern of fields infested with G. pallida, with an average of 4,263 cysts/ha and egg viability of 25%, facilitates quarantine activities and confines the propagation of this pest to a small area, which in 2017 was estimated to be 1,233 ha. The tools and methods provided in this study facilitate comprehensive approaches to improve G. pallida control and eradication programs as well as to raise public awareness of the problems surrounding this economically important potato pest.
Multiple hit infection and autoimmunity: the dysbiotic microbiota–ACPA connection in rheumatoid arthritis
Authors: Sakkas Lazaros I. , Bogdanos Dimitrios P.
Published: March 2018

Purpose of review

This review highlights the most recent data obtained in this field and provides clues toward the better understanding of the close interplay between microbiota and host, leading to autoimmune diseases.

Recent findings

A well-described model of microbiota/host interaction of relevance to autoimmunity is linking anti-citrullinated peptide antibody positive rheumatoid arthritis and alterations of microbiota largely concentrating on Porphyromonas gingivalis and more recently of Aggregatibacter actinomycetemcomitans and Prevotella copri.

The perception of the classical link between microbial infection and development of autoimmune disease has evolved to the more recent concept of the connection between the microbiome/dysbiosis and breaking of immunological tolerance.
Fecal transplants in spondyloarthritis and uveitis: ready for a clinical trial?
Authors: Choi Rene Y. , Asquith Mark , Rosenbaum James T.
Published: March 2018

Purpose of review

The intestinal microbiome is thought to play a role in the pathogenesis of inflammatory bowel disease (IBD). There are many shared clinical manifestations between IBD and spondyloarthritis (SpA), of which the most common are peripheral arthritis and uveitis. Clinical overlap along with similar genetics between these diseases suggests a possible shared pathogenetic mechanism, which might center on the intestinal microbiota. In this review, we discuss the available evidence that SpA is a microbiome-driven disease and indicate how SpA-associated uveitis could be tied to gut dysbiosis. We conclude by discussing different treatment paradigms targeting the intestinal microbiome for SpA.

Recent findings

Recent studies support the growing evidence of the intestinal microbiome as a crucial player in SpA disease pathogenesis. There is emerging evidence that the gut microbiome may play a causative role in uveitis.

The field is beginning to discover a new level of understanding how the intestinal microbiome is involved in SpA. Treatment methods to alter intestinal microbiota to treat SpA-related diseases are still in its infancy.
Has the Proportion of Combat-Related Amputations That Develop Heterotopic Ossification Increased?
Authors: Daniels Christopher M. , Pavey Gabriel J. , Arthur Jacob , Noller Michael , Forsberg Jonathan A. , Potter Benjamin K.
Published: March 2018

Objectives:

To determine what proportion of residual limbs formed heterotopic ossification (HO) in amputations sustained by US service members, the injury profile of these amputations, and what effect the number of limb amputations sustained has on resource utilization.

Design:

Retrospective review.

Setting:

A tertiary military medical center.

Patients:

Four-hundred seventy-one consecutive patients with 714 combat-related amputations were treated at our institution between September 2009 and August 2014. Four-hundred thirty-nine amputations had radiographic follow-up beyond 2 months of injury and met the criteria for study inclusion.

Main Outcome Measure:

Formation and grade of HO.

Results:

HO was present in 399 of 439 (91%) residual limbs, including 211 of 216 (98%) transfemoral amputations. Dismounted improvised explosive device blast injury resulted in HO development in 346 of 372 (93%) residual limbs compared with 36 of 44 (82%) in mounted improvised explosive device blast injury [P = 0.014; odds ratio (OR) 2.96, 95% confidence interval (CI), 1.25–7.04]. As the number of amputations per patient increased, so too did blood product utilization [including packed red blood cells (P < 0.001), fresh frozen plasma (P < 0.001), and platelets (P < 0.001)]; the number of days on a ventilator (P < 0.001), in the intensive care unit (P < 0.001), and in the hospital (P = 0.007).

Conclusions:

HO prevalence in the traumatic amputations of war wounded has increased compared with earlier studies, which is temporally associated with higher rates of increasingly severe injuries due to dismounted blast.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Phenotyping Cardiac Arrest: Bench and Bedside Characterization of Brain and Heart Injury Based on Etiology
Authors: Uray Thomas , Lamade Andrew , Elmer Jonathan , Drabek Tomas , Stezoski Jason P. , Missé Amalea , Janesko-Feldman Keri , Garman Robert H. , Chen Niel , Kochanek Patrick M. , Dezfulian Cameron
Published: March 2018

Objectives:

Cardiac arrest etiology may be an important source of between-patient heterogeneity, but the impact of etiology on organ injury is unknown. We tested the hypothesis that asphyxial cardiac arrest results in greater neurologic injury than cardiac etiology cardiac arrest (ventricular fibrillation cardiac arrest), whereas ventricular fibrillation cardiac arrest results in greater cardiovascular dysfunction after return of spontaneous circulation.

Design:

Prospective observational human and randomized animal study.

Setting:

University laboratory and ICUs.

Patients:

Five-hundred forty-three cardiac arrest patients admitted to ICU.

Subjects:

Seventy-five male Sprague-Dawley rats.

Interventions:

We examined neurologic and cardiovascular injury in Isoflurane-anesthetized rat cardiac arrest models matched by ischemic time. Hemodynamic and neurologic outcomes were assessed after 5 minutes no flow asphyxial cardiac arrest or ventricular fibrillation cardiac arrest. Comparison was made to injury patterns observed after human asphyxial cardiac arrest or ventricular fibrillation cardiac arrest.

Measurements and Main Results:

In rats, cardiac output (20 ± 10 vs 45 ± 9 mL/min) and pH were lower and lactate higher (9.5 ± 1.0 vs 6.4 ± 1.3 mmol/L) after return of spontaneous circulation from ventricular fibrillation cardiac arrest versus asphyxial cardiac arrest (all p < 0.01). Asphyxial cardiac arrest resulted in greater early neurologic deficits, 7-day neuronal loss, and reduced freezing time (memory) after conditioned fear (all p < 0.05). Brain antioxidant reserves were more depleted following asphyxial cardiac arrest. In adjusted analyses, human ventricular fibrillation cardiac arrest was associated with greater cardiovascular injury based on peak troponin (7.8 ng/mL [0.8–57 ng/mL] vs 0.3 ng/mL [0.0–1.5 ng/mL]) and ejection fraction by echocardiography (20% vs 55%; all p < 0.0001), whereas asphyxial cardiac arrest was associated with worse early neurologic injury and poor functional outcome at hospital discharge (n = 46 [18%] vs 102 [44%]; p < 0.0001). Most ventricular fibrillation cardiac arrest deaths (54%) were the result of cardiovascular instability, whereas most asphyxial cardiac arrest deaths (75%) resulted from neurologic injury (p < 0.0001).

Conclusions:

In transcending rat and human studies, we find a consistent phenotype of heart and brain injury after cardiac arrest based on etiology: ventricular fibrillation cardiac arrest produces worse cardiovascular dysfunction, whereas asphyxial cardiac arrest produces worsened neurologic injury associated with greater oxidative stress.
Parkin Mediates Mitophagy to Participate in Cardioprotection Induced by Late Exercise Preconditioning but Bnip3 Does Not
Authors: Yuan Yang , Pan Shan-Shan
Published: March 2018

Background:

Late exercise preconditioning (LEP) is confirmed to have a protective effect on acute cardiovascular stress. However, the mechanisms by which mitophagy participates in exercise preconditioning (EP)-induced cardioprotection remain unclear. LEP may involve mitophagy mediated by the receptors PARK2 gene–encoded E3 ubiquitin ligase (Parkin) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) to scavenge damaged mitochondria.

Methods:

Our EP protocol involved four 10-minute periods of running, separated by 10-minute recovery intervals, plus a period of exhaustive running at 24 hours after EP. We assessed this late protective effect by injection of the autophagy inhibitor wortmannin, transmission electron microscopy, laser scanning confocal microscopy, and other molecular biotechnology methods; we simultaneously detected related markers, analyzed the specific relationships between mitophagy proteins, and assessed mitochondrial translocation.

Results:

Exhaustive exercise (EE) causes serious injuries to cardiomyofibrils, inducing hypoxia–ischemia and changing the ultrastructure. EE fails to clear excessively generated mitochondria to link with LC3 accumulation. After EP, increased autophagy levels at 30 minutes were converted to mitophagy within 24 hours. We found that LEP significantly suppressed EE-induced injuries, which we confirmed by observing decreased levels of the mitochondria-localized proteins COX4/1 and TOM20. LEP to exhaustion caused mitochondrial degradation by increasing the efficiency of LC3–outer mitochondrial membrane translocation in a Parkin-mediated manner, in which activated protein kinase and TOM70 may play both key roles. However, we did not observe mitophagy to be associated with Bnip3 mediation in LEP-induced cardioprotection. However, Bnip3 may play a role in inducing mitochondrial LC3-II increases. Wortmannin had no effect on LC3 translocation; instead, it influenced LC3-I to convert to LC3-II. Thus, suppressing mitophagy led to the attenuation of EP-induced cardioprotection.
Effects of dietary and exercise intervention on weight loss and body composition in obese postmenopausal women: a systematic review and meta-analysis
Authors: Cheng Chao-Chun , Hsu Ching-Yun , Liu Jen-Fang
Published: March 2018

Objective:

This study examined the effects of dietary and exercise interventions on weight loss and body composition in overweight/obese peri- and postmenopausal women.

Methods:

Medline, Central, Embase, and Google Scholar databases were searched for relevant trials conducted until December 31, 2016. Randomized controlled trials (RCTs) and prospective studies of overweight/obese peri- or postmenopausal women that examined the effects of dietary or exercise interventions, alone or combined, on weight loss were included. The primary outcome was percentage reduction in body weight.

Results:

From 292 studies initially identified, 11 studies with 12 sets of participants were included. Both dietary and exercise intervention groups had significantly greater weight loss than control groups (diet vs control: difference in means = −6.55, 95% CI, −9.51 to −3.59, P < 0.001; exercise vs control: difference in means = −3.49, 95% CI, −6.96 to −0.02, P = 0.049). Combined dietary and exercise interventions resulted in greater weight loss than dietary interventions alone (diet plus exercise vs diet: difference in means = −1.22, 95% CI, −2.14 to −0.29, P = 0.010). Diet plus exercise resulted in greater fat loss (difference in means = −0.44, 95% CI, −0.67 to −0.20, P < 0.001) and greater lean mass loss (difference in means = −0.84, 95% CI, −1.13 to −0.55, P < 0.001) than diet alone.

Conclusions:

Dietary interventions reduced body weight and body composition profile parameters in peri- and postmenopausal women more than exercise alone. The addition of exercise reinforced the effect of dietary interventions on changing body weight and composition.
Improvement of Symptoms after Lymphaticovenous Anastomosis in Patients with Abdominal Wall Lymphedema
Authors: Ewalds Lotte , Cornelissen Anouk J. M. , van der Hulst René R. W. J. , Qiu Shan S.
Published: March 2018

At our institution, we performed a lymphaticovenous anastomosis in patients with primary or secondary abdominal lymphedema. Patients report good outcomes and feel relieved of their complaints. To obtain good results, it is important to have decent knowledge on the anatomical state of the lymphatic system. In general, the lymphatic system of the lower abdomen can be compared with the system of the upper legs. According to our current case results, the abdominal area might be susceptible to lymphaticovenous anastomosis procedure. Further research should be performed to confirm the effect of the intervention and the imaging techniques to monitor the improvements.
Can Fat-plug Myringoplasty Be a Good Alternative to Formal Myringoplasty? A Systematic Review and Meta-analysis
Authors: Lee Doh Young , Kim Young Ho
Published: March 2018

Objective:

This study reviewed available literature to evaluate the success rate of fat myringoplasty compared with methods using other graft materials and suggests proper indications for this procedure.

Data Sources:

Studies reporting the success rate of fat myringoplasty were systematically reviewed by searching the MEDLINE, PubMed, and Embase databases for studies published from database inception to 2017.

Study Selection:

The following terms were used for the literature search: (“Fat” OR “Adipose”) and (“Myringoplasty” OR “Tympanoplasty”).

Data Extraction:

Eight case series reported the data of perforation size and audiologic results. The success rate varied according to the perforation size with a cutoff value of 3 to 5 mm in length or 30% of the total tympanic membrane area. The success rate in anterior perforation was lower than that in other sites, ranging from 76.7 and 85.2% to 84.5 and 91.7%, respectively. The meta-analysis was performed on 10 articles. The overall success rate in fat myringoplasty and paper patch technique was not significantly different, while the success rate of fat myringoplasty was lower than that for the conventional myringoplasty technique using fascia or perichondrium (OR 0.63, 95% CI 0.49–0.80). Hyaluronic acid showed a significantly higher success rate than fat myringoplasty (90.1% versus 69.9%) (OR 0.20, 95% CI 0.09–0.46).

Conclusions:

The success rate of fat myringoplasty may be associated with the perforation site and size. The success rate of fat myringoplasty was equivalent to that of the paper patch but inferior to a conventional method using perichondrium or fascia.
A Relationship Between Blood Levels of Otolin-1 and Vitamin D
Authors: Parham Kourosh , Kuchel George A. , McElhaney Janet E. , Haynes Laura
Published: March 2018

Objective:

Low vitamin D levels have been associated with and could play a role in the pathogenesis of idiopathic benign paroxysmal positional vertigo (iBPPV). Since otoconia degeneration contributes to iBPPV and a lack of vitamin D may impact otoconia structure and integrity, we proposed a negative association between vitamin D levels and levels of a proposed circulatory biomarker for otolithic degeneration, otolin-1.

Study Design:

Cross-sectional clinical study.

Setting:

Clinical research center.

Patients:

Seventy-nine men and women ranging in age from 22 to 95 years old without known vertigo.

Interventions:

Diagnostic.

Main Outcome Measures:

Blood levels of 25-OH vitamin D and otolin-1.

Results:

Previously, we had reported higher otolin-1 levels in older age groups. The majority of the subjects (83%) had vitamin D levels that were below 40 ng/ml. Vitamin D level was lowest in the young and increased with age before declining in subjects 70 years of age and older (p = 0.005). There was a negative correlation between vitamin D and otolin-1 levels of subjects over 70 (r = −0.36,p = 0.036).

Conclusion:

Our results demonstrate a relationship between vitamin D and otolin-1. The majority of our subjects had abnormally low vitamin D levels, but only those over 70 years of age showed a negative correlation with high otolin-1 levels. We postulate that a seasonal drop in vitamin D may not be sufficient for otoconia fragmentation and ultimately iBPPV, rather, chronically low vitamin D maybe required to induce otoconia degeneration.
Auricular Clyster, Otenchytes, and Pyoulcos: Precursors of the Ear Syringe
Authors: Rousseau Nathalie , Mudry Albert
Published: March 2018

Objectives/Hypothesis:

In Western medicine, the long history of the ear syringe dates back at least to the end of the 1st millennium BCE; but the corresponding Ancient Greek word surinx designates another tool. Other Greek and Latin words and phrases, in particular auricular clyster, otenchytes, and pyoulcos, were known as names of the ear syringe until modern times. The aim of this article is to study the Greek and Latin words and phrases referred to as names of the ear syringe up until modern times before syringe became the standard word.

Method:

Historical and philological review of ancient Greek and Latin medical literature dealing with the subject.

Results:

Careful reading of ancient medical texts mentioning these tools shows a variety of shapes and uses: beside the piston-driven syringe, the system of a bladder attached to a catheter remained in use throughout Antiquity; the otenchytes, being a piston-driven syringe, obviously was not used to squirt the liquid when the remedy put inside was warmed by a flame; the piston-driven pyoulcos is most likely of greater size, and never linked with ear care in Antiquity.

Conclusion:

Latin auricular clyster and Greek otenchytes and pyoulcos, in the few ancient texts in which they occur, designate tools of a large variety of shapes and uses, significantly different from Heron's description of piston-driven pyoulcos.
Assessment of Hearing During the Early Years of the American Otological Society
Authors: Fitzgerald Matthew B. , Jackler Robert K.
Published: March 2018

Objective:

To describe the manner in which hearing was evaluated in American Otological Practice during the late 19th and early 20th centuries before introduction of the electric audiometer.

Methods:

Primary sources were the Transactions of the American Otological Society and American textbooks, especially those authored by Presidents of the Society.

Results:

In the era before electric audiometry multiple methods were used for evaluating the thresholds of different frequencies. Tuning forks were important for lower frequencies, whisper, and speech for mid-frequencies, and Galton's whistle and Konig's rod evaluated high frequencies. Hearing threshold was often recorded as in terms of duration of a sound, or distance from the source, rather than intensity. Hearing ability was often recorded a fraction, for example, with the distance a watch tick could be heard over the distance of a normal hearing individual. A variety of devices, such as Politzer's Acoumeter, attempted to deliver sound in a calibrated manner, thus enhancing the accuracy and reproducibility of test results.

Conclusion:

The early years of the American Otological Society were marked by a number of ingenious efforts to standardize hearing assessment despite the technical limitations. These efforts facilitated the development of the audiometer, and continue to influence clinical practice even today.
Lymphatic dysfunction in critical illness
Authors: Burke Edmund , Datar Sanjeev A.
Published: March 2018

Purpose of review

The essential role of the lymphatic system in fluid homeostasis, nutrient transport, and immune trafficking is well recognized; however, there is limited understanding of the mechanisms that regulate lymphatic function, particularly in the setting of critical illness. The lymphatics likely affect disease severity and progression in every condition, from severe systemic inflammatory states to respiratory failure. Here, we review structural and functional disorders of the lymphatic system, both congenital and acquired, as they relate to care of the pediatric patient in the intensive care setting, including novel areas of research into medical and procedural therapeutic interventions.

Recent findings

The mainstay of current therapies for congenital and acquired lymphatic abnormalities has involved nonspecific medical management or surgical procedures to obstruct or divert lymphatic flow. With the development of dynamic contrast-enhanced magnetic resonance lymphangiography, image-directed percutaneous intervention may largely replace surgery. Because of new insights into the mechanisms that regulate lymphatic biology, pharmacologic inhibitors of mTOR and leukotriene B4 signaling are each in Phase II clinical trials to treat abnormal lymphatic structure and function, respectively.

As our understanding of normal lymphatic biology continues to advance, we will be able to develop novel strategies to support and augment lymphatic function during critical illness and through convalescence.
A Multi-Institutional Simulation Boot Camp for Pediatric Cardiac Critical Care Nurse Practitioners*
Authors: Brown Kristen M. , Mudd Shawna S. , Hunt Elizabeth A. , Perretta Julianne S. , Shilkofski Nicole A. , Diddle J. Wesley , Yurasek Gregory , Bembea Melania , Duval-Arnould Jordan , Nelson McMillan Kristen
Published: March 2018

Objectives:

Assess the effect of a simulation “boot camp” on the ability of pediatric nurse practitioners to identify and treat a low cardiac output state in postoperative patients with congenital heart disease. Additionally, assess the pediatric nurse practitioners’ confidence and satisfaction with simulation training.

Design:

Prospective pre/post interventional pilot study.

Setting:

University simulation center.

Subjects:

Thirty acute care pediatric nurse practitioners from 13 academic medical centers in North America.

Interventions:

We conducted an expert opinion survey to guide curriculum development. The curriculum included didactic sessions, case studies, and high-fidelity simulation, based on high-complexity cases, congenital heart disease benchmark procedures, and a mix of lesion-specific postoperative complications. To cover multiple, high-complexity cases, we implemented Rapid Cycle Deliberate Practice method of teaching for selected simulation scenarios using an expert driven checklist.

Measurements and Main Results:

Knowledge was assessed with a pre-/posttest format (maximum score, 100%). A paired-sample t test showed a statistically significant increase in the posttest scores (mean [sd], pre test, 36.8% [14.3%] vs post test, 56.0% [15.8%]; p < 0.001). Time to recognize and treat an acute deterioration was evaluated through the use of selected high-fidelity simulation. Median time improved overall “time to task” across these scenarios. There was a significant increase in the proportion of clinically time-sensitive tasks completed within 5 minutes (pre, 60% [30/50] vs post, 86% [43/50]; p = 0.003] Confidence and satisfaction were evaluated with a validated tool (“Student Satisfaction and Self-Confidence in Learning”). Using a five-point Likert scale, the participants reported a high level of satisfaction (4.7 ± 0.30) and performance confidence (4.8 ± 0.31) with the simulation experience.

Conclusions:

Although simulation boot camps have been used effectively for training physicians and educating critical care providers, this was a novel approach to educating pediatric nurse practitioners from multiple academic centers. The course improved overall knowledge, and the pediatric nurse practitioners reported satisfaction and confidence in the simulation experience.
Risk Factors for Titanium Mesh Implant Exposure Following Cranioplasty
Authors: Maqbool Talha , Binhammer Adam , Binhammer Paul , Antonyshyn Oleh M.
Published: March 2018

Purpose:

Titanium mesh is used to reconstruct the neurocranium in cranioplasties. Though it is generally well-tolerated, erosion of the overlying soft tissue with exposure of the implant is a complication that adversely affects patient outcomes. The purpose of this study is to investigate potential risk factors for titanium mesh exposure.

Methods:

This study comprises all consecutive patients who underwent titanium mesh cranioplasty between January 2000 and July 2016. A retrospective chart review was conducted to extract demographics, details of management, and outcome. Latest postoperative computed tomography scans were reviewed to document the thickness of soft tissue coverage over the implant and the presence of significant extradural dead space deep to it.

Results:

Fifty patients were included. Implant exposure occurred in 7 (14%), while threatened exposure was observed in 1 additional patient, for a total complication count of 8 (16%).

Four (50%) exposure and 3 (7.1%) nonexposure patients underwent preoperative radiotherapy (odds ratio [OR] = 19.67, P = 0.018). Similarly, 4 (50%) exposure and 5 (11.9%) nonexposure patients had a free flap tissue transfer for implant coverage (OR = 6.50, P = 0.046). Postoperative computed tomography scans revealed significant thinning of soft tissues over titanium mesh in 7 (87.5%) exposure and 15 (35.7%) nonexposure patients (OR = 10.71 P = 0.040). No significant association was found between transposition/rotation flap, postoperative radiotherapy, or the presence of significant extradural dead space, and exposure (P = 0.595, P = 0.999, P = 0.44).

Conclusion:

Preoperative radiotherapy, free flap coverage, and soft tissue atrophy resulted in greater odds of titanium mesh exposure. The findings of this study provide important considerations for reconstructive surgeons using titanium mesh for cranioplasty.
The Safety and Efficacy of Laparoscopic Common Bile Duct Exploration Combined with Cholecystectomy for the Management of Cholecysto-choledocholithiasis
Authors: Pan Long , Chen Mingyu , Ji Lin , Zheng Longbo , Yan Peijian , Fang Jing , Zhang Bin , Cai Xiujun
Published: March 2018

Objective:

The aim of this study was to compare the efficacy and safety of the laparoscopic common bile duct exploration (LCBDE) and laparoscopic cholecystectomy (LC) with preoperative endoscopic sphincterotomy (pre-EST) and LC for concomitant gallstones and common bile duct (CBD) stones.

Background:

It remains controversial whether LCBDE+LC is better than pre-EST+LC for gallstones and CBD stones.

Methods:

A specific search of online databases was performed from January 2006 to October 2017. Relative outcomes of perioperative safety and postoperative efficacy were synthesized. Single-arm meta-analysis and cumulative meta-analysis were also conducted.

Results:

A total of 13 studies involving 1757 (872 vs 885) patients were included for analysis in our study. The CBD stones clearance rate [94.1% vs 90.1%; odds ratio (OR) 1.56, P = 0.012] was significantly higher in patients who underwent LCBDE+LC than pre-EST+LC, while perioperative complications (7.6% vs 12.0%; OR 0.67, P = 0.015), conversion to other procedure (4.1% vs 7.1%; OR 0.64, P = 0.025), retained stones rate (1.2% vs 7.9%; OR 0.34, P = 0.004), lithiasis recurrence rate (1.8% vs 5.6%, OR 0.32, P = 0.005), operative time [112.28 vs 132.03 minutes; weighted mean difference (WMD) −18.08, P = 0.002], length of hospital stay (4.94 vs 6.62 days; WMD −1.63, P = 0.023), and total charges [standardized mean difference (SMD) −2.76, P = 0.002] were significantly lower in LCBDE+LC. The mortality (0.6% vs 1.1%; OR 0.32, P = 0.117) was similar between the 2 groups. The cumulative meta-analyses indicated the effect sizes of CBD stones clearance rate, perioperative complications, and conversion to other procedure have already stabilized between 2 groups.

Conclusion:

The updated meta-analysis first confirms that LCBDE+LC is superior to pre-EST+LC both in perioperative safety and short- and long-term postoperative efficacy, which should be considered as optimal treatment choice for cholecysto-choledocholithiasis.
PlasmidTron: assembling the cause of phenotypes and genotypes from NGS data
Authors: Page Andrew J. , Wailan Alexander , Shao Yan , Judge Kim , Dougan Gordon , Klemm Elizabeth J. , Thomson Nicholas R. , Keane Jacqueline A.
Published: March 2018

Increasingly rich metadata are now being linked to samples that have been whole-genome sequenced. However, much of this information is ignored. This is because linking this metadata to genes, or regions of the genome, usually relies on knowing the gene sequence(s) responsible for the particular trait being measured and looking for its presence or absence in that genome. Examples of this would be the spread of antimicrobial resistance genes carried on mobile genetic elements (MGEs). However, although it is possible to routinely identify the resistance gene, identifying the unknown MGE upon which it is carried can be much more difficult if the starting point is short-read whole-genome sequence data. The reason for this is that MGEs are often full of repeats and so assemble poorly, leading to fragmented consensus sequences. Since mobile DNA, which can carry many clinically and ecologically important genes, has a different evolutionary history from the host, its distribution across the host population will, by definition, be independent of the host phylogeny. It is possible to use this phenomenon in a genome-wide association study to identify both the genes associated with the specific trait and also the DNA linked to that gene, for example the flanking sequence of the plasmid vector on which it is encoded, which follows the same patterns of distribution as the marker gene/sequence itself. We present PlasmidTron, which utilizes the phenotypic data normally available in bacterial population studies, such as antibiograms, virulence factors, or geographical information, to identify traits that are likely to be present on DNA that can randomly reassort across defined bacterial populations. It is also possible to use this methodology to associate unknown genes/sequences (e.g. plasmid backbones) with a specific molecular signature or marker (e.g. resistance gene presence or absence) using PlasmidTron. PlasmidTron uses a k-mer-based approach to identify reads associated with a phylogenetically unlinked phenotype. These reads are then assembled de novo to produce contigs in a fast and scalable-to-large manner. PlasmidTron is written in Python 3 and is available under the open source licence GNU GPL3 from https://github.com/sanger-pathogens/plasmidtron.
Using synthetic semiochemicals to train canines to detect bark beetle-infested trees
Authors: Johansson Annette , Birgersson Göran , Schlyter Fredrik
Published: March 2018

In this proof of concept study, we report the off season training of two detection dogs on a series of synthetic semiochemicals associated with Ips typographus pest bark beetle infestations of spruce trees. Scent detection training allowed dogs to discriminate between physiologically-relevant infestation (target) odours, quantified by GC-MS using extracted ion chromatogram to be bio-active at levels of < 10−4 ng /15 min or lower, and natural non-target odours that might be encountered in the forest. Detection dogs trained to recognize four different synthetic pheromone compounds in the winter time, well before beetle flight, were able to detect natural infested spruce trees unknown to humans the following summer. The trained detection dogs were able to detect an infested spruce tree from the first hour of bark beetle attack until several weeks after the attack. Trained detection dogs appear to be more efficient than humans in detecting early bark beetle infestations because the canines ability to cover a greater area and by olfaction detect infestations from a far greater distance than can humans. Infested spruce trees could be detected by trained detection dogs out to more than 100 m.

Key Message

Detection dogs were rapidly trained to locate release of synthetic bark beetle pheromone components

Synthetics allowed dog training off-season both in laboratory and field

Dogs trained on synthetics detected naturally target pest insect attacked trees at a distance of more than 100 m.

The method allows rapid removal of single, first attacked trees before offspring emergence, thus curbing local pest increase and lowering spread of attacks in the landscap
Single-strand DNA processing: phylogenomics and sequence diversity of a superfamily of potential prokaryotic HuH endonucleases
Authors: Quentin Yves , Siguier Patricia , Chandler Mick , Fichant Gwennaele
Published: March 2018

Background

Some mobile genetic elements target the lagging strand template during DNA replication. Bacterial examples are insertion sequences IS608and ISDra2(IS200/IS605family members). They use obligatory single-stranded circular DNA intermediates for excision and insertion and encode a transposase, TnpAIS200, which recognizes subterminal secondary structures at the insertion sequence ends. Similar secondary structures, Repeated Extragenic Palindromes (REP), are present in many bacterial genomes. TnpAIS200-related proteins, TnpAREP, have been identified and could be responsible for REP sequence proliferation. These proteins share a conserved HuH/Tyrosine core domain responsible for catalysis and are involved in processes of ssDNA cleavage and ligation. Our goal is to characterize the diversity of these proteins collectively referred as the TnpAY1family.

Results

A genome-wide analysis of sequences similar to TnpAIS200and TnpAREPin prokaryotes revealed a large number of family members with a wide taxonomic distribution. These can be arranged into three distinct classes and 12 subclasses based on sequence similarity. One subclass includes sequences similar to TnpAIS200. Proteins from other subclasses are not associated with typical insertion sequence features. These are characterized by specific additional domains possibly involved in protein/DNA or protein/protein interactions. Their genes are found in more than 25% of species analyzed. They exhibit a patchy taxonomic distribution consistent with dissemination by horizontal gene transfers followed by loss. ThetnpAREPgenes of five subclasses are flanked by typical REP sequences in a REPtron-like arrangement. Four distinct REP types were characterized with a subclass specific distribution. Other subclasses are not associated with REP sequences but have a large conserved domain located in C-terminal end of their sequence. This unexpected diversity suggests that, while most likely involved in processing single-strand DNA, proteins from different subfamilies may play a number of different roles.

Conclusions

We established a detailed classification of TnpAY1proteins, consolidated by the analysis of the conserved core domains and the characterization of additional domains. The data obtained illustrate the unexpected diversity of the TnpAY1family and provide a strong framework for future evolutionary and functional studies. By their potential function in ssDNA edition, they may confer adaptive responses to host cell physiology and metabolism.
Prolonged lag time results in small colony variants and reflects a sub-population of persisters in vivo
Authors: Vulin Clément , Leimer Nadja , Huemer Markus , Ackermann Martin , Zinkernagel Annelies S.
Published: March 2018

Treatment failure and recurrent infections can occur even when patients are treated with antibiotics to which bacteria are susceptible. These treatment failures could be due to a sub-population of bacteria persisting through the treatment. In this study, we tested the hypothesis that such bacterial persisters manifest in clinical samples as small colony variants (SCVs). We worked with the bacterial pathogen Staphylococcus aureus, where SCVs are frequently observed in clinics. The small size of SCV-colonies is often considered to be the result of mutations that reduce the bacterial growth rate. Alternatively, it is possible that the small colony size could result from a long lag time of bacteria in plated samples. We used automated plate imaging and single-cell microscopy to precisely quantify growth kinetics of bacteria sampled from patient and mice abscesses, and from low-pH in vitro cultures mimicking the host. Under these conditions, the small colony size was the consequence of a long lag time and was associated with tolerance towards antibiotics. We found that bacteria with a long lag time emerged de novo during the growth phase in the murine abscess as well as in the low-pH in vitro cultures, and that their proportion increased during stationary phase. Antibiotic exposure further increased the proportion of bacteria with a long lag time. Thus, the persisters found in low-pH host compartments could be a cause of treatment failure, and antibiotic treatment potentially aggravates the problem. These insights call for antibiotic treatment strategies that explicitly address the problem of persister formation.

Significance Statement

Bacterial pathogens often contain subpopulations that are multidrug tolerant and metabolically inactive. These subpopulations are known as persisters and are hypothesised to be linked to treatment failure and recurrent infections even in bacteria that are not genetically resistant to antibiotics. Identifying persisters in clinical samples remains a challenge due to their metabolicaly active state. Here, we used time-lapse plate imaging and single cell microscopy to link the presence of persisters to the nonstable small colony variant (SCV) phenotype that is observed in some Staphylococcus aureus infections. These findings may help to identify treatment regimens that prevent or address the emergence of persistence and thus to reduce relapses.