bluuebunny/crossref_metadata_2025 huggingface dataset:
Recognition of conserved antigens by Th17 cells provides broad protection against pulmonaryHaemophilus influenzaeinfection
Authors: Li Wenchao , Zhang Xinyun , Yang Ying , Yin Qingqin , Wang Yan , Li Yong , Wang Chuan , Wong Sandy M. , Wang Ying , Goldfine Howard , Akerley Brian J. , Shen Hao
Published: July 2018

Significance

NontypeableHaemophilus influenzae(NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. Current effort in NTHi vaccine development has focused on generating antibody responses to surface antigens and has had limited success, largely because of antigenic diversity among the numerous circulating NTHi strains. In this study, we have uncovered Th17 responses as the immune mechanism of cross-protection and identified Th17 antigens that are conserved and induce protection against NTHi lung infection, thus making a critical first step toward development of a broadly protective “universal” vaccine—the Holy Grail of vaccine development against respiratory pathogens.
Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic
ERCC6L2
variants
Authors: Tummala Hemanth , Dokal Arran D. , Walne Amanda , Ellison Alicia , Cardoso Shirleny , Amirthasigamanipillai Saranha , Kirwan Michael , Browne Isobel , Sidhu Jasmin K. , Rajeeve Vinothini , Rio-Machin Ana , Seraihi Ahad Al , Duncombe Andrew S. , Jenner Matthew , Smith Owen P. , Enright Helen , Norton Alice , Aksu Tekin , Özbek Namık Yaşar , Pontikos Nikolas , Cutillas Pedro , Dokal Inderjeet , Vulliamy Tom
Published: July 2018

Significance

Bone marrow failure (BMF) is an inherited life-threatening condition characterized by defective hematopoiesis, developmental abnormalities, and predisposition to cancer. BMF caused by ERCC6L2 mutations is considered to be a genome instability syndrome, because DNA repair is compromised in patient cells. In this study, we report BMF cases with biallelic disease-causing variants and provide evidence from patients’ cells that transcription deficiency can explain the genome instability. Specifically, we demonstrate that ERCC6L2 participates in RNA polymerase II-mediated transcription via interaction with DNA-dependent protein kinase (DNA-PK) and resolves DNA–RNA hybrids (R loops). Collectively, our data point to a causal mechanism in BMF in which patients with
ERCC6L2
mutations are defective in the repair of transcription-associated DNA damage.
Positional specificity of different transcription factor classes within enhancers
Authors: Grossman Sharon R. , Engreitz Jesse , Ray John P. , Nguyen Tung H. , Hacohen Nir , Lander Eric S.
Published: July 2018

Significance

Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. The degree to which the arrangement of motif sites within regulatory elements determines their function remains unclear. Here, we show that the positional distribution of TF motif sites within nucleosome-depleted regions of DNA fall into six distinct classes. These patterns are highly consistent across cell types and bring together factors that have similar functional and binding properties. Furthermore, the position of motif sites appears to be related to their known functions. Our results suggest that TFs play distinct roles in forming a functional enhancer, facilitated by their position within a regulatory sequence.
Confinement transition of ℤ
2
gauge theories coupled to massless fermions: Emergent quantum chromodynamics and
SO
(5) symmetry
Authors: Gazit Snir , Assaad Fakher F. , Sachdev Subir , Vishwanath Ashvin , Wang Chong
Published: July 2018

Significance

Universal properties of quantum (zero-temperature) phase transitions are typically well-described by the classical Landau theory of spontaneous symmetry breaking. A paradigmatic counterexample is deconfined criticality, where quantum interference allows for a direct and continuous transition between states with distinct symmetry-breaking patterns, a phenomenon that is classically forbidden. In this work, we extend the scope of deconfined criticality to a case where breaking of a global symmetry coincides with confinement of a local (gauge) symmetry. Using Monte Carlo simulations, we investigate a lattice realization of this transition. Remarkably, we uncover emergent and enlarged global and gauge symmetries. These findings direct us in constructing a critical field theory description.
Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library
Authors: Merkouris Spyros , Barde Yves-Alain , Binley Kate E. , Allen Nicholas D. , Stepanov Alexey V. , Wu Nicholas C. , Grande Geramie , Lin Chih-Wei , Li Meng , Nan Xinsheng , Chacon-Fernandez Pedro , DiStefano Peter S. , Lindsay Ronald M. , Lerner Richard A. , Xie Jia
Published: July 2018

Significance

Neurotrophin receptors are a class of receptor tyrosine kinases that couple to signaling pathways critical for neuronal survival and growth. One member, TrkB, is particularly interesting because it plays a role in many severe degenerative neurological diseases. The TrkB natural ligand brain-derived neurotrophic factor (BDNF) is not suitable to be developed as a drug or therapy as proved by previous unsuccessful clinical trials. Here we report a selection method that produced potent full agonist antibodies that mimic BDNF function, yet with better biophysical properties. This study paves the road for the development of agonist antibodies for other receptor tyrosine kinases.
Template and primer requirements for DNA Pol θ-mediated end joining
Authors: He Peng , Yang Wei
Published: July 2018

Significance

Using oligonucleotides comprised solely of purines or pyrimidines, we find that human Polθ is a bona fide template-dependent DNA polymerase and has no terminal transferase activity under physiological conditions. Polθ requires a minimum of 2 bp and optimally 4 bp between a template/primer pair for efficient and processive DNA synthesis. Polθ polymerase activity is inhibited by a 3′-overhang on the template strand. Consistent with in vivo observations of DNA deletion during TMEJ, 3′-exonucleases or 3′-flap endonucleases are likely recruited to remove such hindrances when microhomology is internal to the 3′ ends. In contrast to a previously report, we observed limited strand displacement activity by Polθ. Because Pol θ lacks a proofreading exonuclease activity and is error prone, minimal strand displacement can be only beneficial for TMEJ.
Integration of cell cycle signals by multi-PAS domain kinases
Authors: Mann Thomas H. , Shapiro Lucy
Published: July 2018

Significance

Cells must constantly make decisions involving many pieces of information at a molecular level. Kinases containing multiple PAS sensory domains detect multiple signals to determine their signaling outputs. In the asymmetrically dividing bacterium
Caulobacter crescentus
, the multisensor proteins DivL and CckA promote different cell types depending upon their subcellular location. We reconstituted the DivL–CckA interaction in vitro and showed that specific PAS domains of each protein function to switch CckA between kinase and phosphatase activities, which reflects their functions in vivo. Within the context of the cell, our reconstitution illustrates how multisensor proteins can use their subcellular location to regulate their signaling functions.
Deconstructing teleology
Authors: Mithun Marianne
Published: July 2018

A central issue in typology is the role of implicational hierarchies
in shaping individual languages. One view is that the hierarchies
guide language change, or at least constrain it: “Since a hierarchy
constrains what is a possible language, it is also a constraint on
language change, because languages move from one possible state to
another” (Corbett 2011).
Other approaches take a different perspective: “Hierarchies simply
capture the outputs of independent diachronic processes” (Cristofaro & Zúñiga this
volume). Here the relationship between typology and
diachrony is examined with respect to the most frequently-cited
hierarchies, the cluster of Referential/Topicality/Animacy/Empathy
hierarchies. While such hierarchies might appear to drive diachronic
development in some single-step changes, multi-step developments are
a different matter.
The direction(s) of analogical change in direct/inverse
systems
Authors: Jacques Guillaume , Antonov Anton
Published: July 2018

In this chapter, we extract general principles of language change
from the study of the evolution of the conjunct order in various
Algonquian languages, and propose four generalizations concerning
the directionality of the spread of analogy in these systems. These
generalizations are expected to bring insights on the analysis of
data from other language families with direct/inverse marking but
insufficient philological record, such as for instance
Sino-Tibetan.
Extensive stuttering therapy in Turkish children who stutter
Authors: Akin Senkal Ozgul , Ciyiltepe Muzeyyen
Published: July 2018

Background/aim:

In this study, the immediate and extended outcomes of the stuttering therapy programme were investigated for the first time in Turkey. This paper reports the results of an eight-week extensive stuttering therapy programme for 35 school-aged and adolescents who stutter.

Materials and methods:

Measurements were made immediately before and after the treatment and again during the follow-up period, 6 months’ post-treatment. The measures included percentage of stuttering and syllables spoken per minute.

Results:

Turkish school-aged and adolescent children who stutter showed more within-word dysfluencies than between-word dysfluencies. In addition, stuttering characteristics included (in) audible sound prolongations (24%) and sound/syllable repetition (49%). The results indicated that substantial positive changes occurred and were maintained in speech performance with an eight-week stuttering therapy.

Conclusion:

The present study examined the characteristics of dysfluencies in school-aged and adolescents and then dysfluency characteristics were taken to account before and after stuttering therapy of children and adolescents who stutter at moderate degree in Turkey. Extensive therapy courses were determined for children and adolescents who stutter and their families changed the stuttering behaviour of the participants.
iCFN: an efficient exact algorithm for multistate protein design
Authors: Karimi Mostafa , Shen Yang
Published: July 2018

Motivation

Multistate protein design addresses real-world challenges, such as multi-specificity design and backbone flexibility, by considering both positive and negative protein states with an ensemble of substates for each. It also presents an enormous challenge to exact algorithms that guarantee the optimal solutions and enable a direct test of mechanistic hypotheses behind models. However, efficient exact algorithms are lacking for multistate protein design.

Results

We have developed an efficient exact algorithm called interconnected cost function networks (iCFN) for multistate protein design. Its generic formulation allows for a wide array of applications such as stability, affinity and specificity designs while addressing concerns such as global flexibility of protein backbones. iCFN treats each substate design as a weighted constraint satisfaction problem (WCSP) modeled through a CFN; and it solves the coupled WCSPs using novel bounds and a depth-first branch-and-bound search over a tree structure of sequences, substates, and conformations. When iCFN is applied to specificity design of a T-cell receptor, a problem of unprecedented size to exact methods, it drastically reduces search space and running time to make the problem tractable. Moreover, iCFN generates experimentally-agreeing receptor designs with improved accuracy compared with state-of-the-art methods, highlights the importance of modeling backbone flexibility in protein design, and reveals molecular mechanisms underlying binding specificity.

Availability and implementation

https://shen-lab.github.io/software/iCFN

Supplementary information

Supplementary data are available at Bioinformatics online.
Clinical applications of machine learning in cardiovascular disease and its relevance to cardiac imaging
Authors: Al’Aref Subhi J , Anchouche Khalil , Singh Gurpreet , Slomka Piotr J , Kolli Kranthi K , Kumar Amit , Pandey Mohit , Maliakal Gabriel , van Rosendael Alexander R , Beecy Ashley N , Berman Daniel S , Leipsic Jonathan , Nieman Koen , Andreini Daniele , Pontone Gianluca , Schoepf U Joseph , Shaw Leslee J , Chang Hyuk-Jae , Narula Jagat , Bax Jeroen J , Guan Yuanfang , Min James K
Published: July 2018

Artificial intelligence (AI) has transformed key aspects of human life. Machine learning (ML), which is a subset of AI wherein machines autonomously acquire information by extracting patterns from large databases, has been increasingly used within the medical community, and specifically within the domain of cardiovascular diseases. In this review, we present a brief overview of ML methodologies that are used for the construction of inferential and predictive data-driven models. We highlight several domains of ML application such as echocardiography, electrocardiography, and recently developed non-invasive imaging modalities such as coronary artery calcium scoring and coronary computed tomography angiography. We conclude by reviewing the limitations associated with contemporary application of ML algorithms within the cardiovascular disease field.
Mahalanobis distance informed by clustering
Authors: Lahav Almog , Talmon Ronen , Kluger Yuval
Published: July 2018

A fundamental question in data analysis, machine learning and signal processing is how to compare between data points. The choice of the distance metric is specifically challenging for high-dimensional data sets, where the problem of meaningfulness is more prominent (e.g. the Euclidean distance between images). In this paper, we propose to exploit a property of high-dimensional data that is usually ignored, which is the structure stemming from the relationships between the coordinates. Specifically, we show that organizing similar coordinates in clusters can be exploited for the construction of the Mahalanobis distance between samples. When the observable samples are generated by a nonlinear transformation of hidden variables, the Mahalanobis distance allows the recovery of the Euclidean distances in the hidden space. We illustrate the advantage of our approach on a synthetic example where the discovery of clusters of correlated coordinates improves the estimation of the principal directions of the samples. Our method was applied to real data of gene expression for lung adenocarcinomas (lung cancer). By using the proposed metric we found a partition of subjects to risk groups with a good separation between their Kaplan–Meier survival plot.
Strong convergence rates of semidiscrete splitting approximations for the stochastic Allen–Cahn equation
Authors: Bréhier Charles-Edouard , Cui Jianbo , Hong Jialin
Published: July 2018

This article analyses an explicit temporal splitting numerical scheme for the stochastic Allen–Cahn equation driven by additive noise in a bounded spatial domain with smooth boundary in dimension $d\leqslant 3$. The splitting strategy is combined with an exponential Euler scheme of an auxiliary problem. When $d=1$ and the driving noise is a space–time white noise we first show some a priori estimates of this splitting scheme. Using the monotonicity of the drift nonlinearity we then prove that under very mild assumptions on the initial data this scheme achieves the optimal strong convergence rate $\mathcal{O}(\delta t^{\frac 14})$. When $d\leqslant 3$ and the driving noise possesses some regularity in space we study exponential integrability properties of the exact and numerical solutions. Finally, in dimension $d=1$, these properties are used to prove that the splitting scheme has a strong convergence rate $\mathcal{O}(\delta t)$.
Classic Papers Revisited: An Early Study of Cardioprotection by Volatile Anesthetics
Authors: Warltier David C.
Published: July 2018

Recovery of Contractile Function of Stunned Myocardium in Chronically Instrumented Dogs Is Enhanced by Halothane or Isoflurane. By Warltier DC, al-Wathiqui MH, Kampine JP, and Schmeling WT. Anesthesiology 1988; 69:552–65. Reprinted with permission.

Following brief periods (5–15 min) of total coronary artery occlusion and subsequent reperfusion, despite an absence of tissue necrosis, a decrement in contractile function of the postischemic myocardium may nevertheless be present for prolonged periods. This has been termed “stunned” myocardium to differentiate the condition from ischemia or infarction. Because the influence of volatile anesthetics on the recovery of postischemic, reperfused myocardium has yet to be studied, the purpose of this investigation was to compare the effects of halothane and isoflurane on systemic and regional hemodynamics following a brief coronary artery occlusion and reperfusion. Nine groups comprising 79 experiments were completed in 42 chronically instrumented dogs. In awake, unsedated dogs a 15-min coronary artery occlusion resulted in paradoxical systolic lengthening in the ischemic zone. Following reperfusion active systolic shortening slowly returned toward control levels but remained approximately 50% depressed from control at 5 h. In contrast, dogs anesthetized with halothane or isoflurane (2% inspired concentration) demonstrated complete recovery of function 3–5 h following reperfusion. Because the anesthetics directly depressed contractile function, additional experiments were conducted in which a 15-minute coronary artery occlusion was produced during volatile anesthesia; however, each animal was allowed to emerge from the anesthetized state at the onset of reperfusion. Similar results were obtained in these experiments, demonstrating total recovery of contractile function within 3–5 h following reperfusion. Thus, despite comparable degrees of contractile dysfunction during coronary artery occlusion in awake and anesthetized dogs, the present results demonstrate that halothane and isoflurane produce marked improvement in the recovery of segment function following a transient ischemic episode. Therefore, volatile anesthetics may attenuate postischemic left ventricular dysfunction occurring intraoperatively and enhance recovery of regional wall motion abnormalities during reperfusion.
Surgical Technique: Achieving Reduction With Temporizing, Knee-Spanning External Fixation
Authors: Liskutin Tomas , Bernstein Mitchell , Lack William , Perry Michael , Summers Hobie
Published: July 2018

Introduction:

Peri- and intra-articular fractures about the knee are frequently managed with joint-spanning external fixation before definitive treatment. With a systematic approach, a near-anatomic reduction with respect to length, alignment, and rotation can be obtained.

Methods:

This video highlights 2 clinical cases: a bicondylar tibial plateau fracture-dislocation and a distal femur fracture, both of which were treated with temporizing, knee-spanning external fixation.

Results:

The indications, principles, and biomechanics of knee-spanning external fixation are presented. In addition, we demonstrate a systematic approach to applying knee-spanning external fixation.

Conclusions:

Temporizing, joint-spanning external fixation is a critical treatment modality in the orthopaedic armamentarium for managing fractures about the knee. With a systematic approach, it is possible to obtain a near-anatomic reduction with respect to length, alignment, and rotation.
Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness*
Authors: Silversides Jonathan A. , Fitzgerald Emma , Manickavasagam Uma S. , Lapinsky Stephen E. , Nisenbaum Rosane , Hemmings Noel , Nutt Christopher , Trinder T. John , Pogson David G. , Fan Eddy , Ferguson Andrew J. , McAuley Daniel F. , Marshall John C.
Published: July 2018

Objectives:

To characterize current practice in fluid administration and deresuscitation (removal of fluid using diuretics or renal replacement therapy), the relationship between fluid balance, deresuscitative measures, and outcomes and to identify risk factors for positive fluid balance in critical illness.

Design:

Retrospective cohort study.

Setting:

Ten ICUs in the United Kingdom and Canada.

Patients:

Adults receiving invasive mechanical ventilation for a minimum of 24 hours.

Interventions:

None.

Measurements and Main Results:

Four-hundred patients were included. Positive cumulative fluid balance (fluid input greater than output) occurred in 87.3%: the largest contributions to fluid input were from medications and maintenance fluids rather than resuscitative IV fluids. In a multivariate logistic regression model, fluid balance on day 3 was an independent risk factor for 30-day mortality (odds ratio 1.26/L [95% CI, 1.07–1.46]), whereas negative fluid balance achieved in the context of deresuscitative measures was associated with lower mortality. Independent predictors of greater fluid balance included treatment in a Canadian site.

Conclusions:

Fluid balance is a practice-dependent and potentially modifiable risk factor for adverse outcomes in critical illness. Negative fluid balance achieved with deresuscitation on day 3 of ICU stay is associated with improved patient outcomes. Minimization of day 3 fluid balance by limiting maintenance fluid intake and drug diluents, and using deresuscitative measures, represents a potentially beneficial therapeutic strategy which merits investigation in randomized trials.
Methodologic Innovation in Creating Clinical Practice Guidelines: Insights From the 2018 Society of Critical Care Medicine Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption Guideline Effort
Authors: Devlin John W. , Skrobik Yoanna , Rochwerg Bram , Nunnally Mark E. , Needham Dale M. , Gelinas Celine , Pandharipande Pratik P. , Slooter Arjen J. C. , Watson Paula L. , Weinhouse Gerald L. , Kho Michelle E. , Centofanti John , Price Carrie , Harmon Lori , Misak Cheryl J. , Flood Pamela D. , Alhazzani Waleed
Published: July 2018

Objectives:

To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine’s 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults.

Design:

We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges.

Setting/Subjects:

Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff.

Interventions:

Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps.

Measurements and Main Results:

Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and “evidence to decision” frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled “check-ins” mitigated communication gaps.

Conclusions:

Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines.
Educational Analytics
Authors: Roche Cathy C. , Wingo Nancy P. , Westfall Andrew O. , Azuero Andres , Dempsey Donald M. , Willig James H.
Published: July 2018

To determine the effects of gamification on student education, researchers implemented “Kaizen,” a software-based knowledge competition, among a first-year class of undergraduate nursing students. Multiple-choice questions were released weekly or biweekly during two rounds of play. Participation was voluntary, and students could play the game using any Web-enabled device. Analyses of data generated from the game included (1) descriptive, (2) logistic regression modeling of factors associated with user attrition, (3) generalized linear mixed model for retention of knowledge, and (4) analysis of variance of final examination performance by play styles. Researchers found a statistically significant increase in the odds of a correct response (odds ratio, 1.8; 95% confidence interval, 1.0–3.4) for a round 1 question repeated in round 2, suggesting retention of knowledge. They also found statistically significant differences in final examination performance among different play styles.

To maximize the benefits of gamification, researchers must use the resulting data both to power educational analytics and to inform nurse educators how to enhance student engagement, knowledge retention, and academic performance.
Public Perception of Ethical Issues in Dermatology: Evidenced by New York Times Commenters
Authors: Martin Elise , Huang William W. , Strowd Lindsay C. , Hinkel Victoria S. , Feldman Steven R. , Williford Phillip M.
Published: July 2018

BACKGROUND

A 2017 New York Times (NYT) article questioning the appropriateness of skin cancer treatment modality by dermatology providers stimulated discussion among the public pertaining to ethics in the current state of dermatologic practice.

OBJECTIVE

The purpose of this study is to characterize issues raised by the comments on the NYT article, discuss strategies to address these concerns, and encourage reflection on ethics in dermatologic care.

MATERIALS AND METHODS

A qualitative analysis was performed on the 309 comments on the NYT article. General themes were identified, resulting in the inclusion of 222 comments. These comments were reviewed and characterized by the type of commenter, his or her stance on health care, and what issues they raised.

RESULTS

Providers interested in “profit over patient” was the most common theme, followed by mistrust of APPs, health care system interested in “profit over patient,” inadequate supervision by advanced practice providers (APPs), finding the “right” provider, support for coordinated APP and physician care, support for APP credentials, and finally inappropriate elderly care.

CONCLUSION

The NYT article raises the concern of identifying quality care and choosing the “right provider”—one who successfully balances the various incentives affecting skin cancer management including appropriate usage of APPs.
Ammonia, ammonium, and the risk of asthma: A register-based case–control study in Danish children
Authors: Holst Gitte , Thygesen Malene , Pedersen Carsten B. , Peel Robert G. , Brandt Jørgen , Christensen Jesper H. , Bønløkke Jakob H. , Hertel Ole , Sigsgaard Torben
Published: July 2018

Background:

Evidence concerning the health effects of exposure to fine particulate matter less than 2.5 μm in diameter (PM2.5) and particulate components such as ammonium (NH4
+) is limited. We aimed to investigate gaseous ammonia (NH3), particulate ammonium (NH4
+), the total concentration of these pollutants (NHx), and PM2.5 and their association with asthma in Danish preschool children.

Methods:

Estimates of incidence rate ratios associated with exposure to air pollution were calculated for children followed for the development of childhood asthma (n = 335,629) from their first to their sixth birthday during the time period 2006–2012 using a time-matched case–control design by combining register information. Modeled average concentrations of NH3, NH4
+, NHx, and PM2.5 (5.56 km × 5.56 km grid resolution) during the past 3 months prior to the date of first diagnosis of asthma for cases.

Results:

We identified 12,935 incident cases of asthma. The base adjusted hazard ratio of incident asthma was 1.74 for children exposed to the highest decile of NH3 exposure (95% confidence interval = 1.60, 1.89) compared to children exposed to the lowest decile of NH3 exposure during the past 3 months prior to first diagnosis. Similar hazard ratios were found for the highest levels of NH4
+ (2.33; 2.04, 2.65) and NHx (1.82; 1.68, 1.96). The positive associations were slightly attenuated, when adjusting for socioeconomic status, but disappeared when additionally adjusting for region, except in a two-pollutant model including NH4
+ and PM2.5. No association was found with PM2.5. The findings were robust when using different exposure time windows.

Conclusions:

Increased NH4
+ exposure may be a risk factor for the onset of asthma in preschool children.
Complications Associated With Nasogastric Tube Placement in the Acute Phase of Stroke: A Systematic Review
Authors: Nascimento Ana , Carvalho Mariana , Nogueira Jerina , Abreu Pedro , Nzwalo Hipólito
Published: July 2018

This systematic review explores the frequency of complications associated with nasogastric tube (NGT) placement in patients with acute stroke. The unique condition of the dysphasic, immobile, confused immunosuppressed patient who has had an acute stroke hampers any consistent inference from other neurological or nonneurological condition in which NGT placement is used. Twelve studies including 921 patients fed by NGT in the acute phase (first 4 weeks) were included in the analysis. The overall quality of the included studies was good. The main limitation was the heterogeneity and small size of most studies. The occurrence of NGT placement failure and malposition, hypoxemia, and regurgitation was addressed in the selected studies. Recurrent NGT dislodgement and a combination of tube dislodgement and blockage of the tube were the main reasons for NGT placement failure. In the absence of chronic hypoxemic pulmonary or cardiac disorders, NGT feeding was not associated with clinically significant hypoxemia in patients who have had an acute stroke. Data are scarce on the topic. Research about the frequency of local and systemic NGT complications and strategies for prevention will certainly contribute to enhance evidence-based management of dysphagia in acute stroke.
Patients' Experiences of Their Recovery Process After Minor Physical Trauma
Authors: Nasirian Sara , Fagevik Olsén Monika , Engström My
Published: July 2018

Injuries due to trauma are the leading cause of death in Sweden among people younger than 45 years, and more than 120,000 patients were admitted to hospitals in 2014 as a result of trauma. Patients suffering from less serious physical trauma are often discharged directly from the trauma unit, commonly without any follow-up plans. There is a lack of knowledge about how these patients experience their recovery process.

Eight women and 6 men were interviewed 3 months after being directly discharged from a trauma unit. Data were analyzed using the constructive grounded theory approach.

The main finding was the core category of social support, the key to recovery. Patients' roads to recapturing their health and to recovery had several barriers, which can be clustered together to either physical or psychological symptoms that enhanced their feelings of ill health and delayed their recovery. Participants described different strategies that they used to deal with these barriers. Most important was the support of others, that is, family, social life, work, and health care (primary health care).

The participants in this study described managing the recovery process by themselves as troublesome. This is partly because they do not view themselves as healthy, as the health care providers do, and many are in need of further health care after discharge. Health care providers should give better information on the expected process of recovery and the importance of social support, as it might enable patients to better overcome physical and psychological barriers in their recovery.
Clozapine-Associated Pulmonary Embolism: A High-Mortality, Dose-Independent and Early-Onset Adverse Effect
Authors: Sarvaiya Nilofar , Lapitskaya Yevgeniya , Dima Lorena , Manu Peter
Published: July 2018

Background:

Recent epidemiological studies have identified an excess of pulmonary embolism (PE) cases in patients treated with antipsychotic drugs. The findings are particularly relevant for patients treated with clozapine, which has many potentially life-threatening adverse drug effects. Among these adverse drug effects are myocarditis and agranulocytosis that have early onset and are dose independent, but also seizures and myocardial repolarization delay, which are dose dependent and may occur at any time. Together with death rates, these variables have important implications for clinical practice.

Areas of Uncertainty:

Study Question: What are the time of onset, dose relationship, and mortality of clozapine-associated PE?

Data sources:

The published case reports of clozapine-associated PE were identified in a MEDLINE search. Cases occurring within 6 months of starting clozapine were considered to have early onset. Dosages of clozapine at the time of PE were defined as low (200 mg/d or less) or high (300 mg/d or greater). Patient outcome was divided into survival of the PE event and death.

Results:

The search identified 23 cases of clozapine-associated PE. The PE had early onset (6.4 ± 7.0 weeks) in 20 patients (87%, 95% confidence interval 67.9%–95.5%). PE occurred in 9 patients treated with low doses (152.8 ± 50.7 mg/d) and in 11 patients on high doses (372.7 ± 127.2 mg/d) of clozapine. Six patients (26.1%, 95% confidence interval 12.6%–46.5%) died.

Conclusions:

A systematic review of the published case reports of clozapine-associated PE indicates that this adverse effect is highly lethal, has early onset and is dose independent. The findings should prompt careful monitoring and consideration of prophylactic treatment for venous thromboembolism for 6 months after starting treatment with clozapine.
Genetic Diversity of Norovirus Infections, Coinfections, and Undernutrition in Children From Brazilian Semiarid Region
Authors: Gondim Rafhaella D.G. , Pankov Rafaela C. , Prata Mara M.G. , Medeiros Pedro H.Q.S. , Veras Herlice N. , Santos Ana K.S. , Magalhães Lyvia M.C. , Havt Alexandre , Fumian Tulio M. , Miagostovich Marize P. , Leite José P.G. , Lima Aldo A.M.
Published: July 2018

Background and Objective:

Norovirus (NoV) infections are known to have high‐morbidity and mortality rates and are a major health problem globally. The impact of NoV on child development is, however, poorly understood. We evaluated the distribution of NoV genotypes in children from a low‐income Brazilian semiarid region, in relation with their clinical symptoms, nutritional status, and co‐pathogens.

Methods:

The test population included children aged 2 to 36 months from 6 cities of the Brazilian semiarid region. Fecal samples were collected from each child, along with the information regarding their socioeconomic/clinical conditions using a standardized questionnaire. Detection and quantification of NoV were performed by reverse‐transcription quantitative polymerase chain reaction, followed by molecular and phylogenetic analyses.

Results:

The NoV detection rate was 45.2%. Presence of NoV was associated with lower z scores for weight‐for‐age (P = 0.03), weight‐for‐height (P = 0.03), and body mass index‐for‐age (P = 0.03). NoV infection was associated with more frequent respiratory illnesses (P < 0.01). GII.P7 (polymerase) and GII.3 (capsid) were the most frequent NoV genotypes. Analysis of the open reading frame (ORF)1‐2 junction identified recombinant NoV strains in 80% of the sequenced samples. Enteroaggregative Escherichia coli coinfection was the major predictor for diarrhea in NoV‐positive samples (P < 0.02). Moreover, Shigella spp was also associated with NoV‐positive diagnosis (P = 0.02).

Conclusions:

This study highlights the genetic variability of NoV and, associated co‐infections and undernutrition in infants from low‐income Brazilian semiarid region.
Switching From Originator to Biosimilar Infliximab in Paediatric Inflammatory Bowel Disease Is Feasible and Uneventful
Authors: Gervais Lisa , McLean Luke L. , Wilson Michelle L. , Cameron Carol , Curtis Lee , Garrick Vikki , Armstrong Kat , Tayler Rachel , Henderson Paul , Hansen Richard , Chalmers Iain , Wilson David C. , Russell Richard K.
Published: July 2018

The safety, clinical efficacy, and cost‐effectiveness of biosimilar infliximab in adult inflammatory bowel disease (IBD) have now been extensively shown. Limited data have been collected in the paediatric setting. We report nationwide, prospective, clinical safety and effectiveness data for patients from all 3 Scottish paediatric inflammatory bowel disease networks switching from originator to biosimilar infliximab. Prospective clinical data were collected for 33 patients. Information was collected from electronic patient records, laboratory reports, and patient case notes. There were no clinically significant changes to disease activity, biomarkers, antidrug antibodies, or trough drug levels (P> 0.1) within a 12‐month follow‐up period; in addition, there were no significant adverse events reported. No infusion reactions were seen in the 264 infusions delivered. Switching from originator infliximab to the biosimilar (CT‐P13) appears to be associated with neither an increase in infusion reactions nor significant loss of effectiveness in the short term.
Survey of Obstetrician-gynecologists in the United States About Trichomoniasis, 2016
Authors: Liu Eugene W. , Workowski Kimberly A. , Taouk Laura H. , Schulkin Jay , Secor William E. , Jones Jeffrey L.
Published: July 2018

Purpose

Trichomoniasis is the most prevalent nonviral sexually transmitted infection (STI) in the United States. It can present with vaginitis in women and urethritis in men, but is most often asymptomatic or occurs with minimal symptoms. It is associated with other STIs, adverse pregnancy outcomes and pelvic inflammatory disease. For these reasons, health care provider awareness of trichomoniasis is of public health importance.

Methods

To assess practitioner knowledge, attitudes, and practices concerning trichomoniasis management, the American College of Obstetricians and Gynecologists conducted an online survey in 2016 of its members, and we analyzed results from 230 respondents.

Results

We note discrepancies between practice and recommendations among surveyed providers: a minority of respondents routinely screen human immunodeficiency virus (HIV)-positive patients for trichomoniasis (10.7%, “most of the time”; 95% confidence interval [CI], 6.7–15.8; 33.0%, “always”; 95% CI, 26.5%–40.0%), treat trichomoniasis in HIV-positive patients with the recommended dose of metronidazole 500 mg twice a day for 7 days (25.8%; 95% CI, 20.0%–32.3%), or retest patients diagnosed with trichomoniasis 3 months after treatment (9.6%; 95% CI, 6.1%–14.3%). Only 29.0% (95% CI, 23.0%–35.5%) retreat with metronidazole 500 mg twice a day for 7 days in patients who have failed prior treatment.

Conclusions

Screening for and treatment of trichomoniasis in HIV-positive patients, and retesting and retreatment for trichomoniasis in the general population appear to be suboptimal. Continuing education for providers is needed for this common but “neglected” STI.
Antiretroviral Drug Use and HIV Drug Resistance Among Young Women in Rural South Africa: HPTN 068
Authors: Zhang Yinfeng , Sivay Mariya V. , Hudelson Sarah E. , Clarke William , Breaud Autumn , Wang Jing , Piwowar-Manning Estelle , Agyei Yaw , Fogel Jessica M. , Hamilton Erica L. , Selin Amanda , MacPhail Catherine , Kahn Kathleen , Gómez-Olivé Francesc Xavier , Hughes James P. , Pettifor Audrey , Eshleman Susan H.
Published: July 2018

Background:

Antiretroviral (ARV) drugs are used for HIV treatment and prevention. We analyzed ARV drug use and HIV drug resistance in a cohort of young women in rural South Africa enrolled in the HIV Prevention Trials Network (HPTN) 068 study, which evaluated the use of a cash transfer conditional on school attendance to reduce HIV incidence.

Methods:

ARV drug testing was performed using plasma samples from 2526 young women. This included 2526 enrollment samples (80 HIV-infected and 2446 HIV-uninfected) and 162 seroconversion samples (first HIV-positive study visit). Testing was performed using a qualitative assay that detects 20 ARV drugs from 5 drug classes. HIV drug resistance testing was performed with the ViroSeq HIV-1 Genotyping System for samples that had HIV viral loads ≥400 copies per milliliter.

Results:

At enrollment, ARV drugs were detected in 10 (12.5%) of 80 HIV-infected young women. None of 2446 HIV-uninfected young women had ARV drugs detected at enrollment. ARV drugs were also detected in 16 (9.9%) of 162 seroconverters. At enrollment, 9 (13.4%) of 67 young women with genotyping results had HIV drug resistance; resistance was also detected in 9 (6.9%) of 131 seroconverters with genotyping results.

Conclusions:

Most of the HIV-infected young women in this cohort from rural South Africa were not taking ARV drugs, suggesting they were unaware of their HIV status or were not in care. HIV drug resistance was detected in young women with both prevalent and new HIV infection.
Impact of Protease Inhibitors on HIV-Associated Kaposi Sarcoma Incidence: A Systematic Review
Authors: Chang Elaine , Mapakshi Srikar R. , Mbang Pamela , El-Mallawany Nader Kim , Kramer Jennifer R. , White Donna L. , Chiao Elizabeth Y.
Published: July 2018

Background:

Protease inhibitors (PIs) may inhibit Kaposi sarcoma (KS) carcinogenesis. However, PI-based antiretroviral therapy (ART) is rarely a first-line choice in people living with HIV (PLWH) because of cost and toxicities. This is the first systematic review to assess KS incidence stratified by ART type.

Methods:

We searched PubMed to identify original, full research reports of KS incidence in ART-treated adult PLWH, stratified by ART class, published between 1996 and 2017. For overlapping cohorts, we included only the most recent study and supplemented data with earlier relevant analyses. We described study design, sociodemographic characteristics, statistical adjustment factors, and KS incidence.

Results:

We identified 3 unique retrospective cohort studies, and supplemented one of the studies with results from 6 previous subgroup reports, which included 242,309 PLWH and 3570 incident KS cases. Overall, KS crude incidence decreased by a factor of 10 between untreated and ART-treated PLWH; CD4-adjusted KS incidence decreased by ∼50%, with either non-nucleoside reverse transcriptase inhibitor– or PI-based ART. A single study measured a cumulative dose-/time-dependent effect of ART, which reported a relative risk reduction in only the cohort receiving boosted PI-based ART. Other studies defined ART categories by first-line therapy only.

Conclusions:

The risk of incident KS was significantly reduced, regardless of ART class even after adjusting for CD4 count. The quality of evidence (ie, most studies categorizing users by first-line ART) does not permit KS risk reduction comparisons across ART types. Given the limited number and retrospective nature of these studies, prospective data are indicated.
Risk of infectious complications in pelvic fracture urethral injury patients managed with internal fixation and suprapubic catheter placement
Authors: Johnsen Niels V. , Vanni Alex J. , Voelzke Bryan B.
Published: July 2018

BACKGROUND

There exists significant controversy regarding the use of suprapubic tubes (SPT) in pelvic fracture urethral injury (PFUI) patients undergoing internal fixation (IF) as to the potential risk of infection. Using the National Trauma Data Bank, we sought to examine if placement of SPT in patients with traumatic urethral injuries undergoing IF of pelvic fractures increases the risks of infectious complications during the index hospitalization.

PATIENTS AND METHODS

Using International Classification of Disease, version 9 and Abbreviated Injury Scale codes, patients with PFUI were identified in the National Trauma Data Bank between 2002 and 2014. International Classification of Disease, version 9 codes were used to identify patients who underwent IF of pelvic fractures, as well as those who underwent SPT placement. Covariates analyzed included age, Injury Severity Score (ISS), diabetes, hypertension, coronary artery disease, obesity, smoking status, associated colorectal injuries, and pelvic angioembolization. Demographics, management and infectious complications were compared between IF patients who did or did not undergo SPT placement using χ2 and t tests. Poisson regression analysis was performed to identify independent predictors of infectious complications.

RESULTS

Six hundred ninety-six PFUI patients were identified. Two hundred four (29.3%) patients underwent IF during the index hospitalization, of which 35 underwent concomitant SPT placement during that same admission. There was no difference in likelihood of undergoing IF in patients with or without SPT (p = 0.36). Multivariate analysis revealed that only ISS (Relative risk [RR], 4.00; 95% confidence interval, 1.25–12.77) and smoking status (RR, 2.45; 95% confidence interval, 1.11–5.43) were significant predictors of infectious complications, while SPT placement was not.

CONCLUSION

Among patients with PFUI undergoing IF, SPT placement does not appear to increase the risk for acute infectious complications during the index hospitalization, while higher ISS and smoking are significantly associated. Further longitudinal studies are required to provide definitive recommendations regarding the long-term safety of SPT placement in this patient population.

LEVEL OF EVIDENCE

Prognostic, level IV.