bluuebunny/crossref_metadata_2025_split huggingface dataset:
Origins of Combination Therapy for Tuberculosis: Lessons for Future Antimicrobial Development and Application
Authors: Kerantzas Christopher A. , Jacobs William R. 
Published: March 2017

ABSTRACT

Tuberculosis is a global health problem that causes the death of approximately 1.5 million people worldwide each year (WHO, p. 1–126,
Global Tuberculosis Report
, 2015). Treatment of drug-susceptible tuberculosis requires combination antimicrobial therapy with a minimum of four antimicrobial agents applied over the course of 6 months. The first instance of combination antimicrobial therapy applied to tuberculosis was the joint use of streptomycin and
para
-aminosalicylic acid as documented by the Medical Research Council of the United Kingdom in 1950. These antimicrobial drugs were the product of many decades of investigation into both organism-derived antibiotics and synthetic chemotherapy and were the first agents in those respective categories to show substantial clinical efficacy and widespread use for tuberculosis. The events leading to the discovery and application of these two agents demonstrate that investments in all aspects of research, from basic science to clinical application, are necessary for the continued success of science in finding treatments for human disease. This observation is especially worth considering given the expanded role that combination therapy may play in combating the current rise in resistance to antimicrobial drugs.
Plaques Formed by Mutagenized Viral Populations Have Elevated Coinfection Frequencies
Authors: Aguilera Elizabeth R. , Erickson Andrea K. , Jesudhasan Palmy R. , Robinson Christopher M. , Pfeiffer Julie K. 
Published: March 2017

ABSTRACT
The plaque assay is a common technique used to measure virus concentrations and is based upon the principle that each plaque represents a single infectious unit. As such, the number of plaques is expected to correlate linearly with the virus dilution plated, and each plaque should be formed by a single founder virus. Here, we examined whether more than one virus can contribute to plaque formation. By using genetic and phenotypic assays with genetically marked polioviruses, we found that multiple parental viruses are present in 5 to 7% of plaques, even at an extremely low multiplicity of infection. We demonstrated through visual and biophysical assays that, like many viral stocks, our viral stocks contain both single particles and aggregates. These data suggest that aggregated virions are capable of inducing coinfection and chimeric plaque formation. In fact, inducing virion aggregation via exposure to low pH increased coinfection in a flow cytometry-based assay. We hypothesized that plaques generated by viruses with high mutation loads may have higher coinfection frequencies due to processes restoring fitness, such as complementation and recombination. Indeed, we found that coinfection frequency correlated with mutation load, with 17% chimeric plaque formation for heavily mutagenized viruses. Importantly, the frequency of chimeric plaques may be underestimated by up to threefold, since coinfection with the same parental virus cannot be scored in our assay. This work indicates that more than one virus can contribute to plaque formation and that coinfection may assist plaque formation in situations where the amount of genome damage is high.

IMPORTANCE
One of the most common methods to quantify viruses is the plaque assay, where it is generally presumed that each plaque represents a single infectious virus. Using genetically marked polioviruses, we demonstrate that a plaque can contain more than one parental virus, likely due to aggregates within virus stocks that induce coinfection of a cell. A relatively small number of plaques are the products of coinfection for our standard virus stocks. However, mutagenized virus stocks with increased genome damage give rise to a higher amount of plaques that are chimeric. These results suggest that coinfection may aid plaque formation of viruses with genome damage, possibly due to processes such as complementation and recombination. Overall, our results suggest that the relationship between viral dilution and plaque number may not be linear, particularly for mutagenized viral populations.
Arginine Is a Critical Substrate for the Pathogenesis ofPseudomonas aeruginosain Burn Wound Infections
Authors: Everett Jake , Turner Keith , Cai Qiuxian , Gordon Vernita , Whiteley Marvin , Rumbaugh Kendra 
Published: March 2017

ABSTRACTEnvironmental conditions affect bacterial behavior and can greatly influence the course of an infection. However, the environmental cues that elicit bacterial responses in specific infection sites are relatively unknown.Pseudomonas aeruginosais ubiquitous in nature and typically innocuous. However, it is also one of the most prevalent causes of fatal sepsis in burn wound patients. The aim of this study was to determine the impact of environmental factors, specifically the availability of arginine, on the pathogenesis ofP. aeruginosain burn wound infections. Comparison of burned versus noninjured tissue revealed thatl-arginine (l-Arg) was significantly depleted in burn wounds as a consequence of elevated arginase produced by myeloid-derived suppressor cells. We also observed thatl-Arg was a potent chemoattractant forP. aeruginosa, and while low concentrations ofl-Arg increasedP. aeruginosa’s swimming motility, high concentrations resulted in diminished swimming. Based on these observations, we tested whether the administration of exogenousl-Arg into the burn wound could attenuate the virulence ofP. aeruginosain thermally injured mice. Administration ofl-Arg resulted in decreasedP. aeruginosaspread and sepsis and increased animal survival. Taken together, these data demonstrate that the availability of environmental arginine greatly influences the virulence ofP. aeruginosa in vivoand may represent a promising phenotype-modulating tool for future therapeutic avenues.IMPORTANCEDespite our growing understanding of the pathophysiology of burn wounds and the evolution of techniques and practices to manage infections, sepsis remains a significant medical concern for burn patients.P. aeruginosacontinues to be a leader among all causes of bacteremic infections due to its tendency to cause complications in immunocompromised patients and its ubiquitous presence in the hospital setting. With the unforgiving emergence of multidrug-resistant strains, it is critical that alternative strategies to control or prevent septic infections in burn patients be developed in parallel with novel antimicrobial agents. In this study, we observed that administration ofl-Arg significantly reduced bacterial spread and sepsis in burned mice infected withP. aeruginosa. Given the safety ofl-Arg in high doses and its potential wound-healing benefits, this conditionally essential amino acid may represent a useful tool to modulate bacterial behaviorin vivoand prevent sepsis in burn patients.
‘The Score Matters’: wide variations in predictive performance of 18 paediatric track and trigger systems
Authors: Chapman Susan M , Wray Jo , Oulton Kate , Pagel Christina , Ray Samiran , Peters Mark J 
Published: March 2017

ObjectiveTo compare the predictive performance of 18 paediatric early warning systems (PEWS) in predicting critical deterioration.DesignRetrospective case-controlled study. PEWS values were calculated from existing clinical data, and the area under the receiver operator characteristic curve (AUROC) compared.SettingUK tertiary referral children's hospital.PatientsPatients without a ‘do not attempt resuscitation’ order admitted between 1 January 2011 and 31 December 2012. All patients on paediatric wards who suffered a critical deterioration event were designated ‘cases’ and matched with a control closest in age who was present on the same ward at the same time.Main outcome measuresRespiratory and/or cardiac arrest, unplanned transfer to paediatric intensive care and/or unexpected death.Results12 ‘scoring’ and 6 ‘trigger’ systems were suitable for comparative analysis. 297 case events in 224 patients were available for analysis. 244 control patients were identified for the 311 events. Three PEWS demonstrated better overall predictive performance with an AUROC of 0.87 or greater. Comparing each system with the highest performing PEWS with Bonferroni's correction for multiple comparisons resulted in statistically significant differences for 13 systems. Trigger systems performed worse than scoring systems, occupying the six lowest places in the AUROC rankings.ConclusionsThere is considerable variation in the performance of published PEWS, and as such the choice of PEWS has the potential to be clinically important. Trigger-based systems performed poorly overall, but it remains unclear what factors determine optimum performance. More complex systems did not necessarily demonstrate improved performance.
‘We identify, discuss, act and promise to prevent similar deaths’: a qualitative study of Ethiopia's Maternal Death Surveillance and Response system
Authors: Abebe Berhanu , Busza Joanna , Hadush Azmach , Usmael Abdurehman , Zeleke Amsalu Belew , Sita Sahle , Hailu Solomon , Graham Wendy J 
Published: March 2017

IntroductionEthiopia introduced national Maternal Death Surveillance and Response (MDSR) in 2013 and is among the first sub-Saharan African countries to capture data on facility-based and community-based maternal deaths. We interviewed frontline MDSR implementers about their experiences of the first 2 years of MDSR, including perceptions of its introduction and outcomes for health services.MethodsWe conducted a qualitative case study in 4 zones in the largest regions, interviewing 69 key informants from regional, zonal, district and facility levels.ResultsA defining feature of Ethiopia's MDSR system is its integration within existing disease surveillance, with both benefits and challenges. Facilitators of the system's introduction were strong political support, alignment with broader health strategies and strong links across health system departments. Barriers included confusion around new responsibilities, high staff turnover and fear of legal repercussions. Stakeholders believed MDSR increased confidence in using local data to improve maternal health services and enhanced communication across the health system.ConclusionsMDSR systems take time to establish, encountering challenges in early implementation. Ensuring MDSR has a clear purpose, explicitly defined roles and responsibilities, and adequate supervisory support from the start will ensure it becomes embedded within the health system as routine practice rather than perceived as a stand-alone system. Countries planning to adopt or extend MDSR can learn from Ethiopia's experience, particularly the decision to make maternal mortality a weekly reportable condition within Public Health Emergency Management.
Payback time? Influence of having children on mortality in old age
Authors: Modig K , Talbäck M , Torssander J , Ahlbom A 
Published: March 2017

BackgroundIt is known that parents have lower mortality than childless individuals. Support from adult children to ageing parents may be of importance for parental health and longevity. The aim of this study was to estimate the association between having a child and the risk of death, and to examine whether the association increased at older ages when health starts to deteriorate and the need of support from a family member increases.MethodsIn this nationwide study, all men and women (born between 1911 and 1925 and residing in Sweden), as well as their children, were identified in population registers and followed over time. Age-specific death risks were calculated for each calendar year for individuals having at least one child and for individuals without children. Adjusted risk differences and risk ratios were estimated.ResultsMen and women having at least one child experienced lower death risks than childless men and women. At 60 years of age, the difference in life expectancy was 2 years for men and 1.5 years for women. The absolute differences in death risks increased with parents' age and were somewhat larger for men than for women. The association persisted when the potential confounding effect of having a partner was taken into account. The gender of the child did not matter for the association between parenthood and mortality.ConclusionsHaving children is associated with increased longevity, particularly in an absolute sense in old age. That the association increased with parents' age and was somewhat stronger for the non-married may suggest that social support is a possible explanation.
Enhancing the diagnosis of fabry disease in cardiology with a targeted information: a before–after control–impact study
Authors: Savary Anne-Louise , Morello Remy , Brasse-Lagnel Carole , Milliez Paul , Bekri Soumeya , Labombarda Fabien 
Published: March 2017

BackgroundCardiac complications in Fabry disease are frequent and dominated by a high frequency of left ventricular hypertrophy; therefore, cardiologists may have an essential role in screening for this disease. Providing cardiologists with targeted information on Fabry disease would be valuable and could reduce both diagnostic and therapeutic delays. The aim of this study was to evaluate the efficiency of such strategy for Fabry screening.MethodsWe conducted a before–after control–impact study by comparing observations made before and after targeted information on Fabry disease among cardiologists. The information on Fabry disease consisted of (1) an educational booklet, (2) oral information and (3) screening kits. The programme was evaluated at the end of a 12-month study period.ResultsForty-two cardiologists participated to this study. None of them had conducted screening test and new diagnostic for Fabry disease in the 3 years prior the information. After the information, screening with dried blood spots was performed in 55 patients (ranged 18–77 years, men: 39) with cardiac monitoring for supposed sarcomeric hypertrophic cardiomyopathy (n=41) or unexplained left ventricular hypertrophy (n=14) from January 2015 to January 2016. Two new cases of Fabry disease were diagnosed (3.4%) in two men (ages 58 and 51 years). The information was deemed relevant in both content and structure and was deemed useful for everyday practice.ConclusionCardiologists valued the targeted information on Fabry disease. This information had a direct clinical impact by allowing the diagnosis of two new families with Fabry disease.
Security in Automotive Networks
Authors: Mundhenk Philipp , Paverd Andrew , Mrowca Artur , Steinhorst Sebastian , Lukasiewycz Martin , Fahmy Suhaib A. , Chakraborty Samarjit 
Published: March 2017

With the increasing amount of interconnections between vehicles, the attack surface of internal vehicle networks is rising steeply. Although these networks are shielded against external attacks, they often do not have any internal security to protect against malicious components or adversaries who can breach the network perimeter. To secure the in-vehicle network, all communicating components must be authenticated, and only authorized components should be allowed to send and receive messages. This is achieved through the use of an authentication framework. Cryptography is widely used to authenticate communicating parties and provide secure communication channels (e.g., Internet communication). However, the real-time performance requirements of in-vehicle networks restrict the types of cryptographic algorithms and protocols that may be used. In particular, asymmetric cryptography is computationally infeasible during vehicle operation.
In this work, we address the challenges of designing authentication protocols for automotive systems. We present Lightweight Authentication for Secure Automotive Networks (LASAN), a full lifecycle authentication approach. We describe the core LASAN protocols and show how they protect the internal vehicle network while complying with the real-time constraints and low computational resources of this domain. By leveraging the fixed structure of automotive networks, we minimize bandwidth and computation requirements. Unlike previous work, we also explain how this framework can be integrated into all aspects of the automotive product lifecycle, including manufacturing, vehicle maintenance, and software updates. We evaluate LASAN in two different ways: First, we analyze the security properties of the protocols using established protocol verification techniques based on formal methods. Second, we evaluate the timing requirements of LASAN and compare these to other frameworks using a new highly modular discrete event simulator for in-vehicle networks, which we have developed for this evaluation.
Nonreciprocal homeostatic compensation in Drosophila potassium channel mutants
Authors: Kim Eugene Z. , Vienne Julie , Rosbash Michael , Griffith Leslie C. 
Published: March 2017

Homeostatic control of intrinsic excitability is important for long-term regulation of neuronal activity. In conjunction with many other forms of plasticity, intrinsic homeostasis helps neurons maintain stable activity regimes in the face of external input variability and destabilizing genetic mutations. In this study, we report a mechanism by which Drosophila melanogaster larval motor neurons stabilize hyperactivity induced by the loss of the delayed rectifying K+ channel Shaker cognate B ( Shab), by upregulating the Ca2+-dependent K+ channel encoded by the slowpoke ( slo) gene. We also show that loss of SLO does not trigger a reciprocal compensatory upregulation of SHAB, implying that homeostatic signaling pathways utilize compensatory pathways unique to the channel that was mutated. SLO upregulation due to loss of SHAB involves nuclear Ca2+ signaling and dCREB, suggesting that the slo homeostatic response is transcriptionally mediated. Examination of the changes in gene expression induced by these mutations suggests that there is not a generic transcriptional response to increased excitability in motor neurons, but that homeostatic compensations are influenced by the identity of the lost conductance. NEW & NOTEWORTHY The idea that activity-dependent homeostatic plasticity is driven solely by firing has wide credence. In this report we show that homeostatic compensation after loss of an ion channel conductance is tailored to identity of the channel lost, not its properties.
In vivo optogenetic activation of Nav1.8+ cutaneous nociceptors and their responses to natural stimuli
Authors: Uhelski Megan L. , Bruce Daniel J. , Séguéla Philippe , Wilcox George L. , Simone Donald A. 
Published: March 2017

Optogenetic methods that utilize expression of the light-sensitive protein channelrhodopsin-2 (ChR2) in neurons have enabled selective activation of specific subtypes or groups of neurons to determine their functions. Using a transgenic mouse model in which neurons natively expressing Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) also express the light-gated channel ChR2, we have been able to determine the functional properties of Nav1.8-expressing cutaneous nociceptors of the glabrous skin in vivo. Most (44 of 53) of the C-fiber nociceptors isolated from Nav1.8-ChR2+ mice were found to be responsive to blue (470 nm) light. Response characteristics, including conduction velocity and responses to mechanical stimuli, were comparable between nociceptors isolated from Nav1.8-ChR2+ and control mice. Interestingly, while none of the non–light-responsive C-fibers were sensitive to heat or cold, nearly all (77%) light-sensitive fibers were excited by mechanical and thermal stimuli, suggesting that Nav1.8 is predominantly expressed by C-fiber nociceptors that are responsive to multiple stimulus modalities. The ability to activate peripheral nociceptors with light provides a method of stimulation that is noninvasive, does not require mechanical interruption of the skin, and accesses receptive fields that might be difficult or impossible to stimulate with standard stimuli while allowing repeated stimulation without injuring the skin. NEW & NOTEWORTHY Transgenic mice that express the blue light-sensitive protein channelrhodopsin2 (ChR2) in nociceptive nerve fibers that contain voltage-gated sodium channel Nav1.8 were used to determine functional properties of these afferent fibers. Electrophysiological recordings in vivo revealed that most nociceptive fibers that possess Nav1.8 are C-fiber nociceptors that respond to multiple stimulus modalities. Furthermore, responses evoked by blue light stimulation were comparable to those elicited by noxious mechanical, heat, and cold stimuli.
Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer
Authors: Willuda Jörg , Linden Lars , Lerchen Hans-Georg , Kopitz Charlotte , Stelte-Ludwig Beatrix , Pena Carol , Lange Claudia , Golfier Sven , Kneip Christoph , Carrigan Patricia E. , Mclean Kirk , Schuhmacher Joachim , von Ahsen Oliver , Müller Jörg , Dittmer Frank , Beier Rudolf , El Sheikh Sherif , Tebbe Jan , Leder Gabriele , Apeler Heiner , Jautelat Rolf , Ziegelbauer Karl , Kreft Bertolt 
Published: March 2017

Abstract
C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non–small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody–drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker. In vitro, C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC. In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing. Mol Cancer Ther; 16(5); 893–904. ©2017 AACR.