bluuebunny/crossref_metadata_2025 huggingface dataset:
The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study
Authors: Kiessling Peter , Lledo-Garcia Rocio , Watanabe Shikiko , Langdon Grant , Tran Diep , Bari Muhammad , Christodoulou Louis , Jones Emma , Price Graham , Smith Bryan , Brennan Frank , White Ian , Jolles Stephen
Published: November 2017

A first-in-human study of rozanolixizumab (UCB7665), an antihuman FcRn monoclonal antibody for IgG autoantibody-mediated diseases, is reported.
A completely biological “off-the-shelf” arteriovenous graft that recellularizes in baboons
Authors: Syedain Zeeshan H. , Graham Melanie L. , Dunn Ty B. , O’Brien Timothy , Johnson Sandra L. , Schumacher Robert J. , Tranquillo Robert T.
Published: November 2017

A decellularized tissue tube grown from human skin cells and fibrin becomes repopulated by recipient cells when tested in baboons as a vascular graft for hemodialysis access.
A 3.0-Angstrom Resolution Cryo-Electron Microscopy Structure and Antigenic Sites of Coxsackievirus A6-Like Particles
Authors: Chen Jinhuan , Zhang Chao , Zhou Yu , Zhang Xiang , Shen Chaoyun , Ye Xiaohua , Jiang Wen , Huang Zhong , Cong Yao
Published: November 2017

Coxsackievirus A6 (CVA6) has recently emerged as one of the predominant causative agents of hand, foot, and mouth disease (HFMD). The structure of the CVA6 mature viral particle has not been solved thus far. Our previous work shows that recombinant virus-like particles (VLPs) of CVA6 represent a promising CVA6 vaccine candidate. Here, we report the first cryo-electron microscopy (cryo-EM) structure of the CVA6 VLP at 3.0-Å resolution. The CVA6 VLP exhibits the characteristic features of enteroviruses but presents an open channel at the 2-fold axis and an empty, collapsed VP1 pocket, which is broadly similar to the structures of the enterovirus 71 (EV71) VLP and coxsackievirus A16 (CVA16) 135S expanded particle, indicating that the CVA6 VLP is in an expanded conformation. Structural comparisons reveal that two common salt bridges within protomers are maintained in the CVA6 VLP and other viruses of the
Enterovirus
genus, implying that these salt bridges may play a critical role in enteroviral protomer assembly. However, there are apparent structural differences among the CVA6 VLP, EV71 VLP, and CVA16 135S particle in the surface-exposed loops and C termini of subunit proteins, which are often antigenic sites for enteroviruses. By immunological assays, we identified two CVA6-specific linear B-cell epitopes (designated P42 and P59) located at the GH loop and the C-terminal region of VP1, respectively, in agreement with the structure-based prediction of antigenic sites. Our findings elucidate the structural basis and important antigenic sites of the CVA6 VLP as a strong vaccine candidate and also provide insight into enteroviral protomer assembly.

IMPORTANCE
Coxsackievirus A6 (CVA6) is becoming one of the major pathogens causing hand, foot, and mouth disease (HFMD), leading to significant morbidity and mortality in children and adults. However, no vaccine is currently available to prevent CVA6 infection. Our previous work shows that recombinant virus-like particles (VLPs) of CVA6 are a promising CVA6 vaccine candidate. Here, we present a 3.0-Å structure of the CVA6 VLP determined by cryo-electron microscopy. The overall architecture of the CVA6 VLP is similar to those of the expanded structures of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), but careful structural comparisons reveal significant differences in the surface-exposed loops and C termini of each capsid protein of these particles. In addition, we identified two CVA6-specific linear B-cell epitopes and mapped them to the GH loop and the C-terminal region of VP1, respectively. Collectively, our findings provide a structural basis and important antigenic information for CVA6 VLP vaccine development.
VP1 and VP3 Are Required and Sufficient for Translation Initiation of Uncapped Infectious Bursal Disease Virus Genomic Double-Stranded RNA
Authors: Ye Chengjin , Wang Yu , Zhang Enli , Han Xinpeng , Yu Zhaoli , Liu Hebin
Published: November 2017

Infectious bursal disease virus (IBDV) is a bisegmented double-strand RNA (dsRNA) virus of the
Birnaviridae
family. While IBDV genomic dsRNA lacks a 5′ cap, the means by which the uncapped IBDV genomic RNA is translated effectively is unknown. In this study, we describe a cap-independent pathway of translation initiation of IBDV uncapped RNA that relies on VP1 and VP3. We show that neither purified IBDV genomic dsRNA nor the uncapped viral plus-sense RNA transcripts were directly translated and rescued into infectious viruses in host cells. This defect in translation of the uncapped IBDV genomic dsRNA was rescued by
trans
-supplementation of the viral proteins VP1 and VP3 which was dependent on both the intact polymerase activity of VP1 and the dsRNA binding activity of VP3. Deletion analysis showed that both 5′ and 3′ untranslated regions (UTRs) of IBDV dsRNA were essential for VP1/VP3-dependent translation initiation. Significantly, VP1 and VP3 could also mediate the recovery of infectious IBDV from the authentic minus-sense strand of IBDV dsRNA. Moreover, downregulation or inhibition of the cap-binding protein eIF4E did not decrease but, rather, enhanced the VP1/VP3-mediated translation of the uncapped IBDV RNA. Collectively, our findings for the first time reveal that VP1 and VP3 compensate for the deficiency of the 5′ cap and replace eIF4E to confer upon the uncapped IBDV RNA the ability to be translated and rescued into infectious viruses.

IMPORTANCE
A key point of control for virus replication is viral translation initiation. The current study shows that the uncapped IBDV RNA cannot be translated into viral proteins directly by host translation machinery and is thus noninfectious. Our results constitute the first direct experimental evidence that VP1 and VP3 are required and sufficient to initiate translation of uncapped IBDV genomic RNA by acting as a substitute for cap and replacing the cap-binding protein eIF4E. Significantly, VP1/VP3 mediate the recovery of infectious IBDV not only from the plus-sense strand but also from the minus-sense strand of the IBDV dsRNA. These findings provide not only new insights into the molecular mechanisms of the life cycle of IBDV but also a new tool for an alternative strategy for the recovery of IBDV from both the plus- and the minus-sense strands of the viral genomic dsRNA.
Characterization of Recombinant Flaviviridae Viruses Possessing a Small Reporter Tag
Authors: Tamura Tomokazu , Fukuhara Takasuke , Uchida Takuro , Ono Chikako , Mori Hiroyuki , Sato Asuka , Fauzyah Yuzy , Okamoto Toru , Kurosu Takeshi , Setoh Yin Xiang , Imamura Michio , Tautz Norbert , Sakoda Yoshihiro , Khromykh Alexander A. , Chayama Kazuaki , Matsuura Yoshiharu
Published: November 2017

The family
Flaviviridae
consists of four genera,
Flavivirus
,
Pestivirus
,
Pegivirus
, and
Hepacivirus
, and comprises important pathogens of human and animals. Although the construction of recombinant viruses carrying reporter genes encoding fluorescent and bioluminescent proteins has been reported, the stable insertion of foreign genes into viral genomes retaining infectivity remains difficult. Here, we applied the 11-amino-acid subunit derived from NanoLuc luciferase to the engineering of the
Flaviviridae
viruses and then examined the biological characteristics of the viruses. We successfully generated recombinant viruses carrying the split-luciferase gene, including dengue virus, Japanese encephalitis virus, hepatitis C virus (HCV), and bovine viral diarrhea virus. The stability of the viruses was confirmed by five rounds of serial passages in the respective susceptible cell lines. The propagation of the recombinant luciferase viruses in each cell line was comparable to that of the parental viruses. By using a purified counterpart luciferase protein, this split-luciferase assay can be applicable in various cell lines, even when it is difficult to transduce the counterpart gene. The efficacy of antiviral reagents against the recombinant viruses could be monitored by the reduction of luciferase expression, which was correlated with that of viral RNA, and the recombinant HCV was also useful to examine viral dynamics
in vivo
. Taken together, our findings indicate that the recombinant
Flaviviridae
viruses possessing the split NanoLuc luciferase gene generated here provide powerful tools to understand viral life cycle and pathogenesis and a robust platform to develop novel antivirals against
Flaviviridae
viruses.

IMPORTANCE
The construction of reporter viruses possessing a stable transgene capable of expressing specific signals is crucial to investigations of viral life cycle and pathogenesis and the development of antivirals. However, it is difficult to maintain the stability of a large foreign gene, such as those for fluorescence and bioluminescence, after insertion into a viral genome. Here, we successfully generated recombinant
Flaviviridae
viruses carrying the 11-amino-acid subunit derived from NanoLuc luciferase and demonstrated that these viruses are applicable to
in vitro
and
in vivo
experiments, suggesting that these recombinant
Flaviviridae
viruses are powerful tools for increasing our understanding of viral life cycle and pathogenesis and that these recombinant viruses will provide a robust platform to develop antivirals against
Flaviviridae
viruses.
Inducible MicroRNA-3570 Feedback Inhibits the RIG-I-Dependent Innate Immune Response to Rhabdovirus in Teleost Fish by Targeting MAVS/IPS-1
Authors: Xu Tianjun , Chu Qing , Cui Junxia , Bi Dekun
Published: November 2017

Effectively recognizing invading viruses and subsequently inducing innate antiviral immunity are essential for host antiviral defense. Although these processes are closely regulated by the host to maintain immune balance, viruses have evolved the ability to downregulate or upregulate these processes for their survival. MicroRNAs (miRNAs) are a family of small noncoding RNAs that play vital roles in modulating host immune response. Accumulating evidence demonstrates that host miRNAs as mediators are involved in regulating viral replication and host antiviral immunity in mammals. However, the underlying regulatory mechanisms in fish species are still poorly understood. Here, we found that rhabdovirus infection significantly upregulated host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulated RNA virus-triggered type I interferon (IFN) and antiviral gene production, thus facilitating viral replication. Furthermore, miR-3570 was found to target and posttranscriptionally downregulate mitochondrial antiviral signaling protein (MAVS), which functions as a platform for innate antiviral signal transduction. Moreover, we demonstrated that miR-3570 suppressed the expression of MAVS, thereby inhibiting MAVS-mediated NF-κB and IRF3 signaling. The collective results demonstrated a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miRNA.

IMPORTANCE
RNA viral infection could upregulate host miR-3570 expression in miiuy croaker macrophages. Induced miR-3570 negatively modulates RNA virus-triggered type I IFN and antiviral gene production, thus facilitating viral replication. Remarkably, miR-3570 could target and inhibit MAVS expression, which thus modulates MAVS-mediated NF-κB and IRF3 signaling. The collective results of this study suggest a novel regulation mechanism of MAVS-mediated immunity during RNA viral infection by miR-3570. Thus, a novel mechanism for virus evasion in fish is proposed.
Glycan Shield and Fusion Activation of a Deltacoronavirus Spike Glycoprotein Fine-Tuned for Enteric Infections
Authors: Xiong Xiaoli , Tortorici M. Alejandra , Snijder Joost , Yoshioka Craig , Walls Alexandra C. , Li Wentao , McGuire Andrew T. , Rey Félix A. , Bosch Berend-Jan , Veesler David
Published: November 2017

Coronaviruses recently emerged as major human pathogens causing outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome. They utilize the spike (S) glycoprotein anchored in the viral envelope to mediate host attachment and fusion of the viral and cellular membranes to initiate infection. The S protein is a major determinant of the zoonotic potential of coronaviruses and is also the main target of the host humoral immune response. We report here the 3.5-Å-resolution cryo-electron microscopy structure of the S glycoprotein trimer from the pathogenic porcine deltacoronavirus (PDCoV), which belongs to the recently identified
Deltacoronavirus
genus. Structural and glycoproteomics data indicate that the glycans of PDCoV S are topologically conserved compared with the human respiratory coronavirus NL63 S, resulting in similar surface areas being shielded from neutralizing antibodies and implying that both viruses are under comparable immune pressure in their respective hosts. The structure further reveals a shortened S
2
′ activation loop, containing a reduced number of basic amino acids, which participates in rendering the spike largely protease resistant. This property distinguishes PDCoV S from recently characterized betacoronavirus S proteins and suggests that the S protein of enterotropic PDCoV has evolved to tolerate the protease-rich environment of the small intestine and to fine-tune its fusion activation to avoid premature triggering and reduction of infectivity.

IMPORTANCE
Coronaviruses use transmembrane S glycoprotein trimers to promote host attachment and fusion of the viral and cellular membranes. We determined a near-atomic-resolution cryo-electron microscopy structure of the S ectodomain trimer from the pathogenic PDCoV, which is responsible for diarrhea in piglets and has had devastating consequences for the swine industry worldwide. Structural and glycoproteomics data reveal that PDCoV S is decorated with 78 N-linked glycans obstructing the protein surface to limit accessibility to neutralizing antibodies in a way reminiscent of what has recently been described for a human respiratory coronavirus. PDCoV S is largely protease resistant, which distinguishes it from most other characterized coronavirus S glycoproteins and suggests that enteric coronaviruses have evolved to fine-tune fusion activation in the protease-rich environment of the small intestine of infected hosts.
Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
Authors: Krishnamoorthy Ganesh , Leus Inga V. , Weeks Jon W. , Wolloscheck David , Rybenkov Valentin V. , Zgurskaya Helen I.
Published: November 2017

Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens
Acinetobacter baumannii
,
Pseudomonas aeruginosa
, and
Burkholderia
spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens.

IMPORTANCE
Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of
P. aeruginosa
,
A. baumannii
,
Burkholderia thailandensis
, and
B. cepacia
. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.
The Metallophore Staphylopine Enables
Staphylococcus aureus
To Compete with the Host for Zinc and Overcome Nutritional Immunity
Authors: Grim Kyle P. , San Francisco Brian , Radin Jana N. , Brazel Erin B. , Kelliher Jessica L. , Párraga Solórzano Paola K. , Kim Philip C. , McDevitt Christopher A. , Kehl-Fie Thomas E.
Published: November 2017

During infection, the host sequesters essential nutrients, such as zinc, to combat invading microbes. Despite the ability of the immune effector protein calprotectin to bind zinc with subpicomolar affinity,
Staphylococcus aureus
is able to successfully compete with the host for zinc. However, the zinc importers expressed by
S. aureus
remain unknown. Our investigations have revealed that
S. aureus
possesses two importers, AdcABC and CntABCDF, which are induced in response to zinc limitation. While AdcABC is similar to known zinc importers in other bacteria, CntABCDF has not previously been associated with zinc acquisition. Concurrent loss of the two systems severely impairs the ability of
S. aureus
to obtain zinc and grow in zinc-limited environments. Further investigations revealed that the Cnt system is responsible for the ability of
S. aureus
to compete with calprotectin for zinc in culture and contributes to acquisition of zinc during infection. The
cnt
locus also enables
S. aureus
to produce the broad-spectrum metallophore staphylopine. Similarly to the Cnt transporter, loss of staphylopine severely impairs the ability of
S. aureus
to resist host-imposed zinc starvation, both in culture and during infection. Further investigations revealed that together staphylopine and the Cnt importer function analogously to siderophore-based iron acquisition systems in order to facilitate zinc acquisition by
S. aureus
. Analogous systems are found in a broad range of Gram-positive and Gram-negative bacterial pathogens, suggesting that this new type of zinc importer broadly contributes to the ability of bacteria to cause infection.

IMPORTANCE
A critical host defense against infection is the restriction of zinc availability. Despite the subpicomolar affinity of the immune effector calprotectin for zinc,
Staphylococcus aureus
can successfully compete for this essential metal. Here, we describe two zinc importers, AdcABC and CntABCDF, possessed by
S. aureus
, the latter of which has not previously been associated with zinc acquisition. The ability of
S. aureus
to compete with the host for zinc is dependent on CntABCDF and the metallophore staphylopine, both in culture and during infection. These results expand the mechanisms utilized by bacteria to obtain zinc, beyond Adc-like systems, and demonstrate that pathogens utilize strategies similar to siderophore-based iron acquisition to obtain other essential metals during infection. The staphylopine synthesis machinery is present in a diverse collection of bacteria, suggesting that this new family of zinc importers broadly contributes to the ability of numerous pathogens to cause infection.
The Csr System Regulates
Escherichia coli
Fitness by Controlling Glycogen Accumulation and Energy Levels
Authors: Morin Manon , Ropers Delphine , Cinquemani Eugenio , Portais Jean-Charles , Enjalbert Brice , Cocaign-Bousquet Muriel
Published: November 2017

In the bacterium
Escherichia coli
, the posttranscriptional regulatory system Csr was postulated to influence the transition from glycolysis to gluconeogenesis. Here, we explored the role of the Csr system in the glucose-acetate transition as a model of the glycolysis-to-gluconeogenesis switch. Mutations in the Csr system influence the reorganization of gene expression after glucose exhaustion and disturb the timing of acetate reconsumption after glucose exhaustion. Analysis of metabolite concentrations during the transition revealed that the Csr system has a major effect on the energy levels of the cells after glucose exhaustion. This influence was demonstrated to result directly from the effect of the Csr system on glycogen accumulation. Mutation in glycogen metabolism was also demonstrated to hinder metabolic adaptation after glucose exhaustion because of insufficient energy. This work explains how the Csr system influences
E. coli
fitness during the glycolysis-gluconeogenesis switch and demonstrates the role of glycogen in maintenance of the energy charge during metabolic adaptation.

IMPORTANCE
Glycogen is a polysaccharide and the main storage form of glucose from bacteria such as
Escherichia coli
to yeasts and mammals. Although its function as a sugar reserve in mammals is well documented, the role of glycogen in bacteria is not as clear. By studying the role of posttranscriptional regulation during metabolic adaptation, for the first time, we demonstrate the role of sugar reserve played by glycogen in
E. coli
. Indeed, glycogen not only makes it possible to maintain sufficient energy during metabolic transitions but is also the key component in the capacity of cells to resume growth. Since the essential posttranscriptional regulatory system Csr is a major regulator of glycogen accumulation, this work also sheds light on the central role of posttranscriptional regulation in metabolic adaptation.
Cryptococcus neoformans
Iron-Sulfur Protein Biogenesis Machinery Is a Novel Layer of Protection against Cu Stress
Authors: Garcia-Santamarina Sarela , Uzarska Marta A. , Festa Richard A. , Lill Roland , Thiele Dennis J.
Published: November 2017

Copper (Cu) ions serve as catalytic cofactors to drive key biochemical processes, and yet Cu levels that exceed cellular homeostatic control capacity are toxic. The underlying mechanisms for Cu toxicity are poorly understood. During pulmonary infection by the fungal pathogen
Cryptococcus neoformans
, host alveolar macrophages compartmentalize Cu to the phagosome, and the ability to detoxify Cu is critical for its survival and virulence. Here, we report that iron-sulfur (Fe-S) clusters are critical targets of Cu toxicity in both
Saccharomyces cerevisiae
and
C. neoformans
in a manner that depends on the accessibility of Cu to the Fe-S cofactor. To respond to this Cu-dependent Fe-S stress,
C. neoformans
induces the transcription of mitochondrial ABC transporter Atm1, which functions in cytosolic-nuclear Fe-S protein biogenesis in response to Cu and in a manner dependent on the Cu metalloregulatory transcription factor Cuf1. As Atm1 functions in exporting an Fe-S precursor from the mitochondrial matrix to the cytosol,
C. neoformans
cells depleted for Atm1 are sensitive to Cu even while the Cu-detoxifying metallothionein proteins are highly expressed. We provide evidence for a previously unrecognized microbial defense mechanism to deal with Cu toxicity, and we highlight the importance for
C. neoformans
of having several distinct mechanisms for coping with Cu toxicity which together could contribute to the success of this microbe as an opportunistic human fungal pathogen.

IMPORTANCE
C. neoformans
is an opportunistic pathogen that causes lethal meningitis in over 650,000 people annually. The severity of
C. neoformans
infections is further compounded by the use of toxic or poorly effective systemic antifungal agents as well as by the difficulty of diagnosis. Cu is a natural potent antimicrobial agent that is compartmentalized within the macrophage phagosome and used by innate immune cells to neutralize microbial pathogens. While the Cu detoxification machinery of
C. neoformans
is essential for virulence, little is known about the mechanisms by which Cu kills fungi. Here we report that Fe-S cluster-containing proteins, including members of the Fe-S protein biogenesis machinery itself, are critical targets of Cu toxicity and therefore that this biosynthetic process provides an important layer of defense against high Cu levels. Given the role of Cu ionophores as antimicrobials, understanding how Cu is toxic to microorganisms could lead to the development of effective, broad-spectrum antimicrobials. Moreover, understanding Cu toxicity could provide additional insights into the pathophysiology of human diseases of Cu overload such as Wilson’s disease.
One-year outcomes following surgery for necrotising enterocolitis: a UK-wide cohort study
Authors: Allin Benjamin Saul Raywood , Long Anna-May , Gupta Amit , Lakhoo Kokila , Knight Marian
Published: November 2017

Objective

The objective was to describe outcomes and investigate factors affecting prognosis at 1 year post intervention for infants with surgical necrotising enterocolitis (NEC).

Design

Using the British Association of Paediatric Surgeons Congenital Anomalies Surveillance System, we conducted a prospective, multicentre cohort study of every infant reported to require surgical intervention for NEC in the UK and Ireland between 1 March 2013 and 28 February 2014. Association of independent variables with 1-year mortality was investigated using multivariable logistic regression analysis.

Setting

All 28 paediatric surgical centres in the UK and Ireland.

Patients

Infants were eligible for inclusion if they were diagnosed with NEC and deemed to require surgical intervention, regardless of whether that intervention was delivered.

Outcomes

Primary outcome was mortality within 1 year of the decision to intervene surgically.

Results

236 infants were included in the study. 208 (88%) infants had 1-year follow-up. 59 of the 203 infants with known survival status (29%, 95% CI 23% to 36%) died within 1 year of the decision to intervene surgically. Following adjustment, key factors associated with reduced 1-year mortality included older gestational age at birth (adjusted OR (aOR) 0.87, 95% CI 0.78 to 0.96). Being small for gestational age (SGA) (aOR 3.6, 95% CI 1.4 to 9.5) and requiring parenteral nutrition at 28 days post-decision to intervene surgically (aOR 3.5, 95% CI 1.1 to 11.03) were associated with increased 1-year mortality.

Conclusions

Parents of infants undergoing surgery for NEC should be counselled that there is approximately a 1:3 risk of death in the first post-operative year but that the risk is lower for infants who are of greater gestational age at birth, who are not SGA and who do not require parenteral nutrition at 28 days post-intervention.
Hair thread tourniquet syndrome in a male infant: a rare surgical emergency
Authors: Dunphy Louise , Verma Yash , Morhij Rossel , Lamyman Michael
Published: November 2017

Hair thread tourniquet syndrome (HTTS) is a rare surgical emergency that occurs when one or more appendages are acutely circumferentially strangulated by human hair. If left untreated it may induce prolonged ischaemia, resulting in tissue necrosis or autoamputation of the affected digit. It may involve the fingers, toes, penis or labia. It typically occurs in infants, but cases have also been reported in adults. Prompt recognition and treatment by complete removal of the constricting agent is crucial to preserve the affected tissue. We report a case of HTTS affecting the left middle toe of an 8-week-old male infant successfully treated by surgical release of the hair. The authors aim to raise awareness of HTTS among physicians, emergency doctors, paediatricians and surgeons, as prompt recognition and management prevents adverse outcomes and tissue necrosis.
Is living in a gas-flaring host community associated with being hypertensive? Evidence from the Niger Delta region of Nigeria
Authors: Maduka Omosivie , Tobin-West Charles
Published: November 2017

Background

Researchers have linked gas flaring to climate change, the hastening of the epidemiological transition and an upsurge in the prevalence of non-communicable diseases. We sought to determine if a relationship exists between residing in a gas-flaring host community and hypertension.

Methods

We conducted an analytical cross-sectional household survey among residents of 600 households in three gas-flaring and three non-gas-flaring host communities in the Niger Delta region of Nigeria. We took geo-coordinates, administered a modified WHO-STEPS questionnaire and built on Android mobile phones using Open-Data-Kit (ODK) software. We also took biological measurements and carried out descriptive and inferential statistical analysis using SPSS and STATA.

Results

We interviewed a total of 912 adults: 437 (47.9%) from non-gas-flaring and 475 (52.1%) from gas-flaring host communities. There were differences in level of education (x2=42.99; p=0.00), occupation category (x2=25.42; p=0.00) and BMI category (x2=15.37; 0.003) among the two groups. The overall prevalence of hypertension was 23.7%: 20.7% among persons living in non-gas-flaring host communities compared with 25.3% among persons living in gas-flaring host communities (x2=2.89; p=0.89). Residence in a gas-flaring host community, (AdjOR=1.75; 95% CI=1.11 to 2.74) and mean age (AdjOR=1.05; 95% CI=1.03 to 1.07) were identified as the predictors of hypertension. There was a significant association between hypertension and age, 1.05 (1.04–1.06) while the probability of being hypertensive was higher among residents of gas-flaring host communities between 20 to 40 years and 60 to 80 years.

Conclusion

There is a need for the relevant agencies to scale up environmental and biological monitoring of air pollutants. The implication of a possible relationship between gas-flaring and hypertension brings to the fore the need for interventions to regulate gas-flaring activities.
Patient preference and choice of healthcare providers in Shanghai, China: a cross-sectional study
Authors: Yu Wenya , Li Meina , Ye Feng , Xue Chen , Zhang Lulu
Published: November 2017

Objectives

This study aimed to assess patients’ healthcare-seeking preferences in mild, chronic, and serious illness; identify influential factors; and examine the reasons underlying patients’ healthcare-seeking preference.

Design

A retrospective study.

Setting

The study was conducted in 14 tertiary hospitals in Shanghai, China.

Participants

Questionnaires were distributed to 1519 patients, and 1114 were completed and returned. All patients participated in the study voluntarily, provided written informed consent, and possessed the ability to complete the questionnaire.

Main outcome measures

We measured and compared preferences and choice of healthcare providers in patients if they had experienced mild, chronic, or serious illness.

Results

More than 50% of participants, including those who were >60 years of age, had consulted a doctor more than three times during the preceding year, were single, and were most likely to decide not to seek medical treatment. Community health facilities were the most frequently selected healthcare provider in mild illness. In addition, patients who had no personal preference, did not express a preference for a good environment or first-class medical technology, were concerned about close proximity and short waiting times, and pursued low medical costs were most likely to choose a community health facility. General hospitals were the most frequently selected healthcare provider in chronic and serious illness. In addition, patients who earned higher monthly incomes, did not pursue low medical costs, were not concerned about short waiting times or close proximity, and expressed a preference for first-class medical technology, were most likely to choose general hospitals.

Conclusion

Patients’ healthcare-seeking preference was influenced mainly by healthcare providers’ characteristics, illness severity, and sociodemographic characteristics. These findings indicate that patients’ current healthcare-seeking preference was not ideal and requires optimisation.
Markers of pubertal timing and leisure-time physical activity from ages 36 to 68 years: findings from a British birth cohort
Authors: Elhakeem Ahmed , Cooper Rachel , Bann David , Kuh Diana , Hardy Rebecca
Published: November 2017

Objectives

We aimed to examine associations between markers of pubertal timing and leisure-time physical activity (LTPA) from ages 36 to 68 years in men and women from the Medical Research Council National Survey of Health and Development.

Study design

Pubertal timing was ascertained by physicians at age 14–15 years. Boys were grouped, based on their secondary sexual characteristics, as prepubescent, in early-stage puberty, advanced stage puberty or fully mature at age 14–15 years. Girls were grouped as reaching menarche ≤11, 12, 13 or ≥14 years. LTPA was reported at ages 36, 43, 53, 60–64 and 68 years and classified as active or inactive at each age. Associations were examined using standard and mixed-effects logistic regression models.

Results

Of 5362 singleton births recruited, 1499 men and 1409 women had at least one measure of LTPA and data on pubertal timing and selected covariates. When compared with men that were fully mature at age 14–15 years, those that were in advanced stage and early-stage puberty, but not the prepubescent stage, had lower likelihood of LTPA at younger but not older adult ages (p=0.06 for pubertal status-by-age at LTPA interaction in mixed-effects model). For example, fully adjusted ORs of LTPA (vs no LTPA) at ages 36 and 68 years, respectively, for advanced puberty versus fully mature were 0.69 (95% CIs 0.50 to 0.96) and 1.03 (0.72 to 1.47). Age at menarche was not associated with LTPA at any age (pinteractionwith age at LTPA=0.9). For example, OR (from mixed-effects model) of LTPA between 36 and 68 years was 1.23 (0.93, 1.63) for menarche at 13 vs ≤11 years.

Conclusions

In a nationally representative study, there was little evidence to suggest that pubertal timing was an important correlate of LTPA between ages 36 and 68 years. Maturity-related variations in adolescents’ LTPA may be transitory and lose importance over time.
Physiotherapy and physical activity: a cross-sectional survey exploring physical activity promotion, knowledge of physical activity guidelines and the physical activity habits of UK physiotherapists
Authors: Lowe Anna , Littlewood Chris , McLean Sionnadh , Kilner Karen
Published: November 2017

Objective

Physical inactivity is a public health priority and embedding promotion of physical activity (PA) within healthcare systems is an important lever for change. Many factors influence PA promotion in routine healthcare practice; these include the PA habits of healthcare professionals and also their knowledge of the PA guidelines. Little is known about the extent to which PA is currently promoted in physiotherapy practice or the factors that influence it.

Methods

Following ethical approval, a cross-sectional survey of UK physiotherapists was conducted. Findings were analysed and reported in accordance with STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines.

Results

There were 522 respondents, 514 of whom were physiotherapists. Seventy-seven per cent of respondents routinely discussed PA with patients and 68% routinely delivered brief interventions. Assessment of PA status was not routine practice, neither was signposting to further sources of PA support. Only 16% of respondents correctly answered questions about the content of the PA guidelines. Only 38% of respondents met current PA recommendations. Clinicians' PA levels were not associated with PA promotion activity.

Conclusion

Despite the promising finding that some form of PA promotion is integrated into most respondents' practice, we report a poor understanding of brief interventions and poor knowledge of the PA guidelines. Additionally, the majority of respondents were not sufficiently active to meet current PA recommendations.
Trial registration and adherence to reporting guidelines in cardiovascular journals
Authors: Sims Matt Thomas , Bowers Aaron Marc , Fernan Jamie Morgan , Dormire Kody Duane , Herrington James Murphy , Vassar Matt
Published: November 2017

Objective

This study investigated the policies of cardiac and cardiovascular system journals concerning clinical trial registration and guideline adoption to understand how frequently journals use these mechanisms to improve transparency, trial reporting and overall study quality.

Methods

We selected the top 20 (by impact factor) journals cited in the subcategory ‘Cardiac and Cardiovascular Systems’ of the Expanded Science Citation Index of the 2014 Journal Citation Reports to extract journal policies concerning the 17 guidelines we identified. In addition, trial and systematic review registration adherence statements were extracted. 300 randomised controlled trials published in 2016 in the top 20 journals were searched for clinical trial registry numbers and CONSORT diagrams.

Results

Of the 19 cardiac and cardiovascular system journals included in our analysis, eight journals (42%) did not require or recommend trial or review registration. Seven (37%) did not recommend or require a single guideline within their instructions to authors. Consolidated Standards for Reporting Trials guidelines (10/19, 53%) were recommended or required most often. Of the trials surveyed, 122/285 (42.8%) published a CONSORT diagram in their manuscript, while 236/292 (80.8%) published a trial registry number.

Discussion

Cardiac and cardiovascular system journals infrequently require, recommend or enforce the use of reporting guidelines. Furthermore, too few require or enforce the use of clinical trial registration. Cardiology journal editors should consider guideline adoption due to their potential to limit bias and increase transparency.
Comparison between pre-exercise casein peptide and intact casein supplementation on glucose tolerance in mice fed a high-fat diet
Authors: Matsunaga Yutaka , Tamura Yuki , Sakata Yasuyuki , Nonaka Yudai , Saito Noriko , Nakamura Hirohiko , Shimizu Takashi , Takeda Yasuhiro , Terada Shin , Hatta Hideo
Published: November 2017

We hypothesized that along with exercise, casein peptide supplementation would have a higher impact on improving glucose tolerance than intact casein. Male 6-week-old ICR mice were provided a high-fat diet to induce obesity and glucose intolerance. The mice were randomly divided into 4 treatment groups: control (Con), endurance training (Tr), endurance training with intact casein supplementation (Cas+Tr), and endurance training with casein peptide supplementation (CP+Tr). The mice in each group were orally administrated water, intact casein, or casein peptide (1.0 mg/g body weight, every day), and then subjected to endurance training (15–25 m/min, 60 min, 5 times/week for 4 weeks) on a motor-driven treadmill 30 min after ingestion. Our results revealed that total intra-abdominal fat was significantly lower in CP+Tr than in Con (p < 0.05). Following an oral glucose tolerance test, the blood glucose area under the curve (AUC) was found to be significantly smaller for CP+Tr than for Con (p < 0.05). Moreover, in the soleus muscle, glucose transporter 4 (GLUT4) protein levels were significantly higher in CP+Tr than in Con (p < 0.01). However, intra-abdominal fat, blood glucose AUC, and GLUT4 protein content in the soleus muscle did not alter in Tr and Cas+Tr when compared with Con. These observations suggest that pre-exercise casein peptide supplementation has a higher effect on improving glucose tolerance than intact casein does in mice fed a high-fat diet.
Influence of invasive shrubs and deer browsing on regeneration in temperate deciduous forests
Authors: Ward Jeffrey S. , Williams Scott C. , Linske Megan A.
Published: November 2017

While both chronic white-tailed deer (Odocoileus virginianus Zimmermann) overbrowsing and invasive shrubs have been linked to native regeneration failure in temperate hardwood forests, little is known of their relative importance and possible synergistic effects. Therefore, we established three study areas in Connecticut to examine the interaction of three levels of invasive shrub control and absence or presence of deer herbivory on forest regeneration over 9 years. Five observations suggest that obtaining forest regeneration requires a comprehensive management strategy. First, competitive interference by invasive shrubs in intact thickets continued to impede forest regeneration, especially taller seedlings, after deer were excluded. Second, density of small seedlings increased following removal of the competitive interference by invasive shrubs. Third, deer browsing depressed growth of small seedlings into taller height classes. Fourth, preferential browsing reduced species richness, especially in taller seedling classes, by favoring growth of low palatability species such as beech. Lastly, if a disturbance (e.g., cutting) does not kill the root system of the invasive shrubs, the window of forest regeneration recruitment may be narrow because invasive shrubs can quickly recover. In stands with both established shrub thickets and high deer densities, invasive shrub control and multiyear reduction of deer densities are both recommended to obtain adequate forest regeneration.
On super-resolution imaging as a multiparameter estimation problem
Authors: Chrostowski Andrzej , Demkowicz-Dobrzański Rafał , Jarzyna Marcin , Banaszek Konrad
Published: November 2017

We consider the problem of characterizing the spatial extent of a composite light source using the super-resolution imaging technique based on mode demultiplexing when the centroid of the source is not known precisely. We show that the essential features of this problem can be mapped onto a simple qubit model for joint estimation of a phase shift and a dephasing strength.
Change in dielectric relaxation with the presence of water in highly filled composites
Authors: Tuncer Enis
Published: November 2017

It is important to determine the dielectric characteristics of semiconductor encapsulation materials based on epoxy resins. We employed the dielectric spectroscopy technique to investigate the dielectric relaxation in the presence of water and how it changes the relaxation. It was observed that the dielectric relaxation of the material was significantly influenced by absorbed water, the local segmental motion (also known as Johari–Goldstein ([Formula: see text]) relaxation) was influenced most by the presence of the water, it was modified by the wet sample compared to dry one, and required high activation energy. The relaxation related to the glass transition was contributed by the cooperative motion (the [Formula: see text]-relaxation) of the epoxy resin system. The [Formula: see text]-relaxation was shifted to a low temperature in the wet sample compared to dry one. The relaxation was modeled with a clear Vogel–Fulcher–Tammann–Hesse (VFTH) behavior; the Vogel temperature of the wet sample was 8[Formula: see text]K lower than the dry sample. The presence of water acts as a plasticizer for the molecular relaxation, and speed-up the cooperative process. The measured data were also used to estimate the electrical properties of the resin system by employing an effective-medium model together with a porous media continuum model by taking into account the physical properties of the system. It is already known that the influence of water in semiconductor packaging is important in sensitive applications. The presented measurements and the analysis method would be appreciated within the semiconductor packaging community to improve material selection and performance evaluation efforts.
Shadow state encoding for efficient monitoring of block-level properties
Authors: Vorobyov Kostyantyn , Signoles Julien , Kosmatov Nikolai
Published: November 2017

Memory shadowing associates addresses from an application's memory to values stored in a disjoint memory space called shadow memory. At runtime shadow values store metadata about application memory locations they are mapped to. Shadow state encodings -- the structure of shadow values and their interpretation -- vary across different tools. Encodings used by the state-of-the-art monitoring tools have been proven useful for tracking memory at a byte-level, but cannot address properties related to memory block boundaries. Tracking block boundaries is however crucial for spatial memory safety analysis, where a spatial violation such as out-of-bounds access, may dereference an allocated location belonging to an adjacent block or a different struct member.

This paper describes two novel shadow state encodings which capture block-boundary-related properties. These encodings have been implemented in E-ACSL - a runtime verification tool for C programs. Initial experiments involving checking validity of pointer and array accesses in computationally intensive runs of programs selected from SPEC CPU benchmarks demonstrate runtime and memory overheads comparable to state-of-the-art memory debuggers.
RTHMS: a tool for data placement on hybrid memory system
Authors: Peng Ivy Bo , Gioiosa Roberto , Kestor Gokcen , Cicotti Pietro , Laure Erwin , Markidis Stefano
Published: November 2017

Traditional scientific and emerging data analytics applications require fast, power-efficient, large, and persistent memories. Combining all these characteristics within a single memory technology is expensive and hence future supercomputers will feature different memory technologies side-by-side. However, it is a complex task to program hybrid-memory systems and to identify the best object-to-memory mapping. We envision that programmers will probably resort to use default configurations that only require minimal interventions on the application code or system settings. In this work, we argue that intelligent, fine-grained data placement can achieve higher performance than default setups.

We present an algorithm for data placement on hybrid-memory systems. Our algorithm is based on a set of single-object allocation rules and global data placement decisions. We also present RTHMS, a tool that implements our algorithm and provides recommendations about the object-to-memory mapping. Our experiments on a hybrid memory system, an Intel Knights Landing processor with DRAM and HBM, show that RTHMS is able to achieve higher performance than the default configuration. We believe that RTHMS will be a valuable tool for programmers working on complex hybrid-memory systems.
A marshalled data format for pointers in relocatable data blocks
Authors: Vrvilo Nick , Yu Lechen , Sarkar Vivek
Published: November 2017

As future computing hardware progresses towards extreme-scale technology, new challenges arise for addressing heterogeneous compute and memory resources, for providing application resilience in the presence of more frequent failures, and for working within strict energy constraints. While C++ has gained popularity in recent years within the HPC community, some concepts of object-oriented program design may be at odds with the techniques we use to address the challenges of extreme-scale computing. In this work, we focus on the challenges related to using aggregate data structures that include pointer values within a programming model where the runtime may frequently relocate data, and traditional serialization techniques are not practical. We propose and evaluate a marshalled encoding for relocatable data blocks, and present a C++ library and other tools to simplify the work of the application programmer developing new applications or porting existing applications to such emerging programming models.