bluuebunny/crossref_metadata_2025 huggingface dataset:
Cooperative bird discriminates between individuals based purely on their aerial alarm calls
Authors: Farrow Lucy F , Barati Ahmad , McDonald Paul G
Published: October 2019

From an evolutionary perspective, the ability to recognize individuals provides great selective advantages, such as avoiding inbreeding depression during breeding. Whilst the capacity to recognize individuals for these types of benefits is well established in social contexts, why this recognition might arise in a potentially deadly alarm-calling context following predator encounters is less obvious. For example, in most avian systems, alarm signals directed toward aerial predators represent higher predation risk and vulnerability than when individuals vocalize toward a terrestrial-based predator. Although selection should favor simple, more effective alarm calls to these dangerous aerial predators, the potential of these signals to nonetheless encode additional information such as caller identity has not received a great deal of attention. We tested for individual discrimination capacity in the aerial alarm vocalizations of the noisy miner (Manorina melanocephala), a highly social honeyeater that has been previously shown to be able to discriminate between the terrestrial alarm signals of individuals. Utilizing habituation–discrimination paradigm testing, we found conclusive evidence of individual discrimination in the aerial alarm calls of noisy miners, which was surprisingly of similar efficiency to their ability to discriminate between less urgent terrestrial alarm signals. Although the mechanism(s) driving this behavior is currently unclear, it most likely occurs as a result of selection favoring individualism among other social calls in the repertoire of this cooperative species. This raises the intriguing possibility that individualistic signatures in vocalizations of social animals might be more widespread than currently appreciated, opening new areas of bioacoustics research.
γ-TRIS: a graph-algorithm for comprehensive identification of vector genomic insertion sites
Authors: Calabria Andrea , Beretta Stefano , Merelli Ivan , Spinozzi Giulio , Brasca Stefano , Pirola Yuri , Benedicenti Fabrizio , Tenderini Erika , Bonizzoni Paola , Milanesi Luciano , Montini Eugenio
Published: October 2019

Retroviruses and their vector derivatives integrate semi-randomly in the genome of host cells and are inherited by their progeny as stable genetic marks. The retrieval and mapping of the sequences flanking the virus-host DNA junctions allows the identification of insertion sites in gene therapy or virally infected patients, essential for monitoring the evolution of genetically modified cells in vivo. However, since ∼30% of insertions land in low complexity or repetitive regions of the host cell genome, they cannot be correctly assigned and are currently discarded, limiting the accuracy and predictive power of clonal tracking studies. Here, we present γ-TRIS, a new graph-based genome-free alignment tool for identifying insertion sites even if embedded in low complexity regions. By using γ-TRIS to reanalyze clinical studies, we observed improvements in clonal quantification and tracking.

Availability and implementation

Source code at https://bitbucket.org/bereste/g-tris.

Supplementary information

Supplementary data are available at Bioinformatics online.
Regulatory oversight, causal inference, and safe and effective health care machine learning
Authors: Stern Ariel Dora , Price W Nicholson
Published: October 2019

In recent years, the applications of Machine Learning (ML) in the health care delivery setting have grown to become both abundant and compelling. Regulators have taken notice of these developments and the U.S. Food and Drug Administration (FDA) has been engaging actively in thinking about how best to facilitate safe and effective use. Although the scope of its oversight for software-driven products is limited, if FDA takes the lead in promoting and facilitating appropriate applications of causal inference as a part of ML development, that leadership is likely to have implications well beyond regulated products.
Social Workers in a Modernising Welfare State: Professionals or Street-Level Bureaucrats?
Authors: Trappenburg Margo , Kampen Thomas , Tonkens Evelien
Published: October 2019

Social workers are often depicted as street-level bureaucrats (SLBs) or professionals interchangeably. However, to find out how social workers relate to new policy measures, a clear distinction between SLBs and professionals is helpful. Ideal–typical SLBs subscribe to new policies although they may diverge from them in practice, to accommodate clients. Ideal–typical professionals weigh new policies against their ethical code. If the new policy goes against their professional principles, they protest on behalf of their clients. In this article, we study Dutch social workers who have to implement a new policy that (i) obliges their clients to actively participate in society and (ii) obliges them to rely on family and friends when they need help. The data for this article are derived from two projects: interviews with twenty-nine experienced social workers and interviews with social workers in neighbourhood teams and observations of their interactions with clients in six municipalities. We found that Dutch social workers think as professionals: they weigh the new policy against their ethical code and have serious doubts about the second part of the new policy. Hence, they find ways to avoid implementation. However, they behave as SLBs, bending the rules in practice. They rarely confront policymakers or higher management.
Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia
Authors: Vaz Frédéric M , McDermott John H , Alders Mariëlle , Wortmann Saskia B , Kölker Stefan , Pras-Raves Mia L , Vervaart Martin A T , van Lenthe Henk , Luyf Angela C M , Elfrink Hyung L , Metcalfe Kay , Cuvertino Sara , Clayton Peter E , Yarwood Rebecca , Lowe Martin P , Lovell Simon , Rogers Richard C ,   Deciphering Developmental Disorders Study, van Kampen Antoine H C , Ruiter Jos P N , Wanders Ronald J A , Ferdinandusse Sacha , van Weeghel Michel , Engelen Marc , Banka Siddharth
Published: October 2019

CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.
Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain
Authors: Van Steenwinckel Juliette , Schang Anne-Laure , Krishnan Michelle L , Degos Vincent , Delahaye-Duriez Andrée , Bokobza Cindy , Csaba Zsolt , Verdonk Franck , Montané Amélie , Sigaut Stéphanie , Hennebert Olivier , Lebon Sophie , Schwendimann Leslie , Le Charpentier Tifenn , Hassan-Abdi Rahma , Ball Gareth , Aljabar Paul , Saxena Alka , Holloway Rebecca K , Birchmeier Walter , Baud Olivier , Rowitch David , Miron Veronique , Chretien Fabrice , Leconte Claire , Besson Valérie C , Petretto Enrico G , Edwards A David , Hagberg Henrik , Soussi-Yanicostas Nadia , Fleiss Bobbi , Gressens Pierre
Published: October 2019

Inflammatory activation of microglia in the brains of prematurely born infants can lead to permanent neurological sequelae. Van Steenwinckel et al. show that a reduction in microglial Wnt signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination, and establish the Wnt pathway as a viable therapeutic target.
Laxative Use Does Not Preclude Diagnosis or Reduce Disease Severity in Clostridiodes difficile Infection
Authors: White Nicole C , Mendo-Lopez Rafael , Papamichael Konstantinos , Cuddemi Christine A , Barrett Caitlin , Daugherty Kaitlyn , Pollock Nira , Kelly Ciaran P , Alonso Carolyn D
Published: October 2019

Background

To optimize utility of laboratory testing for Clostridiodes difficile infection (CDI), the 2017 Infectious Diseases Society of America–Society for Healthcare Epidemiology of America (IDSA-SHEA) clinical practice guidelines recommend excluding patients from stool testing for C. difficile if they have received laxatives within the preceding 48 hours. Sparse data support this recommendation.

Methods

Patients with new-onset diarrhea (≥3 bowel movements in any 24-hour period in the 48 hours before stool collection) and a positive stool C. difficile nucleic acid amplification test were enrolled. Laxative use within 48 hours before stool testing, severity of illness (defined by 4 distinct scoring methods), and clinical outcomes were recorded.

Results

209 patients with CDI were studied, 65 of whom had received laxatives. There were no significant differences in the proportion of patients meeting severe CDI criteria by 4 severity scoring methods in patients receiving versus not receiving laxatives (66.2% vs 56.3%, respectively; P = .224) by IDSA-SHEA, the primary scoring system. Similar rates of serious outcomes attributable to CDI, including death, intensive care unit admission, and colectomy, were observed in the laxative and no laxative groups.

Conclusions

Our study found similar rates of severe CDI and serious CDI-attributable clinical outcomes in CDI-diagnosed patients who did or did not receive laxatives. Precluding recent laxative users from CDI testing, as proposed by the IDSA-SHEA guideline, carries a potential for harm due to delayed diagnosis and treatment.
Deprivation and kidney disease—a predictor of poor outcomes
Authors: Guthrie Greg D , Bell Samira
Published: October 2019

There is a growing body of evidence for the role of deprivation in a broad spectrum of diseases including renal disease. Deprivation has been demonstrated to be associated with poorer outcomes across a range of renal diseases including acute kidney injury (AKI), chronic kidney disease and transplantation. In this issue of Clinical Kidney Journal, Hounkpatin et al. describe the association of socioeconomic deprivation with incidence, mortality and resolution of AKI in a large UK cohort. Investigating deprivation as a factor influencing either incidence or outcome of disease is challenging due to variations in measures of deprivation used and other confounding factors that may be contributing to the observed differences. In this editorial, we review the current literature examining the role of deprivation in renal disease.
Duration of early systolic lengthening: prognostic potential in the general population
Authors: Brainin Philip , Biering-Sørensen Sofie Reumert , Møgelvang Rasmus , Jensen Jan Skov , Biering-Sørensen Tor
Published: October 2019

Background

When the left ventricle pressure rises during early systole, myocardial fibres with reduced contractility tend to stretch instead of shortening. This interval is known as duration of early systolic lengthening (DESL). We sought to investigate if DESL provides prognostic information on cardiovascular events.

Methods and results

In this prospective study we included 1210 participants from a low-risk general population who underwent speckle tracking echocardiography (men 41%, mean age 56 years, SD 16). Primary endpoints were incident heart failure (HF), myocardial infarction (MI), and cardiovascular death (CVD). We defined DESL as time from onset of Q-wave on the electrocardiogram to peak positive systolic strain. In addition, we assessed the ratio between DESL and duration of cardiac systole, DESLsystole.

During median follow-up of 16 years, 90 (7%) developed HF, 50 (4%) MI, and 70 (6%) experienced CVD. Both DESL [hazard ratio (HR) 1.58 95%CI 1.16–2.15, P = 0.004 per 10 ms increase] and DESLsystole (HR 1.74 95%CI 1.24–2.47, P = 0.001 per 1% increase) were predictors of HF. Similarly, DESL (HR 1.40 95%CI 1.09–1.78, P = 0.007 per 10 ms increase) and DESLsystole (HR 1.58 95%CI 1.01–2.49, P = 0.047 per 1% increase) were predictors of MI. No associations were found with CVD. After adjusting for clinical and echocardiographic parameters, the associations remained significant. DESLsystole was superior to systolic echocardiographic parameters for predicting HF (P = 0.012).

Conclusion

DESL and the novel index of DESLsystole provide independent and novel prognostic information on the risk of HF and MI in the general population. Evaluation of DESL should be explored in future echocardiographic studies.
Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood–brain barrier integrity: a translational study
Authors: Liberale Luca , Gaul Daniel S , Akhmedov Alexander , Bonetti Nicole R , Nageswaran Vanasa , Costantino Sarah , Pahla Jürgen , Weber Julien , Fehr Vera , Vdovenko Daria , Semerano Aurora , Giacalone Giacomo , Kullak-Ublick Gerd A , Sessa Maria , Eriksson Urs , Paneni Francesco , Ruschitzka Frank , Montecucco Fabrizio , Beer Jürg H , Lüscher Thomas F , Matter Christian M , Camici Giovanni G
Published: October 2019

Aims

Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood–brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke.

Methods and results

SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6−/−) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6−/− animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6−/− mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome.

Conclusion

Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.
Transcatheter aspiration of large pacemaker and implantable cardioverter-defibrillator lead vegetations facilitating safe transvenous lead extraction
Authors: Starck Christoph T , Schaerf Raymond H M , Breitenstein Alexander , Najibi Sasan , Conrad John , Berendt Joseph , Esmailian Fardad , Eulert-Grehn Jürgen , Dreizler Thomas , Falk Volkmar
Published: October 2019

Aims

Treatment of patients with systemic cardiac implantable electronic device (CIED) infection with large lead vegetations is challenging and associated with relevant morbidity and mortality. To avoid complications from open surgical extraction, a novel approach with percutaneous aspiration of large vegetations prior to transvenous lead extraction was instituted. The results of this treatment concept were retrospectively analysed in this multicentre study.

Methods and results

One hundred and one patients [mean age 68.2 ± 13.1 (30–92) years] were treated in four centres for endovascular CIED infection with large lead vegetations. Mean lead vegetation size was 30.7 ± 13.5 mm. Two hundred and forty-seven leads were targeted for extraction (170 pacemaker leads, 77 implantable cardioverter-defibrillator leads). Mean lead implant duration was 81.7 (1–254) months. The transcatheter aspiration system with a specialized long venous drainage cannula and a funnel-shaped tip was based on a veno-venous extracorporeal circuit with an in-line filter. The aspiration of vegetations showed complete procedural success in 94.0% (n = 95), partial success in 5.0% (n = 5). Three major complications (3.0%) were encountered. Complete procedural success (per lead) of the subsequently performed transvenous lead extraction procedure was 99.2% (n = 245). Thirty-day mortality was 3.0% (n = 3). Five patients (5.0%) died in the further course on Days 51, 54, 68, 134, and 182 post-procedure (septic complications: n = 4; heart failure: n = 1).

Conclusion

The percutaneous aspiration procedure is highly effective and is associated with a low complication profile. The aspiration of vegetations immediately prior and during the lead extraction procedure may avoid septic embolization into the pulmonary circulation. This may potentially lead to a long-term survival benefit.
Evolution and Unprecedented Variants of the Mitochondrial Genetic Code in a Lineage of Green Algae
Authors: Žihala David , Eliáš Marek
Published: September 2019

Mitochondria of diverse eukaryotes have evolved various departures from the standard genetic code, but the breadth of possible modifications and their phylogenetic distribution are known only incompletely. Furthermore, it is possible that some codon reassignments in previously sequenced mitogenomes have been missed, resulting in inaccurate protein sequences in databases. Here we show, considering the distribution of codons at conserved amino acid positions in mitogenome-encoded proteins, that mitochondria of the green algal order Sphaeropleales exhibit a diversity of codon reassignments, including previously missed ones and some that are unprecedented in any translation system examined so far, necessitating redefinition of existing translation tables and creating at least seven new ones. We resolve a previous controversy concerning the meaning the UAG codon in Hydrodictyaceae, which beyond any doubt encodes alanine. We further demonstrate that AGG, sometimes together with AGA, encodes alanine instead of arginine in diverse sphaeroplealeans. Further newly detected changes include Arg-to-Met reassignment of the AGG codon and Arg-to-Leu reassignment of the CGG codon in particular species. Analysis of tRNAs specified by sphaeroplealean mitogenomes provides direct support for and molecular underpinning of the proposed reassignments. Furthermore, we point to unique mutations in the mitochondrial release factor mtRF1a that correlate with changes in the use of termination codons in Sphaeropleales, including the two independent stop-to-sense UAG reassignments, the reintroduction of UGA in some Scenedesmaceae, and the sense-to-stop reassignment of UCA widespread in the group. Codon disappearance seems to be the main drive of the dynamic evolution of the mitochondrial genetic code in Sphaeropleales.
Draft genome sequence of Solanum aethiopicum provides insights into disease resistance, drought tolerance, and the evolution of the genome
Authors: Song Bo , Song Yue , Fu Yuan , Kizito Elizabeth Balyejusa , Kamenya Sandra Ndagire , Kabod Pamela Nahamya , Liu Huan , Muthemba Samuel , Kariba Robert , Njuguna Joyce , Maina Solomon , Stomeo Francesca , Djikeng Appolinaire , Hendre Prasad S , Chen Xiaoli , Chen Wenbin , Li Xiuli , Sun Wenjing , Wang Sibo , Cheng Shifeng , Muchugi Alice , Jamnadass Ramni , Shapiro Howard-Yana , Van Deynze Allen , Yang Huanming , Wang Jian , Xu Xun , Odeny Damaris Achieng , Liu Xin
Published: October 2019

Background

The African eggplant (Solanum aethiopicum) is a nutritious traditional vegetable used in many African countries, including Uganda and Nigeria. It is thought to have been domesticated in Africa from its wild relative, Solanum anguivi. S. aethiopicum has been routinely used as a source of disease resistance genes for several Solanaceae crops, including Solanum melongena. A lack of genomic resources has meant that breeding of S. aethiopicum has lagged behind other vegetable crops.

Results

We assembled a 1.02-Gb draft genome of S. aethiopicum, which contained predominantly repetitive sequences (78.9%). We annotated 37,681 gene models, including 34,906 protein-coding genes. Expansion of disease resistance genes was observed via 2 rounds of amplification of long terminal repeat retrotransposons, which may have occurred ~1.25 and 3.5 million years ago, respectively. By resequencing 65 S. aethiopicum and S. anguivi genotypes, 18,614,838 single-nucleotide polymorphisms were identified, of which 34,171 were located within disease resistance genes. Analysis of domestication and demographic history revealed active selection for genes involved in drought tolerance in both “Gilo” and “Shum” groups. A pan-genome of S. aethiopicum was assembled, containing 51,351 protein-coding genes; 7,069 of these genes were missing from the reference genome.

Conclusions

The genome sequence of S. aethiopicum enhances our understanding of its biotic and abiotic resistance. The single-nucleotide polymorphisms identified are immediately available for use by breeders. The information provided here will accelerate selection and breeding of the African eggplant, as well as other crops within the Solanaceae family.
Personal development, wellbeing and empowerment gains for nutrition peer educators: a South Australian perspective
Authors: Mehta Kaye , Dent Carolyn , Middleton Georgia , Booth Sue
Published: October 2019

This study aimed to explore the experience of being a Community Foodies (CF) peer educator with respect to personal benefits, specifically, personal development, wellbeing and empowerment. Qualitative semi-structured telephone interviews conducted with metropolitan and country peer educators of the CF programme. The CF programme in South Australia (SA) delivers nutrition education to disadvantaged communities. Ten adult peer educators from the CF programme: seven from country SA and three from Adelaide. Phenomenon of interest is that peer educators’ perceptions of personal growth and development from involvement in the CF programme. The interviews were audiotaped and analysed thematically. The experience of being a nutrition peer educator improved personal skills and knowledge, dietary habits, self-esteem, confidence, sense of belonging and civic engagement. Peer educators felt that the CF programme was run in a straightforward, easy to understand way, with a welcoming environment and abundant support from the coordinators. Apart from benefits to themselves, peer educators appeared to be most proud of their capacity to contribute to the nutritional health of the broader community. Peer education programmes in disadvantaged communities provide policy makers with valuable and cost-effective approaches to improve health, build self-efficacy, strengthen community engagement, and, foster active participation and trust.
Flatness of the Commutator Map Over SLn
Authors: Larsen Michael , Lu Zhipeng
Published: October 2019

Let $K$ be any field, and let $n$ be a positive integer. If we denote by $\xi _{\textrm{SL}_n}\colon \textrm{SL}_n\times \textrm{SL}_n\to \textrm{SL}_n$ the commutator morphism over $K$, then $\xi _{\textrm{SL}_n}$ is flat over the complement of the center of $\textrm{SL}_n$.
Longitudinal Antibody Responses in People Who Inject Drugs Infected With Similar Human Immunodeficiency Virus Strains
Authors: Redd Andrew D , Doria-Rose Nicole A , Weiner Joshua A , Nason Martha , Seivers Matthew , Schmidt Stephen D , Laeyendecker Oliver , Martens Craig , Bruno Daniel , Keele Brandon F , Raju Nagarajan , Georgiev Ivelin S , Lamers Susanna L , Astemborski Jacquie , Kirk Gregory D , Mascola John R , Ackerman Margaret E , Mehta Shruti H , Quinn Thomas C
Published: October 2019

Background

Multiple factors influence the human immunodeficiency virus (HIV) antibody response produced during natural infection, leading to responses that can vary in specificity, strength, and breadth.

Methods

People who inject drugs identified as recently infected with HIV (n = 23) were analyzed for clustering of their viral sequences (genetic distance, <2%). Longitudinal antibody responses were identified for neutralizing antibody (Nab) potential, and differences in antibody subclass, specificity, and Fc receptor ligation using pseudovirus entry and multiplexed Fc array assays, respectively. Responses were analyzed for differences between subject groups, defined by similarity in the sequence of the infecting virus.

Results

Viral sequences from infected individuals were grouped into 3 distinct clusters with 7 unclustered individuals. Subjects in cluster 1 generally had lower antibody response magnitudes, except for antibodies targeting the V1/V2 region. Subjects in clusters 2 and 3 typically had higher antibody response magnitudes, with the Fv specificity of cluster 2 favoring gp140 recognition. NAb responses differed significantly between clusters for 3 of 18 pseudoviruses examined (P < .05), but there were no differences in overall NAb breadth (P = .62).

Discussion

These data demonstrate that individuals infected with similar viral strains can generate partially similar antibody responses, but these do not drastically differ from those in individuals infected with relatively unrelated strains.
Evaluating a digital sepsis alert in a London multisite hospital network: a natural experiment using electronic health record data
Authors: Honeyford Kate , Cooke Graham S , Kinderlerer Anne , Williamson Elizabeth , Gilchrist Mark , Holmes Alison ,   The Sepsis Big Room, Glampson Ben , Mulla Abdulrahim , Costelloe Ceire
Published: October 2019

Objective

The study sought to determine the impact of a digital sepsis alert on patient outcomes in a UK multisite hospital network.

Materials and Methods

A natural experiment utilizing the phased introduction (without randomization) of a digital sepsis alert into a multisite hospital network. Sepsis alerts were either visible to clinicians (patients in the intervention group) or running silently and not visible (the control group). Inverse probability of treatment-weighted multivariable logistic regression was used to estimate the effect of the intervention on individual patient outcomes.

Outcomes

In-hospital 30-day mortality (all inpatients), prolonged hospital stay (≥7 days) and timely antibiotics (≤60 minutes of the alert) for patients who alerted in the emergency department.

Results

The introduction of the alert was associated with lower odds of death (odds ratio, 0.76; 95% confidence interval [CI], 0.70-0.84; n = 21 183), lower odds of prolonged hospital stay ≥7 days (OR, 0.93; 95% CI, 0.88-0.99; n = 9988), and in patients who required antibiotics, an increased odds of receiving timely antibiotics (OR, 1.71; 95% CI, 1.57-1.87; n = 4622).

Discussion

Current evidence that digital sepsis alerts are effective is mixed. In this large UK study, a digital sepsis alert has been shown to be associated with improved outcomes, including timely antibiotics. It is not known whether the presence of alerting is responsible for improved outcomes or whether the alert acted as a useful driver for quality improvement initiatives.

Conclusions

These findings strongly suggest that the introduction of a network-wide digital sepsis alert is associated with improvements in patient outcomes, demonstrating that digital based interventions can be successfully introduced and readily evaluated.
The (Dis)assembling of Form: Revealing the Ideas Built Into Manchester’s Medical School
Authors: Hopkins James
Published: October 2019

This paper addresses a gap in our understanding of medical history - the architecture of medical schools - and demonstrates the ways in which architectural form can be used to better understand medical epistemology and pedagogy. It examines an instructive case study - the late-nineteenth-century medical school buildings in Manchester - and examines the concepts that were drawn together and expressed in the buildings. Through its exploration, the paper argues first, that medical schools and spaces for medical education should be given greater consideration as a significant category in the history of medical buildings. Second, that buildings such as its case study are an important source of evidence and means to understand the role of medicine in society and the ideas with which its contemporary practitioners and educators were concerned. Third, the paper argues that, to make best use of buildings as sources, we should view them as agents which have assembled divergent ideas and incorporated them into the built form. In this way, such buildings have woven into them an inventory of ideas which can be untangled using designs and physical evidence.
Pragmatic logics for hypotheses and evidence
Authors: Carrara Massimiliano , Chiffi Daniele , De Florio Ciro
Published: October 2019

The present paper is devoted to present two pragmatic logics and their corresponding intended interpretations according to which an illocutionary act of (scientific) hypothesis-making is justified by a scintilla of evidence. The paper first introduces a general pragmatic frame for assertions, expanded to hypotheses, ${\mathsf{AH}}$ and a hypothetical pragmatic logic for evidence ${\mathsf{HLP}}$. Both ${\mathsf{AH}}$ and ${\mathsf{HLP}}$ are extensions of the Logic for Pragmatics, $\mathcal{L}^P$. We compare ${\mathsf{AH}}$ and $\mathsf{HLP}$. Then, we underline the expressive and inferential richness of both systems in dealing with hypothetical judgements, especially when based on different, sometimes conflicting, evidence.
Considerations When Using Breast Cancer Risk Models for Women with Negative BRCA1/BRCA2 Mutation Results
Authors: MacInnis Robert J , Liao Yuyan , Knight Julia A , Milne Roger L , Whittemore Alice S , Chung Wendy K , Leoce Nicole , Buchsbaum Richard , Zeinomar Nur , Dite Gillian S , Southey Melissa C , Goldgar David , Giles Graham G , McLachlan Sue-Anne , Weideman Prue C , Nesci Stephanie , Friedlander Michael L , Glendon Gord ,   kConFab Investigators, Andrulis Irene L , John Esther M , Daly Mary B , Buys Saundra S , Phillips Kelly Anne , Hopper John L , Terry Mary Beth
Published: October 2019

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%–56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.
Circulating Lysophosphatidylcholines, Phosphatidylcholines, Ceramides, and Sphingomyelins and Ovarian Cancer Risk: A 23-Year Prospective Study
Authors: Zeleznik Oana A , Clish Clary B , Kraft Peter , Avila-Pacheco Julian , Eliassen A Heather , Tworoger Shelley S
Published: October 2019

Background

Experimental evidence supports a role of lipid dysregulation in ovarian cancer progression. We estimated associations with ovarian cancer risk for circulating levels of four lipid groups, previously hypothesized to be associated with ovarian cancer, measured 3–23 years before diagnosis.

Methods

Analyses were conducted among cases (N = 252) and matched controls (N = 252) from the Nurses’ Health Studies. We used logistic regression adjusting for risk factors to investigate associations of lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), ceramides (CERs), and sphingomyelins (SMs) with ovarian cancer risk overall and by histotype. A modified Bonferroni approach (0.05/4 = 0.0125, four lipid groups) and the permutation-based Westfall and Young approach were used to account for testing multiple correlated hypotheses. Odds ratios (ORs; 10th–90th percentile), and 95% confidence intervals of ovarian cancer risk were estimated. All statistical tests were two-sided.

Results

SM sum was statistically significantly associated with ovarian cancer risk (OR = 1.97, 95% CI = 1.16 to 3.32; P = .01/permutation-adjusted P = .20). C16:0 SM, C18:0 SM, and C16:0 CERs were suggestively associated with risk (OR = 1.95–2.10; P = .004–.01; permutation-adjusted P = .08–.21). SM sum, C16:0 SM, and C16:0 CER had stronger odds ratios among postmenopausal women (OR = 2.16–3.22). Odds ratios were similar for serous/poorly differentiated and endometrioid/clear cell tumors, although C18:1 LPC and LPC to PC ratio were suggestively inversely associated, whereas C18:0 SM was suggestively positively associated with risk of endometrioid/clear cell tumors. No individual metabolites were associated with risk when using the permutation-based approach.

Conclusions

Elevated levels of circulating SMs 3–23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women. Further studies are required to validate and understand the role of lipid dysregulation in ovarian carcinogenesis.
Doppler tomography as a tool for detecting exoplanet atmospheres
Authors: Watson C A , de Mooij E J W , Steeghs D , Marsh T R , Brogi M , Gibson N P , Matthews S
Published: October 2019

High-resolution Doppler spectroscopy is a powerful tool for identifying molecular species in the atmospheres of both transiting and non-transiting exoplanets. Currently, such data are analysed using cross-correlation techniques to detect the Doppler shifting signal from the orbiting planet. In this paper we demonstrate that, compared to cross-correlation methods currently used, the technique of Doppler tomography has improved sensitivity in detecting the subtle signatures expected from exoplanet atmospheres. This is partly due to the use of a regularizing statistic, which acts to suppress noise, coupled to the fact that all the data is fit simultaneously. In addition, we show that the technique can also effectively suppress contaminating spectral features that may arise due to overlapping lines, repeating line patterns, or the use of incorrect linelists. These issues can confuse conventional cross-correlation approaches, primarily due to aliasing issues inherent in such techniques, whereas Doppler tomography is less susceptible to such effects. In particular, Doppler tomography shows exceptional promise for simultaneously detecting multiple line species (e.g. isotopologues), even when there are high contrasts between such species – and far outperforms current cross-correlation function (CCF) in this respect. Finally, we demonstrate that Doppler tomography is capable of recovering molecular signals from exoplanets using real data, by confirming the strong detection of CO in the atmosphere of τ Boo b. We recover a signal with a planetary radial velocity semi-amplitude Kp = 109.6 ± 2.2 km s−1, in excellent agreement with the previously reported value of 110.0 ± 3.2 km s−1.
The southern stellar stream spectroscopic survey (S5): Overview, target selection, data reduction, validation, and early science
Authors: Li T S , Koposov S E , Zucker D B , Lewis G F , Kuehn K , Simpson J D , Ji A P , Shipp N , Mao Y-Y , Geha M , Pace A B , Mackey A D , Allam S , Tucker D L , Da Costa G S , Erkal D , Simon J D , Mould J R , Martell S L , Wan Z , De Silva G M , Bechtol K , Balbinot E , Belokurov V , Bland-Hawthorn J , Casey A R , Cullinane L , Drlica-Wagner A , Sharma S , Vivas A K , Wechsler R H , Yanny B ,   (S5 Collaboration)
Published: October 2019

We introduce the southern stellar stream spectroscopy survey (S5), an on-going program to map the kinematics and chemistry of stellar streams in the southern hemisphere. The initial focus of S5 has been spectroscopic observations of recently identified streams within the footprint of the dark energy survey (DES), with the eventual goal of surveying streams across the entire southern sky. Stellar streams are composed of material that has been tidally striped from dwarf galaxies and globular clusters and hence are excellent dynamical probes of the gravitational potential of the Milky Way, as well as providing a detailed snapshot of its accretion history. Observing with the 3.9 m Anglo-Australian Telescope’s 2-degree-Field fibre positioner and AAOmega spectrograph, and combining the precise photometry of DES DR1 with the superb proper motions from Gaia DR2, allows us to conduct an efficient spectroscopic survey to map these stellar streams. So far S5 has mapped nine DES streams and three streams outside of DES; the former are the first spectroscopic observations of these recently discovered streams. In addition to the stream survey, we use spare fibres to undertake a Milky Way halo survey and a low-redshift galaxy survey. This paper presents an overview of the S5 program, describing the scientific motivation for the survey, target selection, observation strategy, data reduction, and survey validation. Finally, we describe early science results on stellar streams and Milky Way halo stars drawn from the survey. Updates on S5, including future public data releases, can be found at http://s5collab.github.io.
Illuminating the Tadpole’s metamorphosis – I. MUSE observations of a small globule in a sea of ionizing photons
Authors: Reiter Megan , McLeod Anna F , Klaassen Pamela D , Guzmán Andrés E , Dale J E , Mottram Joseph C , Garay Guido
Published: October 2019

We present new MUSE/VLT observations of a small globule in the Carina H ii region that hosts the HH 900 jet+outflow system. Data were obtained with the GALACSI ground-layer adaptive optics system in wide-field mode, providing spatially resolved maps of diagnostic emission lines. These allow us to measure the variation of the physical properties in the globule and jet+outflow system. We find high temperatures (Te ≈ 104 K), modest extinction (AV ≈ 2.5 mag), and modest electron densities (ne ≈ 200 cm−3) in the ionized gas. Higher excitation lines trace the ionized outflow; both the excitation and ionization in the outflow increase with distance from the opaque globule. In contrast, lower excitation lines that are collisionally de-excited at densities ≳104 cm−3 trace the highly collimated protostellar jet. Assuming the globule is an isothermal sphere confined by the pressure of the ionization front, we compute a Bonnor–Ebert mass of ∼3.7 M⊙. This is two orders of magnitude higher than previous mass estimates, calling into question whether small globules like the Tadpole contribute to the bottom of the initial mass function. The derived globule properties are consistent with a cloud that has been and/or will be compressed by the ionization front on its surface. At the estimated globule photoevaporation rate of ∼5 × 10−7 M⊙ yr−1, the globule will be completely ablated in ∼7 Myr. Stars that form in globules like the Tadpole will emerge into the H ii later and may help resolve some of the temporal tension between disc survival and enrichment.
Synonymous genome recoding: a tool to explore microbial biology and new therapeutic strategies
Authors: Martínez Miguel Angel , Jordan-Paiz Ana , Franco Sandra , Nevot Maria
Published: October 2019

Synthetic genome recoding is a new means of generating designed organisms with altered phenotypes. Synonymous mutations introduced into the protein coding region tolerate modifications in DNA or mRNA without modifying the encoded proteins. Synonymous genome-wide recoding has allowed the synthetic generation of different small-genome viruses with modified phenotypes and biological properties. Recently, a decreased cost of chemically synthesizing DNA and improved methods for assembling DNA fragments (e.g. lambda red recombination and CRISPR-based editing) have enabled the construction of an Escherichia coli variant with a 4-Mb synthetic synonymously recoded genome with a reduced number of sense codons (n = 59) encoding the 20 canonical amino acids. Synonymous genome recoding is increasing our knowledge of microbial interactions with innate immune responses, identifying functional genome structures, and strategically ameliorating cis-inhibitory signaling sequences related to splicing, replication (in eukaryotes), and complex microbe functions, unraveling the relevance of codon usage for the temporal regulation of gene expression and the microbe mutant spectrum and adaptability. New biotechnological and therapeutic applications of this methodology can easily be envisaged. In this review, we discuss how synonymous genome recoding may impact our knowledge of microbial biology and the development of new and better therapeutic methodologies.
Systematic search for structural motifs of peptide binding to double-stranded DNA
Authors: Kolchina Nina , Khavinson Vladimir , Linkova Natalia , Yakimov Alexander , Baitin Dmitry , Afanasyeva Arina , Petukhov Michael
Published: September 2019

A large variety of short biologically active peptides possesses antioxidant, antibacterial, antitumour, anti-ageing and anti-inflammatory activity, involved in the regulation of neuro-immuno-endocrine system functions, cell apoptosis, proliferation and differentiation. Therefore, the mechanisms of their biological activity are attracting increasing attention not only in modern molecular biology, biochemistry and biophysics, but also in pharmacology and medicine. In this work, we systematically analysed the ability of dipeptides (all possible combinations of the 20 standard amino acids) to bind all possible combinations of tetra-nucleotides in the central part of dsDNA in the classic B-form using molecular docking and molecular dynamics. The vast majority of the dipeptides were found to be unable to bind dsDNA. However, we were able to identify 57 low-energy dipeptide complexes with peptide-dsDNA possessing high selectivity for DNA binding. The analysis of the dsDNA complexes with dipeptides with free and blocked N- and C-terminus showed that selective peptide binding to dsDNA can increase dramatically with the peptide length.
PDBe-KB: a community-driven resource for structural and functional annotations
Authors:   PDBe-KB consortium, Varadi Mihaly , Berrisford John , Deshpande Mandar , Nair Sreenath S , Gutmanas Aleksandras , Armstrong David , Pravda Lukas , Al-Lazikani Bissan , Anyango Stephen , Barton Geoffrey J , Berka Karel , Blundell Tom , Borkakoti Neera , Dana Jose , Das Sayoni , Dey Sucharita , Micco Patrizio Di , Fraternali Franca , Gibson Toby , Helmer-Citterich Manuela , Hoksza David , Huang Liang-Chin , Jain Rishabh , Jubb Harry , Kannas Christos , Kannan Natarajan , Koca Jaroslav , Krivak Radoslav , Kumar Manjeet , Levy Emmanuel D , Madeira F , Madhusudhan M S , Martell Henry J , MacGowan Stuart , McGreig Jake E , Mir Saqib , Mukhopadhyay Abhik , Parca Luca , Paysan-Lafosse Typhaine , Radusky Leandro , Ribeiro Antonio , Serrano Luis , Sillitoe Ian , Singh Gulzar , Skoda Petr , Svobodova Radka , Tyzack Jonathan , Valencia Alfonso , Fernandez Eloy Villasclaras , Vranken Wim , Wass Mark , Thornton Janet , Sternberg Michael , Orengo Christine , Velankar Sameer
Published: October 2019

The Protein Data Bank in Europe-Knowledge Base (PDBe-KB, https://pdbe-kb.org) is a community-driven, collaborative resource for literature-derived, manually curated and computationally predicted structural and functional annotations of macromolecular structure data, contained in the Protein Data Bank (PDB). The goal of PDBe-KB is two-fold: (i) to increase the visibility and reduce the fragmentation of annotations contributed by specialist data resources, and to make these data more findable, accessible, interoperable and reusable (FAIR) and (ii) to place macromolecular structure data in their biological context, thus facilitating their use by the broader scientific community in fundamental and applied research. Here, we describe the guidelines of this collaborative effort, the current status of contributed data, and the PDBe-KB infrastructure, which includes the data exchange format, the deposition system for added value annotations, the distributable database containing the assembled data, and programmatic access endpoints. We also describe a series of novel web-pages—the PDBe-KB aggregated views of structure data—which combine information on macromolecular structures from many PDB entries. We have recently released the first set of pages in this series, which provide an overview of available structural and functional information for a protein of interest, referenced by a UniProtKB accession.
SEAweb: the small RNA Expression Atlas web application
Authors: Rahman Raza-Ur , Liebhoff Anna-Maria , Bansal Vikas , Fiosins Maksims , Rajput Ashish , Sattar Abdul , Magruder Daniel S , Madan Sumit , Sun Ting , Gautam Abhivyakti , Heins Sven , Liwinski Timur , Bethune Jörn , Trenkwalder Claudia , Fluck Juliane , Mollenhauer Brit , Bonn Stefan
Published: October 2019

We present the Small RNA Expression Atlas (SEAweb), a web application that allows for the interactive querying, visualization and analysis of known and novel small RNAs across 10 organisms. It contains sRNA and pathogen expression information for over 4200 published samples with standardized search terms and ontologies. In addition, SEAweb allows for the interactive visualization and re-analysis of 879 differential expression and 514 classification comparisons. SEAweb's user model enables sRNA researchers to compare and re-analyze user-specific and published datasets, highlighting common and distinct sRNA expression patterns. We provide evidence for SEAweb's fidelity by (i) generating a set of 591 tissue specific miRNAs across 29 tissues, (ii) finding known and novel bacterial and viral infections across diseases and (iii) determining a Parkinson's disease-specific blood biomarker signature using novel data. We believe that SEAweb's simple semantic search interface, the flexible interactive reports and the user model with rich analysis capabilities will enable researchers to better understand the potential function and diagnostic value of sRNAs or pathogens across tissues, diseases and organisms.