bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence of Midline Catheter Complications Among Hospitalized Patients
Authors: Tran Anh Thu , Rizk Elsie , Aryal Dipendra K. , Soto Frank J. , Swan Joshua T.
Published: December 2022

The use of midline catheters has increased to reduce excessive use of central venous access devices, and additional data on midline catheter complications are needed. This study aimed to describe midline catheter complications among hospitalized patients. This retrospective study included a random sample of 300 hospitalized patients with a midline catheter insertion in 2019. The primary outcome was a composite end point of 8 complications: occlusion, bleeding at insertion site, infiltration/extravasation, catheter-related thrombosis, accidental removal, phlebitis, hematoma, and catheter-related infection. Midline catheter failure was defined as removal prior to the end of therapy due to complications. Among 300 midline catheters, the incidence of the composite end point of 1 or more midline complications was 38% (95% confidence interval, 33%–44%). Complications included occlusion (17.0%), bleeding at insertion site (12.0%), infiltration/extravasation (10.0%), catheter-related thrombosis (4.0%), accidental removal (3.0%), phlebitis (0.3%), hematoma (0.3%), and catheter-related infection (0.3%). Midline catheter failure occurred in 16% of midline catheters (n = 48) due to infiltration/extravasation (n = 27), accidental removal (n = 10), catheter-related thrombosis (n = 9), occlusion (n = 4), and catheter-related infection (n = 1). Three catheters had 2 types of failure. The most common complications of occlusion and bleeding rarely resulted in midline catheter failure. The most common causes of midline catheter failure were infiltration/extravasation, accidental removal, and catheter-related thrombosis.
The Many Faces of Hemolysis
Authors: Cook Lynda S.
Published: December 2022

Hemolysis is a problem associated with a variety of red cell pathologies and physiologies not limited to the transfusion of cells. Various pathways lead to the observed outcomes when a hemolytic event occurs. Each event, and the pathway it follows, is based on characteristics of the red cell, the location in which the hemolysis occurs, and the interaction of the immune system. The severity of an event can be predicted with the knowledge of how these 3 factors interface. Although not all hemolytic events are alike, similarities may exist when the pathways overlap.
Prospective Study Evaluating Whether Standard Peripheral Intravenous Catheters Can Be Used for Blood Collection Throughout Hospital Stay
Authors: Psaila Justin , Parsons Thomas F. , Hahn Susan A. , Fichera Leah
Published: December 2022

Blood collection via venipuncture is the most common invasive procedure for inpatients, who experience an average of 1.6 to 2.2 blood collection episodes per day, for a total of approximately 450 million in US hospitals annually. In addition to being painful, venipuncture incurs the risk of vessel depletion, infection, and staff needlestick injury. A possible alternative is to use peripheral intravenous catheters (PIVCs), because PIVCs are placed in the majority of patients admitted to the hospital. Although there are anecdotal accounts of successfully using PIVCs for inpatient blood collection, the utility of this method has not been rigorously studied. The authors conducted a single-center prospective study among inpatients to evaluate blood collection success, defined as sufficient sample volume (4 mL) and no or minimal hemolysis, in PIVCs with a dwell time between 12 and 87 hours. Only 27% (28/105) of aspiration attempts were successful within this time frame. There was no difference in success rate with respect to PIVC dwell time, gauge, or location. These findings highlight the continued need for innovative, alternative solutions to meet the high demand for inpatient blood collection.
Understanding Patient and Clinician Reported Nonroutine Events in Ambulatory Surgery
Authors: Salwei Megan E. , Anders Shilo , Slagle Jason M. , Whitney Gina , Lorinc Amanda , Morley Susan , Pasley Jessica , DeClercq Josh , Shotwell Matthew S. , Weinger Matthew B.
Published: December 2022

Objective

Nonroutine events (NREs, i.e., deviations from optimal care) can identify care process deficiencies and safety risks. Nonroutine events reported by clinicians have been shown to identify systems failures, but this methodology fails to capture the patient perspective. The objective of this prospective observational study is to understand the incidence and nature of patient- and clinician-reported NREs in ambulatory surgery.

Methods

We interviewed patients about NREs that occurred during their perioperative care using a structured interview tool before discharge and in a 7-day follow-up call. Concurrently, we interviewed the clinicians caring for these patients immediately postoperatively to collect NREs. We trained 2 experienced clinicians and 2 patients to assess and code each reported NRE for type, theme, severity, and likelihood of reoccurrence (i.e., likelihood that the same event would occur for another patient).

Results

One hundred one of 145 ambulatory surgery cases (70%) contained at least one NRE. Overall, 214 NREs were reported—88 by patients and 126 by clinicians. Cases containing clinician-reported NREs were associated with increased patient body mass index (P = 0.023) and lower postcase patient ratings of being treated with respect (P = 0.032). Cases containing patient-reported NREs were associated with longer case duration (P = 0.040), higher postcase clinician frustration ratings (P < 0.001), higher ratings of patient stress (P = 0.019), and lower patient ratings of their quality of life (P = 0.010), of the quality of clinician teamwork (P = 0.010), being treated with respect (P = 0.003), and being listened to carefully (P = 0.012). Trained patient raters evaluated NRE severity significantly higher than did clinician raters (P < 0.001), while clinicians rated recurrence likelihood significantly higher than patients for both clinician (P = 0.032) and patient-reported NREs (P = 0.001).

Conclusions

Both patients and clinicians readily report events during clinical care that they believe deviate from optimal care expectations. These 2 primary stakeholders in safe, high-quality surgical care have different experiences and perspectives regarding NREs. The combination of patient- and clinician-reported NREs seems to be a promising patient-centered method of identifying healthcare system deficiencies and opportunities for improvement.
Screening of Potential Core Genes in Peripheral Blood of Adult Patients with Sepsis Based on Transcription Regulation Function
Authors: Liu Jitao , Li Shaolan , Xiong Dianhui , Shang Wenjun , Zhan Tao , Zhu Xingxin , He Sheng , Wang Yu , Zhang Qian , Hu Yingchun
Published: December 2022

Objective

To screen transcription factor genes related to the prognosis of adult patients with sepsis.

Methods

Twenty-three patients with sepsis and ten healthy individuals admitted for RNA-seq. Differential factors were enriched by four transcription factor databases, and survival analysis was adopted for core factors. Then, target genes were submitted to STRING to constitute the PPI network. Single-cell technology was used to localize cell lines. Finally, a transcription-target gene regulation network was constituted.

Results

A total of 4,224 DEGs were obtained between sepsis and NC groups. PPI results showed that FOXO3, NFKB1, SPI1, STAT5A, and PPARA were located in the center of the network. Target genes were related to cytokine-mediated signaling pathway and transcription regulator activity, etc. SPI1 was mainly located in monocyte cell lines, while FOXO3, PPARA, SP1, STAT3, and USF1 were expressed in monocyte cell lines, NK-T cell lines, and B cell lines. Compared with those in the control group, FOXO3, SP1, SPI1, STAT3, and USF1 were highly expressed in the sepsis group, while PPARA had low expression.

Conclusion

Transcription factors such as FOXO3, PPARA, SP1, SPI1, STAT3, and USF1 are correlated with the prognosis of sepsis patients and thus may have a potential research value.

Clinical Trial Registration: The clinical trial registration number is ChiCTR1900021261.
Linguistic concepts are self-generating choice architectures
Authors: Enfield N. J.
Published: December 2022

While the idea of a ‘concept’ has been defined in diverse ways, researchers in the cognitive science of language have largely agreed that linguistic concepts are objects, whether mental or physical, that bits of language stand for. This O-axis view (where O = object), focusing on sign–object relations, sees linguistic concepts as ideas that stand in a static relation to signs, with the function of mediating relations between agents and their environments. But this is only half the story. Because every linguistic concept is moored to a bit of language, and bits of language are mostly learned and encountered in sequences of social interaction, then we must look not only at what signs stand for (their
objects
), but at the
interpretants
, or rational responses, that they elicit. By focusing on sign–interpretant relations, and thus taking an I-axis view (where I = interpretant), we not only acknowledge the direct link between concepts and social interaction, we also discover causal mechanisms that explain how linguistic concepts are distributed in relatively stable form in populations. We find that while concepts are indeed mental objects, they function as choice architectures in the dynamic flow of situated language usage.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Concepts as plug & play devices
Authors: Shea Nicholas
Published: December 2022

Research on concepts has focused on categorization. Categorization starts with a stimulus. Equally important are episodes that start with a thought. We engage in thinking to draw out new consequences from stored information, or to work out how to act. Each of the concepts out of which thought is constructed provides access to a large body of stored information. Access is not always just a matter of retrieving a stored belief (semantic memory). Often it depends on running a simulation. Simulation allows conceptual thought to draw on information in special-purpose systems, information stored in special-purpose computational dispositions and special-purpose representational structures. While the utility of simulation, prospection or imagination is widely appreciated, the role of concepts in the process is not well understood. This paper turns to cognitive and computational neuroscience for a model of how simulations enable thinkers to reach novel conclusions. Carried over to conceptual thought, the model suggests that concepts are ‘plug & play’ devices. The distinctive power of thought-driven simulation derives from the ability of concepts to plug into two kinds of structure at once: the combinatorial structure of a thought at one end and special-purpose structural representations at the other.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Is love an abstract concept? A view of concepts from an interaction-based perspective
Authors: Rączaszek-Leonardi Joanna , Zubek Julian
Published: December 2022

Research concerning concepts in the cognitive sciences has been dominated by the information-processing approach, which has resulted in a certain narrowing of the range of questions and methods of investigation. Recent trends have sought to broaden the scope of such research, but they have not yet been integrated within a theoretical framework that would allow us to reconcile new perspectives with the insights already obtained. In this paper, we focus on the processes involved in early concept acquisition and demonstrate that certain aspects of these processes remain largely understudied. These aspects include the primacy of movement and coordination with others within a structured social environment as well as the importance of first-person experiences pertaining to perception and action. We argue that alternative approaches to cognition, such as ecological psychology, enactivism and interactivism, are helpful for foregrounding these understudied areas. These approaches can complement the extant research concerning concepts to help us obtain a more comprehensive view of knowledge structures, thus providing us with a new perspective on recurring problems, suggesting novel questions and enriching our methodological toolbox.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Sampling statistics are like story creation: a network analysis of parent–toddler exploratory play
Authors: Karmazyn-Raz Hadar , Smith Linda B.
Published: December 2022

Actions in the world elicit data for learning and do so in a stream of interconnected events. Here, we provide evidence on how toddlers with their parent sample information by acting on toys during exploratory play. We observed 10 min of free-flowing and unconstrained object exploration of by toddlers (mean age 21 months) and parents in a room with many available objects (
n
= 32). Borrowing concepts and measures from the study of narratives, we found that the toy selections are not a string of unrelated events but exhibit a suite of what we call coherence statistics: Zipfian distributions, burstiness and a network structure. We discuss the transient memory processes that underlie the moment-to-moment toy selections that create this coherence and the role of these statistics in the development of abstract and generalizable systems of knowledge.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Acquiring religious words: dialogical and individual construction of a word's meaning
Authors: Viertel Franziska E. , Reis Oliver , Rohlfing Katharina J.
Published: December 2022

By the age of eight, there is a significant increase in abstract words in the child's lexicon. A crucial contribution can be seen in the linguistic input, i.e. the way how abstract words are presented by caregivers by means of linguistic perspectivation and emotionalization. Following an interactionist way, we were interested in how the semantics of abstract words is constructed by child and caregiver in duet. We focused on a subset of abstract words and studied the acquisition of meaning of the religious concept
mercy.
We expected religious words to be emotionally anchored and presented with perspectivation, both contributing to learning. Exploring the dialogic constructions, we investigated eight 7- to 8-year olds and their parents during dialogic reading and studied their strategies focusing on the linguistic means of emotionalization and perspectivation in contextualizing the word. In a subsequent test, we analysed these means used by the children and assessed their individual understanding of
mercy
. Our analyses indicate that during reading, the enrichment of semantics by emotionalization was related between child and caregiver, whereas cross-situationally, a simultaneous enrichment of emotionalization and perspectivation was present. Moreover, the children demonstrated a conceptual understanding of
mercy
in religious contexts, but not in secular contexts.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Mechanisms of alignment: shared control, social cognition and metacognition
Authors: Gandolfi Greta , Pickering Martin J. , Garrod Simon
Published: December 2022

In dialogue, speakers process a great deal of information, take and give the floor to each other, and plan and adjust their contributions on the fly. Despite the level of coordination and control that it requires, dialogue is the easiest way speakers possess to come to similar conceptualizations of the world. In this paper, we show how speakers align with each other by mutually controlling the flow of the dialogue and constantly monitoring their own and their interlocutors' way of representing information. Through examples of conversation, we introduce the notions of shared control, meta-representations of alignment and commentaries on alignment, and show how they support mutual understanding and the collaborative creation of abstract concepts. Indeed, whereas speakers can share similar representations of concrete concepts just by mutually attending to a tangible referent or by recalling it, they are likely to need more negotiation and mutual monitoring to build similar representations of abstract concepts.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Social semantics: the organization and grounding of abstract concepts
Authors: Pexman Penny M. , Diveica Veronica , Binney Richard J.
Published: December 2022

Abstract concepts, likejusticeandfriendship, are central features of our daily lives. Traditionally, abstract concepts are distinguished from other concepts in that they cannot be directly experienced through the senses. As such, they pose a challenge for strongly embodied models of semantic representation that assume a central role for sensorimotor information. There is growing recognition, however, that it is possible for meaning to be ‘grounded’ via cognitive systems, including those involved in processing language and emotion. In this article, we focus on the specific proposal thatsocialsignificance is a key feature in the representation of some concepts. We begin by reviewing recent evidence in favour of this proposal from the fields of psycholinguistics and neuroimaging. We then discuss the limited extent to which there is consensus about the definition of ‘socialness’ and propose essential next steps for research in this domain. Taking one such step, we describe preliminary data from an unprecedented large-scale rating study that can help determine how socialness is distinct from other facets of word meaning. We provide a backdrop of contemporary theories regarding semantic representation and social cognition and highlight important predictions for both brain and behaviour.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Social concepts and the cerebellum: behavioural and functional connectivity signatures in cerebellar ataxic patients
Authors: Lopes da Cunha Pamela , Fittipaldi Sol , González Campo Cecilia , Kauffman Marcelo , Rodríguez-Quiroga Sergio , Yacovino Darío Andrés , Ibáñez Agustín , Birba Agustina , García Adolfo M.
Published: December 2022

Neurocognitive research on social concepts underscores their reliance on fronto-temporo-limbic regions mediating broad socio-cognitive skills. Yet, the field has neglected another structure increasingly implicated in social cognition: the cerebellum. The present exploratory study examines this link combining a novel naturalistic text paradigm, a relevant atrophy model and functional magnetic resonance imaging. Fifteen cerebellar ataxia (CA) patients with focal cerebellar atrophy and 29 matched controls listened to a social text (highlighting interpersonal events) as well as a non-social text (focused on a single person's actions), and answered comprehension questionnaires. We compared behavioural outcomes between groups and examined their association with cerebellar connectivity. CA patients showed deficits in social text comprehension and normal scores in the non-social text. Also, social text outcomes in controls selectively correlated with connectivity between the cerebellum and key regions subserving multi-modal semantics and social cognition, including the superior and medial temporal gyri, the temporal pole and the insula. Conversely, brain-behaviour associations involving the cerebellum were abolished in the patients. Thus, cerebellar structures and connections seem involved in processing social concepts evoked by naturalistic discourse. Such findings invite new theoretical and translational developments integrating social neuroscience with embodied semantics.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Mapping the mental space of emotional concepts through kinematic measures of decision uncertainty
Authors: Barca Laura , Candidi Matteo , Lancia Gian Luca , Maglianella Valerio , Pezzulo Giovanni
Published: December 2022

Emotional concepts and their mental representations have been extensively studied. Yet, some ecologically relevant aspects, such as how they are processed in ambiguous contexts (e.g., in relation to other emotional stimuli that share similar characteristics), are incompletely known. We employed a similarity judgement of emotional concepts and manipulated the contextual congruency of the responses along the two main affective dimensions of hedonic valence and physiological activation, respectively. Behavioural and kinematics (mouse-tracking) measures were combined to gather a novel ‘similarity index’ between emotional concepts, to derive topographical maps of their mental representations. Self-report (interoceptive sensibility, positive–negative affectivity, depression) and physiological measures (heart rate variability, HRV) have been collected to explore their possible association with emotional conceptual representation. Results indicate that emotional concepts typically associated with low arousal profit by contextual congruency, with faster responses and reduced uncertainty when contextual ambiguity decreases. The emotional maps recreate two almost orthogonal axes of valence and arousal, and the similarity measure captures the smooth boundaries between emotions. The emotional map of a subgroup of individuals with low positive affectivity reveals a narrower conceptual distribution, with variations in positive emotions and in individuals with reduced arousal (such as those with reduced HRV). Our work introduces a novel methodology to study emotional conceptual representations, bringing the behavioural dynamics of decision-making processes and choice uncertainty into the affective domain.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Abstract concepts and emotion: cross-linguistic evidence and arguments against affective embodiment
Authors: Winter Bodo
Published: December 2022

How are abstract concepts such as ‘freedom' and ‘democracy' represented in the mind? One prominent proposal suggests that abstract concepts are grounded in emotion. Supporting this ‘affective embodiment' account, abstract concepts are rated to be more strongly positive or more strongly negative than concrete concepts. This paper demonstrates that this finding generalizes across languages by synthesizing rating data from Cantonese, Mandarin Chinese, Croatian, Dutch, French, German, Indonesian, Italian, Polish and Spanish. However, a deeper look at the same data suggests that the idea of emotional grounding only characterizes a small subset of abstract concepts. Moreover, when the concreteness/abstractness dimension is not operationalized using concreteness ratings, it is actually found that concrete concepts are rated as more emotional than abstract ones. Altogether, these results suggest limitations to the idea that emotion is an important factor in the grounding of abstract concepts.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Olfactory abstraction: a communicative and metacognitive account
Authors: Deroy Ophelia
Published: December 2022

The usual puzzle raised about olfaction is that of a deficit of abstraction: smells, by contrast notably with colours, do not easily lend themselves to abstract categories and labels. Some studies have argued that the puzzle is culturally restricted and that abstraction is more common outside urban Western societies. Here, I argue that the puzzle is misconstrued and should be reversed: given that odours are constantly changing and that their commonalities are difficult for humans to identify, what is surprising is not that abstract terms are rare, but that they should be used at all for olfaction. Given the nature of the olfactory environment and our cognitive equipment, concrete labels referring to sources seem most adaptive. To explain the use and presence of abstract terms, we need to examine their social and communicative benefits. Here these benefits are spelt out as securing a higher agreement among individuals varying in their olfactory experiences as well as the labels they use, as well as feeling a heightened sense of confidence in one's naming capacities.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
Concepts, abstractness and inner speech
Authors: Borghi Anna M. , Fernyhough Charles
Published: December 2022

We explore the role of inner speech (covert self-directed talk) during the acquisition and use of concepts differing in abstractness. Following Vygotsky, inner speech results from the internalization of linguistically mediated interactions that regulate cognition and behaviour. When we acquire and process abstract concepts, uncertainties about word meaning might lead us to search actively for their meaning. Inner speech might play a role in this searching process and be differentially involved in concept learning compared with use of known concepts. Importantly, inner speech comes in different varieties—e.g. it can be expanded or condensed (with the latter involving syntactic and semantic forms of abbreviation). Do we use inner speech differently with concepts varying in abstractness? Which kinds of inner speech do we preferentially use with different kinds of abstract concepts (e.g. emotions versus numbers)? What other features of inner speech, such as dialogicality, might facilitate our use of concepts varying in abstractness (by allowing us to monitor the limits of our knowledge in simulated social exchanges, through a process we term
inner social metacognition
)? In tackling these questions, we address the possibility that different varieties of inner speech are flexibly used during the acquisition of concepts and their everyday use.

This article is part of the theme issue ‘Concepts in interaction: social engagement and inner experiences’.
First-in-human case report: AAV9-hGAA gene therapy for a patient with infantile-onset Pompe disease
Authors: Ma Xiuwei , Li Jun , Wang Xiaodong , Ma Wenhao , Wang Jianhua , Gu Ruijie , Zhu Zhiming , Wang Yongxia , Du Ying , Xu Juan , He Fang , Yang Xiao , Zhang Sheng , Zhu Lina , Li Qiuping , Xiong Hui , Wu Xiaobing , Feng Zhichun
Published: December 2022

Background

The classic infantile-onset Pompe disease (IOPD) is characterized by cardiac hypertrophy, respiratory insufficiency, and rapidly progressive muscle weakness due to the acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) is the current approach for IOPD, but it entails several limitations. Aiming to overcome the limited efficiency of ERT, we developed adeno-associated virus (AAV) gene therapy for IOPD patients.

Method

One IOPD patient received a single intravenous dose of GC301, a recombinant adeno-associated virus 9 (rAAV9) expressing the human GAA (rAAV-hGAA). During the follow-up, safety was accessed by the physical examinations, cardiac and laboratory evaluations. GAA activity, the titers of serum antibodies to AAV9 and GAA, and motor development were monitored regularly.

Result

The infant showed significant improvements in motor milestones. The GAA enzyme activity increased to the normal range. The cardiac function improved notably.

Conclusion

In patient with IOPD, a single intravenous AAV9-hGAA gene therapy improved the clinical outcomes remarkably. The trial is still ongoing, the safety of this gene therapy and the long-term clinical benefit remain to be monitored for months and years to come.
Genotype-driven downregulation of interleukin 6 signaling and periodontitis
Authors: Nolde Michael , Alayash Zoheir , Reckelkamm Stefan Lars , Kocher Thomas , Ehmke Benjamin , Holtfreter Birte , Baurecht Hansjörg , Georgakis Marios K. , Baumeister Sebastian-Edgar
Published: December 2022

Interleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. To explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis, we tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis. As proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL6 receptor (IL6R) that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575,531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17,353 cases and 28,210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed. Genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296). In conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis.
TaME-seq2: Tagmentation-assisted multiplex PCR enrichment sequencing for viral genomic profiling
Authors: Løvestad Alexander Hesselberg , Stosic Milan S. , Costanzi Jean-Marc , Christiansen Irene Kraus , Aamot Hege Vangstein , Ambur Ole Herman , Rounge Trine B.
Published: December 2022

Background

Previously developed TaME-seq method for deep sequencing of HPV, allowed simultaneous identification of the HPV DNA consensus sequence, low-frequency variable sites, and chromosomal integration events. The method has been successfully validated and applied to the study of five carcinogenic high-risk (HR) HPV types (HPV16, 18, 31, 33, and 45). Here, we present TaME-seq2 with an updated laboratory workflow and bioinformatics pipeline. The HR-HPV type repertoire was expanded with HPV51, 52, and 59. As a proof-of-concept, TaME-seq2 was applied on SARS-CoV-2 positive samples showing the method’s flexibility to a broader range of viruses, both DNA and RNA.

Results

Compared to TaME-seq version 1, the bioinformatics pipeline of TaME-seq2 is approximately 40x faster. In total, 23 HPV-positive samples and seven SARS-CoV-2 clinical samples passed the threshold of 300x mean depth and were submitted to further analysis. The mean number of variable sites per 1000 bp was ∼ 1.5x higher in SARS-CoV-2 than in HPV-positive samples. Reproducibility and repeatability of the method were tested on a subset of samples. A viral integration breakpoint followed by a partial genomic deletion was found in within-run replicates of HPV59-positive sample. Identified viral consensus sequence in two separate runs was >99.9 % identical between replicates, differing by a couple of nucleotides identified in only one of the replicates. Conversely, the number of identical minor nucleotide variants (MNVs) differed greatly between replicates, probably caused by PCR-introduced bias. The total number of detected MNVs, calculated gene variability and mutational signature analysis, were unaffected by the sequencing run.

Conclusion

TaME-seq2 proved well suited for consensus sequence identification, and the detection of low-frequency viral genome variation and viral-chromosomal integrations. The repertoire of TaME-seq2 now encompasses seven HR-HPV types. Our goal is to further include all HR-HPV types in the TaME-seq2 repertoire. Moreover, with a minor modification of previously developed primers, the same method was successfully applied for the analysis of SARS-CoV-2 positive samples, implying the ease of adapting TaME-seq2 to other viruses.
Assessing the availability of Repurposed Orphan Drugs in India
Authors: Rajueni Khujith , Chakraborty Choudhury Mohua
Published: December 2022

India has a massive burden of rare diseases (RDs), estimated to be around 96 million living patients but limited options for treatment. Drugs used for RDs are known as Orphan Drugs. Globally, 95% of RDs do not have an approved drug for treatment. Novel orphan drugs are characteristically expensive and out of reach for most Indian patients. Repurposing drugs used for other common conditions have been considered an essential alternative for RDs due to their cost-effectiveness and reduced timeline resulting in higher success rates than novel drugs. India’s patent regime prevents the evergreening of drugs, and a large generic manufacturing industry provides ample opportunity to explore the potential of repurposed drugs for treating RDs. However, information on the availability of repurposed orphan drugs (RODs) in India is limited. Also, there is no portal for information on orphan drugs in India. This study assesses the availability of RODs in India through quantitative empirical analysis. In the absence of a separate orphan drug designation in India, we consider USFDA-approved orphan-designated products as the reference. We searched for the availability of FDA-approved RODs in recognized sources in India, such as CDSCO, AYUSH gazette, and Indian Pharmacopeia, which provides a list of drugs approved for marketing in India. We classified the drugs into separate groups based on their availability in different sources and explored the regulatory implications of the differential representations. We found that 76% of RODs approved by the USFDA are entirely or partially available in India. Information on RODs will help relevant stakeholders in the better management of RDs in India.
Benefits of sphingosine-1-phosphate receptor modulators in relapsing MS estimated with a treatment sequence model
Authors: Corsten Cato E.A. , Huygens Simone A. , Versteegh Matthijs M. , Wokke Beatrijs H.A. , Smets Ide , Smolders Joost
Published: December 2022

Background

Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient’s lifespan.

Methods

Incorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naive patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes.

Results

In deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod.

Conclusion

Our model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care.

Highlights

Disease-modifying therapies (DMTs) are the largest cost driver in MS

Three sphingosine-1-phosphate receptor (S1PR) modulators are used for relapsing MS

Our model compares sequences of up to 5 DMTs in terms of health (relapses, progression) and costs

Comparing sequences including S1PR modulators, ponesimod is the most cost-effective drug

Cost-effectiveness research helps to prioritize when prescribing drugs of a similar class
Robotically-controlled three-dimensional micro-ultrasound for prostate biopsy guidance
Authors: Vassallo Reid , Aleef Tajwar Abrar , Zeng Qi , Wodlinger Brian , Black Peter , Salcudean Septimiu E.
Published: December 2022

Purpose

Prostate imaging to guide biopsy remains unsatisfactory, with current solutions suffering from high complexity and poor accuracy and reliability. One novel entrant into this field is microultrasound (microUS), which uses a high frequency imaging probe to achieve very high spatial resolution, and achieves prostate cancer detection rates equivalent to multiparametric magnetic resonance imaging (mpMRI). However, the ExactVu transrectal microUS probe has a unique geometry that makes it challenging to acquire controlled, repeatable three-dimensional (3D) transrectal ultrasound (TRUS) volumes. We describe the design, fabrication, and validation of a 3D acquisition system that allows for the accurate use of the ExactVu microUS device for volumetric prostate imaging.

Methods

The design uses a motorized, computer-controlled brachytherapy stepper to rotate the ExactVu transducer about its axis. We carry geometric validation using a phantom with known dimensions and we compare performance with magnetic resonance imaging (MRI) using a commercial quality assurance anthropomorphic prostate phantom.

Results

Our geometric validation shows accuracy of 1 mm or less in all three directions, and images of an anthropomorphic phantom qualitatively match those acquired using MRI and show good agreement quantitatively.

Conclusion

We describe the first system to acquire robotically- controlled 3D microUS images using the ExactVu microUS system. The reconstructed 3D microUS images are accurate, which will allow for applications of the ExactVu microUS system in prostate specimen andin vivoimaging.
Asymmetric HIV-1 envelope trimers bound to one and two CD4 molecules are intermediates during membrane binding
Authors: Li Wenwei , Nand Elizabeth , Qin Zhuan , Grunst Michael W. , Grover Jonathan R. , Bess Julian W. , Lifson Jeffrey D. , Zwick Michael B. , Tagare Hemant D. , Uchil Pradeep D. , Mothes Walther
Published: December 2022

Human immunodeficiency virus 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein (Env) to the cell-surface receptor CD4. Although high resolution structures of Env complexed with soluble domains of CD4 have been determined, the binding process is less understood on native membranes. Here, we apply cryo-electron tomography (cryo-ET) to monitor Env-CD4 interactions at membrane-membrane interfaces formed between HIV-1 and CD4-presenting virus-like particles. Env-CD4 complexes organized into clusters and rings, bringing opposing membranes closer together. Additionally, Env-CD4 clustering was dependent on capsid maturation. Subtomogram averaging and classification revealed that Env bound one, two, and finally three CD4 molecules, upon which Env adopted a partially open state. Our data indicate that asymmetric HIV-1 Env trimers bound to one and two CD4 molecules are detectable intermediates during virus binding to host cell membranes, which likely has consequences for antibody-mediated immune responses and vaccine immunogen design.
An Interplay of Phytoplankton Donor Species and Transformation of Released Compounds over Time Defines Bacterial Communities Following Phytoplankton DOMp Pulses
Authors: Eigemann Falk , Rahav Eyal , Grossart Hans-Peter , Aharonovich Dikla , Voss Maren , Sher Daniel
Published: December 2022

Phytoplankton-bacteria interactions are stimulated by phytoplankton-released dissolved organic matter (DOMp). Two factors that shape the accompanying bacterial community are i) the “donor” phytoplankton species, defining the initial composition of released DOMp, and ii) the DOMp transformation over time. We added phytoplankton DOM from two globally abundant species - the diatomSkeletonema marinoiand the cyanobacteriumProchlorococcusMIT9312 - to natural bacterial communities in the Eastern Mediterranean and determined the bacterial responses over a time-course of 72 h in terms of cell numbers, bacterial production (BP), alkaline phosphatase activity (APA), and changes in active bacterial community compositions based on rRNA amplicon sequencing. Both DOMp types were demonstrated to serve the bacterial community as carbon and potentially phosphorus source. Diatom-derived DOM induced higher BP and lower APA compared to cyanobacterium DOM after 24 h, but not after 48 and 72 h of incubation, and also maintained higher Shannon diversities over the course of the experiment, indicating a better bacterial accessibility and broader disposability of diatom derived DOM. Bacterial communities significantly differed between DOMp types as well as different incubation times, pointing to a certain bacterial specificity for the DOMp donor as well as a successive utilization of phytoplankton DOM by different bacterial taxa. The highest differences in bacterial community composition with DOMp types occurred shortly after additions, suggesting a high specificity towards highly bioavailable DOMp compounds. We conclude that phytoplankton associated bacterial communities are strongly shaped by an interplay between phytoplankton donor and the transformation of its released DOMp over time.

IMPORTANCE

Phytoplankton-bacteria interactions maintain biogeochemical cycles of global importance. Phytoplankton photosynthetically fix carbon dioxide and subsequently release the synthesized compounds as dissolved organic matter (DOMp), which becomes processed and recycled by heterotrophic bacteria. Yet, the combined effect of the phytoplankton donor species and time-dependent transformation of DOMp compounds on the accessibility to the bacterial community has not been explored until now. The diatomSkeletonema marinoiand the cyanobacteriumProchlorococcusMIT9312 are globally important phytoplankton species, and our study revealed that DOMp of both species was selectively incorporated by the bacterial community. The donor species had the highest impact shortly after DOMp appropriation, and its effect diminished over time. Our results improve the understanding of biogeochemical cycles between phytoplankton and bacteria, and solve yet unresolved questions of phytoplankton-bacteria interactions.
The contribution of Mediterranean connectivity to morphological variability in Iron Age sheep of the Eastern Mediterranean
Authors: Harding Sierra A. , Hadjikoumis Angelos , Vermeersch Shyama , Shafir Roee , Marom Nimrod
Published: December 2022

The movement of livestock across the Mediterranean is well-documented in the Neolithic era, but its significance during subsequent periods has received less attention. Here we start addressing this lacuna by analyzing astragal bone morphology from four coastal and inland sites in Israel and Cyprus, seeking potential evidence for maritime connections between sheep populations in the Iron Age eastern Mediterranean. Employing an established geometric morphometric protocol, we investigated the hypothesis that intra-site morphological variability is higher in coastal sites, reflecting greater genetic diversity in the livestock populations. While our findings support this hypothesis, the conclusions are constrained by contextual and sample size limitations.
A semi-field system for quantifyingAnopheles gambiaeattraction to human scent
Authors: Giraldo Diego , Rankin-Turner Stephanie , Corver Abel , Tauxe Genevieve M. , Gao Anne L. , Jackson Dorian M. , Simubali Limonty , Book Christopher , Stevenson Jennifer C. , Thuma Philip E. , Gordus Andrew , Mburu Monicah M. , Simulundu Edgar , McMeniman Conor J.
Published: December 2022

Variability in the chemical composition of human scent has the potential to modulate mosquito attraction to certain humans. We have engineered a large-scale, semi-field system in Zambia for quantifying mosquito olfactory preferences towards whole body odor sourced from different humans under naturalistic conditions. In a flight cage arena with infrared tracking, we document that the African malaria mosquitoAnopheles gambiaehierarchically prefers to land on heated targets mimicking human skin temperature when they are baited with carbon dioxide (CO2) over background air, human body odor over CO2, and the scent of one individual over another. In a six-choice assay configuration, we further identify humans at both ends of the attractiveness spectrum whose scent is differentially attractive toAn. gambiaerelative to other individuals. We demonstrate integrative use of this multi-choice olfactory assay with whole body volatilomics, establishing a powerful method for discovery of human odorants modulating heterogeneity in biting risk at enhanced throughput.
Discovery and characterization of cyclic peptides selective for theC-terminal bromodomains of BET family proteins
Authors: Franck Charlotte , Patel Karishma , Walport Louise J , Christie Mary , Norman Alexander , Passioura Toby , Suga Hiroaki , Payne Richard J , Mackay Joel P
Published: December 2022

DNA encoded cyclic peptide libraries offer unique opportunities to discover high-potency, high-specificity ligands directed against a target protein. We set out to explore the potential for such libraries to provide ligands that can distinguish between bromodomains from the closely related paralogues of the Bromodomain and ExtraTerminal domain (BET) family of epigenetic regulators. Analysis of peptides isolated from a screen against theC-terminal bromodomain of family member BRD2, together with new peptides discovered in previous screens against the corresponding domain from BRD3 and BRD4, reveals peptides with nanomolar and subnanomolar affinities. X-ray crystal structures of several of these bromodomain-peptide complexes reveal diverse structures and binding modes, which nevertheless display several conserved binding features. A subset of the peptides demonstrates significant paralogue-level specificity, though structural analysis does not reveal clear physicochemical explanations for this specificity. Our data demonstrate the power of cyclic peptides to discriminate between highly similar proteins with high potency and hint that differences in conformational dynamics between BET-family bromodomains might modulate binding affinities amongst family members for particular ligands.