bluuebunny/crossref_metadata_2025 huggingface dataset:
An inventory of early branch points in microbial phosphonate biosynthesis
Authors: Li Siwei , Horsman Geoff P.
Published: February 2022

Microbial phosphonate biosynthetic machinery has been identified in ~5 % of bacterial genomes and encodes natural products like fosfomycin as well as cell surface decorations. Almost all biological phosphonates originate from the rearrangement of phosphoenolpyruvate (PEP) to phosphonopyruvate (PnPy) catalysed by PEP mutase (Ppm), and PnPy is often converted to phosphonoacetaldehyde (PnAA) by PnPy decarboxylase (Ppd). Seven enzymes are known or likely to act on either PnPy or PnAA as early branch points en route to diverse biosynthetic outcomes, and these enzymes may be broadly classified into three reaction types: hydride transfer, aminotransfer, and carbon-carbon bond formation. However, the relative abundance of these branch points in microbial phosphonate biosynthesis is unknown. Also unknown is the proportion of ppm-containing gene neighbourhoods encoding new branch point enzymes and potentially novel phosphonates. In this study we computationally sorted 434 ppm-containing gene neighbourhoods based on these seven branch point enzymes. Unsurprisingly, the majority (56 %) of these pathways encode for production of the common naturally occurring compound 2-aminoethylphosphonate (AEP) or a hydroxylated derivative. The next most abundant genetically encoded intermediates were phosphonoalanine (PnAla, 9.2 %), 2-hydroxyethylphosphonate (HEP, 8.5 %), and phosphonoacetate (PnAc, 6 %). Significantly, about 13 % of the gene neighbourhoods could not be assigned to any of the seven branch points and may encode novel phosphonates. Sequence similarity network analysis revealed families of unusual gene neighbourhoods including possible production of phosphonoacrylate and phosphonofructose, the apparent biosynthetic use of the C-P lyase operon, and a virus-encoded phosphonate. Overall, these results highlight the utility of branch point inventories to identify novel gene neighbourhoods and guide future phosphonate discovery efforts.
Quantitative bias analysis in practice: Review of software for regression with unmeasured confounding
Authors: Kawabata E , Tilling K , Groenwold RHH , Hughes RA
Published: February 2022

Failure to appropriately account for unmeasured confounding may lead to erroneous conclusions. Quantitative bias analysis (QBA) can be used to quantify the potential impact of unmeasured confounding or how much unmeasured confounding would be needed to change a study’s conclusions. Currently, QBA methods are not routinely implemented, partly due to a lack of knowledge about accessible software. We review the latest developments in QBA software between 2011 to 2021 and compare five different programs applicable when fitting a linear regression:treatSens, causalsens, sensemakr, EValue, andkonfound. We illustrate application of these programs to two datasets and provide code to assist analysts in future use of these software programs. Our review found 21 programs with most created post 2016. All are implementations of a deterministic QBA, and the majority are available in the free statistical software environment R. Many programs include features such as benchmarking and graphical displays of the QBA results to aid interpretation. Out of the five programs we compared,sensemakrperforms the most detailed QBA and includes a benchmarking feature for multiple unmeasured confounders. The diversity of QBA methods presents challenges to the widespread uptake of QBA among applied researchers. Provision of detailed QBA guidelines would be beneficial.
Spatial Point Process Model Predicts Survival in Clear Cell Renal Cell Carcinoma
Authors: Bhat Prahlad , Hwang Michael , Jahedi Afrooz , Sircar Kanishka , Kannan Kasthuri
Published: February 2022

Among renal cell carcinomas (RCCs), clear cell RCCs (ccRCCs) is a highly aggressive class characterized by highly invasive clinical course and poor survival. The presence of a sarcomatoid component implicates an even poorer prognosis. Spatial measures can establish features that could be routinely used in clinical practice to stratify important RCC outcomes. Therefore, we tested the effectiveness of spatial features as predictors of survival differentiation in 58 Grade 2 ccRCCs. We developed a machine learning model using the acquired spatial features to predict survival in Grade 2 ccRCCs which we termed “SurvCal”. The receiver operating characteristic accuracy from the derived model was 0.812. Subsequent feature analysis identified the spatial model fitting intensity parameter Gamma and the pair correlation function as critical features in distinguishing the classes. In the light of the increasing digitization of pathology routines, our results demonstrate the importance of spatial point pattern features as determinants of ccRCC survival outcomes and phenotypes.
Complementary non-sputum diagnostic testing using oral swabs and urine LAM testing for TB in people with HIV
Authors: Shapiro Adrienne E. , Olson Alaina M. , Kidoguchi Lara , Niu Xin , Ngcobo Zinhle , Magcaba Zanele P. , Ngwane Mduduzi W. , Whitman Grant R. , Weigel Kris M. , Wood Rachel C. , Wilson Doug P.K. , Drain Paul K. , Cangelosi Gerard A.
Published: February 2022

Testing for mycobacterial lipoarabinomannan (LAM) in urine is a practical but insensitive alternative to sputum testing to diagnose tuberculosis (TB) in people with HIV (PWH). We evaluated urine LAM testing conducted in parallel with tests for Mycobacterium tuberculosis DNA in oral swabs. In a cohort of 131 South Africans (92% with HIV), combined urine LAM and oral swab testing was significantly more sensitive than either sample tested alone (57% vs. 35% and 39%, respectively), and 97% specific, compared to reference sputum testing (TB culture and Xpert Ultra). Complementary non-sputum sample testing increased sensitivity of TB diagnosis, without sacrificing specificity.
Antipsychotic Effects on Longitudinal Cognitive Functioning in First-Episode Psychosis: A randomised, triple-blind, placebo-controlled study
Authors: Allott Kelly , Yuen Hok Pan , Baldwin Lara , O’Donoghue Brian , Fornito Alex , Chopra Sidhant , Nelson Barnaby , Graham Jessica , Kerr Melissa J. , Proffitt Tina , Ratheesh Aswin , Alvarez-Jimenez Mario , Harrigan Susy , Brown Ellie , Thompson Andrew D. , Pantelis Christos , Berk Michael , McGorry Patrick D. , Francey Shona M. , Wood Stephen J.
Published: February 2022

Objective

Cognitive impairment occurs in antipsychotic-naïve first-episode psychosis (FEP), but antipsychotics confound interpretation of the longitudinal course of cognition. The primary aim was to disentangle the effects of illness from antipsychotics on cognition over the first 6-months of FEP treatment.

Methods

Randomised, triple-blind placebo-controlled trial (Staged Treatment and Acceptability Guidelines in Early Psychosis; STAGES), where cognition was a secondary outcome. Antipsychotic-naïve FEP patients were allocated to receive risperidone/paliperidone (N=38) or placebo (N=40) in addition to intensive psychosocial therapy for 6-months. A healthy control group (N=42) was also recruited. A cognitive battery assessing attention, working memory, processing speed, verbal fluency, cognitive control and verbal paired-associate learning and memory was administered at baseline and 6-months. Twelve- and 24-month follow-up was also conducted.

Results

Over the 6-month trial period, cognitive performance remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. The exception was for verbal paired-associate learning and memory, where a significant group-by-time interaction was observed. The placebo and healthy control groups improved, and the medication group deteriorated on immediate paired-associate recall (p=0.039) and delayed cued recall (p=0.005); effect sizes were medium-to-large. Findings were similar when only trial completers were included in the analysis.

Conclusions

Risperidone/paliperidone may cause progression of memory impairment in the early months of FEP. Replication is needed in confirmatory trials. The findings support the need for careful consideration of the risks and benefits of various antipsychotics and the importance of accounting for their cognitive effects in longitudinal research.

Trial registration

Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/ ACTRN12607000608460).
A Human Skin Model for Assessing the Arboviral Infections
Authors: Esterly Allen T. , Lloyd Megan G. , Upadhyaya Prashant , Moffat Jennifer F. , Thangamani Saravanan
Published: February 2022

Arboviruses such as flaviviruses and alphaviruses cause a significant human healthcare burden on the global scale. Transmission of these viruses occurs during human blood feeding at the mosquito-skin interface. Not only do pathogen immune evasion strategies influence the initial infection and replication of pathogens delivered, but arthropod salivary factors also influence transmission foci. In-vitro cell cultures do not provide an adequate environment to study complex interactions between viral, mosquito, and host factors. To address this need for a whole tissue system, we describe a proof-of-concept model for arbovirus infection using adult human skin ex vivo with Zika virus (flavivirus) and Mayaro virus (alphavirus). Replication of these viruses in human skin was observed up to 4 days post-infection. Egressed viruses could be detected in the culture media as well. Antiviral and pro-inflammatory genes, including chemoattractant chemokines, were expressed in infected tissue. Immunohistochemical analysis showed the presence of virus in the skin tissue at 4 days post-infection. This model will be useful to further investigate: 1) the immediate molecular mechanisms of arbovirus infection in human skin, and 2) the influence of arthropod salivary molecules during initial infection of arboviruses in a more physiologically relevant system.
A Ferroptosis-mediated regulation of the biogenesis of the oxidative phosphorylation system
Authors: Murari Anjaneyulu , Kay-Rhooms Shauna , Hossain Kaniz BF , Liu Tong , Li Hong , Goparaju Naga Sri , Osei Cindy , Owusu-Ansah Edward
Published: February 2022

Several subunits in the matrix domain of mitochondrial complex I (CI) have been posited to be redox sensors for CI; but how elevated levels of reactive oxygen species (ROS) impinge on CI assembly is unknown. We report that when the mitochondrial NADPH-generating enzyme – Isocitrate Dehydrogenase 2 – is genetically disrupted, ROS levels are elevated and assembly of the oxidative phosphorylation system (OXPHOS) is impaired. Mechanistically, this begins with a ROS-mediated inhibition of biosynthesis of the matrix domain of CI, which progresses to a point where ferroptotic signals are induced, the mitochondrial unfolded protein response is activated and multiple OXPHOS complexes are impaired. Disruption of other enzymes that eliminate hydrogen peroxide, but not those that eliminate the superoxide radical, recapitulates the phenotype; implicating hydrogen peroxide as the signaling molecule involved. Thus, the redox status of the mitochondrion modulates the assembly of the matrix domain of CI and ultimately that of the entire OXPHOS.
Neural Dysregulation in Post-COVID Fatigue
Authors: Baker Anne M.E. , Maffitt Natalie J. , Del Vecchio Alessandro , McKeating Katherine M. , Baker Mark R. , Baker Stuart N. , Soteropoulos Demetris S.
Published: February 2022

Following infection from SARS-CoV-2, a substantial minority of people develop lingering after-effects known as ‘long COVID’. Fatigue is a common complaint with substantial impact on daily life, but the neural mechanisms behind post-COVID fatigue remain unclear.

We recruited 37 volunteers with self-reported fatigue after a mild COVID infection and carried out a battery of behavioural and neurophysiological tests assessing the central, peripheral and autonomic nervous systems.

In comparison to age and sex matched volunteers without fatigue (n=52), we show underactivity in specific cortical circuits, dysregulation of autonomic function, and myopathic change in skeletal muscle. Cluster analysis revealed no sub-groupings, suggesting post-COVID fatigue is a single entity with individual variation, rather than a small number of distinct syndromes. Based on our analysis we were also able to exclude dysregulation in sensory feedback circuits and descending neuromodulatory control.

These abnormalities on objective tests may indicate novel avenues for principled therapeutic intervention, and could act as fast and reliable biomarkers for diagnosing and monitoring the progression of fatigue over time.
Immunity post-COVID-19 recovery boosts the antibody immune response to SARS-CoV-2 vaccination
Authors: Ebrahim Fawzi , Tabal Salah , Lamami Yosra , Alhudiri Inas M , El Meshri Salah Edin , Al Dwigen Samira M , Arfa Ramadan , Alboeshi Asma , Alemam Hafsa A. , Abuhtna Fauzia , Altrhouni Rabeeah , Milad Mohamed B , Elgriw Nada A , Ruaua Mahmoud A , Abusrewil Zakarya , Harroush Warda , Jallul Mwada , Ali Fouziyah S , Eltaib Farag , Elzaghied Adam
Published: February 2022

Measurement of strength and durability of SARS-COV-2 antibody response is important to understand the waning dynamics of immune response to both vaccines and infection. The study aimed to evaluate the level of IgG antibodies against SARS-CoV-2 and their persistence in recovered, naïve and vaccinated individuals. We randomly investigate Anti-spike RBD IgG antibody responses in 10,000 individuals, both following infection with SARS-CoV-2 and immunization with SARS-COV-2 adenoviral-vector and killed vaccines. Overall, antibody titres in recovered vaccinated individuals and naïve vaccinee persists beyond 20 weeks. The mean levels of anti-spike IgG antibodies were higher in vaccinated participants with prior COVID-19 infections than in individuals without prior infection. Decline for IgG antibodies were faster in vaccinated individuals without previous COVID-19 infection compared to those with previous COVID-19 infection. Vaccination with adenoviral–vector vaccines generates higher antibody titers than for killed virus vaccine. Slightly over half of asymptomatic unvaccinated individuals develops antibody response. Previous COVID-19 infection elicited robust and sustained levels of SARS-CoV-2 antibodies in vaccinated individuals. A single dose of the vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with prior SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals. This study also underlines that asymptomatic infection equally generates antibodies as symptomatic infection. Those vaccinated with inactivated vaccine may require more frequent boosters than those vaccinated with an adenoviral vaccine. These findings are important for formulating public health vaccination strategies during COVID-19 pandemic.

Importance

Measurement of strength and durability of SARS-COV-2 antibody response is important to understand the waning dynamics of immune response to both vaccines and infection. We randomly surveyed 10,000 people for SARS-COV-2 antibodies. One vaccine dose with prior infection generated stronger immune response than two vaccine doses. Overall, antibody titres in recovered vaccinated individuals and naïve vaccinee persists beyond 20 weeks. Vaccination with adenoviral–vector vaccines generates higher antibody titers than for killed virus vaccine slightly over half of asymptomatic unvaccinated individuals develops antibody response. This study emphasise on the benefit of vaccination in inducing strong immune response. These findings are important for formulating public health vaccination strategies during COVID-19 pandemic.
BIRC6 modifies risk of invasive bacterial infection in Kenyan children
Authors: Gilchrist James J , Kariuki Silvia , Watson James A , Band Gavin , Uyoga Sophie , Ndila Carolyne M , Mturi Neema , Mwarumba Salim , Mohammed Shebe , Mosobo Moses , Rockett Kirk A , Mentzer Alexander J , Kwiatkowski Dominic P , Hill Adrian VS , Maitland Kathryn , Scott J Anthony G , Williams Thomas N
Published: February 2022

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with P. falciparum parasitaemia. We construct a joint dataset including 1,445 bacteraemia cases and 1,143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.
Resurgence of malaria in Uganda despite sustained indoor residual spraying and repeated long lasting insecticidal net distributions
Authors: Epstein Adrienne , Maiteki-Ssebuguzi Catherine , Namuganga Jane F. , Nankabirwa Joaniter I. , Gonahasa Samuel , Opigo Jimmy , Staedke Sarah G. , Rutazaana Damian , Arinaitwe Emmanuel , Kamya Moses R. , Bhatt Samir , Rodríguez-Barraquer Isabel , Greenhouse Bryan , Donnelly Martin J. , Dorsey Grant
Published: February 2022

Five years of sustained indoor residual spraying (IRS) of insecticide from 2014 to 2019, first using a carbamate followed by an organophosphate, was associated with a marked reduction in the burden of malaria in five districts of Uganda. We assessed malaria burden over an additional 21 months, corresponding to a change in IRS formulations using clothianidin with and without deltamethrin and the start of the COVID-19 pandemic. We document an unprecedented resurgence in malaria burden: in years 4-5 of sustained IRS cases were 84% lower than the pre-IRS period, in year 6 this increased to a 43% reduction, and in the first 9 months of year 7, cases were 39% higher than pre-IRS levels. The timing of this resurgence corresponded to a change of active ingredient to clothianidin, a new IRS active ingredient. Further research is needed to determine mechanisms leading to this resurgence.
Functional Connections Among Neurons within Single Columns of Macaque V1
Authors: Trepka Ethan B. , Zhu Shude , Xia Ruobing , Chen Xiaomo , Moore Tirin
Published: February 2022

Recent developments in high-density neurophysiological tools now make it possible to record from hundreds of single neurons within local, highly interconnected neural networks. Among the many advantages of such recordings is that they dramatically increase the quantity of identifiable, functional connections between neurons thereby providing an unprecedented view of local circuit interactions. Using high-density, Neuropixels recordings from single neocortical columns of primary visual cortex in nonhuman primates, we identified 1000s of functionally connected neuronal pairs using established crosscorrelation approaches. Our results reveal clear and systematic variations in the strength and synchrony of functional connections across the cortical column. Despite neurons residing within the same column, both measures of functional connectivity depended heavily on the vertical distance separating neuronal pairs, as well as on the similarity of stimulus tuning. In addition, we leveraged the statistical power afforded by the large numbers of connected pairs to categorize functional connections between neurons based on their crosscorrelation functions. These analyses identified distinct, putative classes of functional connections within the full population. These classes of functional connections were corroborated by their unique distributions across defined laminar compartments and were consistent with known properties of V1 cortical circuitry, such as the lead-lag relationship between simple and complex cells. Our results provide a clear proof-of-principle for the use of high-density neurophysiological recordings to assess circuit-level interactions within local neuronal networks.
Urocortin-3 neurons in the perifornical area mediate the impact of chronic stress on female infant-directed behavior
Authors: Abdelmesih Brenda , Anderson Robyn , Carta Ilaria , Autry Anita E.
Published: February 2022

Infant avoidance and aggression are promoted by activation of the Urocortin-3 expressing neurons of the perifornical area of hypothalamus (PeFAUcn3) in male and female mice. PeFAUcn3neurons have been implicated in stress, and stress is known to reduce maternal behavior. We asked how chronic restraint stress (CRS) affects infant-directed behavior in virgin and lactating females and what role PeFAUcn3neurons play in this process. Here we show that infant-directed behavior increases activity in the PeFAUcn3neurons in virgin and lactating females. Chemogenetic inhibition of PeFAUcn3neurons facilitates pup retrieval in virgin females. CRS reduces pup retrieval in virgin females and increases activity of PeFAUcn3neurons but does not affect maternal behavior in mothers. Inhibition of PeFAUcn3neurons blocks stress-induced deficits in pup-directed behavior in virgin females. Together, these data illustrate the critical role for PeFAUcn3neuronal activity in mediating the impact of chronic stress on female infant-directed behavior.

Significance statement

While a large body of research has studied the impact of maternal stress on offspring, few studies have focused on the neural circuitry underlying reduced maternal behavior in stressed mothers. In this study, we examine the neural substrates involved in reduced infant-directed behavior caused by chronic stress. We find that perifornical area neurons expressing the neuropeptide urocortin-3 are critical mediators of the impact of stress on infant-directed behavior in females.
Genome assembly and isoform analysis of a highly heterozygous New Zealand fisheries species, the tarakihi (Nemadactylus macropterus)
Authors: Papa Yvan , Wellenreuther Maren , Morrison Mark A. , Ritchie Peter A.
Published: February 2022

Although being some of the most valuable and heavily exploited wild organisms, few fisheries species have been studied at the whole-genome level. This is especially the case in New Zealand, where genomics resources are urgently needed to assist fisheries management attains its sustainability goals. Here we generated 55 Gb of short Illumina reads (92× coverage) and 73 Gb of long Nanopore reads (122×) to produce the first genome assembly of the marine teleost tarakihi (Nemadactylus macropterus), a highly valuable fisheries species in New Zealand. An additional 300 Mb of Iso-Seq RNA reads were obtained from four tissue types of another specimen to assist in gene annotation. The final genome assembly was 568 Mb long and consisted of 1,214 scaffolds with an N50 of 3.37 Mb. The genome completeness was high, with 97.8% of complete Actinopterygii BUSCOs. Heterozygosity values estimated through k-mer counting (1.00%) and bi-allelic SNPs (0.64%) were high compared to the same values reported for other fishes. Repetitive elements covered 30.45% of the genome and 20,169 protein-coding genes were annotated. Iso-Seq analysis recovered 91,313 unique transcripts (isoforms) from 15,515 genes (mean ratio of 5.89 transcripts per gene), and the most common alternative splicing event was intron retention. This highly contiguous genome assembly along with the isoform-resolved transcriptome will provide a useful resource to assist the study of population genomics, as well as comparative eco-evolutionary studies in other teleost and related organisms.
Coupling of metataxonomics and culturing improves bacterial diversity characterization and identifies a novel Rhizorhapis sp. with metal resistance potential in a multi-contaminated waste sediment
Authors: Siles José A. , Hendrickson Andrew J. , Terry Norman
Published: February 2022

Long-term contaminated environments have been recognized as potential hotspots for bacterial discovery in taxonomic and functional terms for bioremediation purposes. Here, bacterial diversity in waste sediment collected from a former industrial dumpsite and contaminated with petroleum hydrocarbon and heavy metals was investigated through the parallel application of culture-independent (16S rRNA gene amplicon sequencing) and -dependent (plate culturing followed by colony picking and identification of isolates by 16S rRNA gene Sanger sequencing) approaches. The bacterial diversities retrieved by both approaches greatly differed. Bacteroidetes and Proteobacteria were dominant in the culture-independent community, while Firmicutes and Actinobacteria were the main culturable groups. Only 2.7% of OTUs (operational taxonomic units) in the culture-independent dataset were cultured. Most of the culturable OTUs were absent or in very low abundances in the culture-independent dataset, revealing that culturing is a useful tool to study the rare bacterial biosphere. One culturable OTUs (comprising only the isolate SPR117) was identified as a potential new species in the genus Rhizorhapis (class Alphaproteobacteria) and was selected for further characterization. Phytopathogenicity tests showed that Rhizorhapis sp. strain SPR117 (ATCC TSD-228) is not pathogenic for lettuce, despite the only described species within this genus, Rhizorhapis suberifaciens, is causal agent of the lettuce corky root disease. The genome of the strain SPR117 was sequenced, assembled in 256 contigs, with a length of 4,419,522 bp and a GC content of 59.9%), and its further annotation revealed the presence of genes related to the resistance to arsenic, copper, iron, and mercury, among other metals. Therefore, the coupling of metataxonomics and culturing is a useful tool to obtain not only an improved description of bacterial communities in contaminated environments, but also to isolate microorganisms with bioremediation potential.
Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala
Authors: Chen Liqiang , Nagaraja Chetan , Daniels Samuel , Fisk Zoe A. , Dvorak Rachel , Meyerdirk Lindsay , Steiner Jennifer A , Galvis Martha L. Escobar , Henderson Michael X. , Rousseaux Maxime W.C. , Brundin Patrik , Chu Hong-Yuan
Published: February 2022

The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson’s disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice.

In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.
A new inactive conformation of SARS-CoV-2 main protease
Authors: Fornasier Emanuele , Macchia Maria Ludovica , Giachin Gabriele , Sosic Alice , Pavan Matteo , Sturlese Mattia , Salata Cristiano , Moro Stefano , Gatto Barbara , Bellanda Massimo , Battistutta Roberto
Published: February 2022

The SARS-CoV-2 main protease (Mpro) has a pivotal role in mediating viral genome replication and transcription of the coronavirus, making it a promising target for drugs against the COVID-19 pandemic. Here, a crystal structure is presented in which Mpro adopts an inactive state that has never been observed before, called new-inactive. It is shown that the oxyanion loop, which is involved in substrate recognition and enzymatic activity, adopts a new catalytically incompetent conformation and that many of the key interactions of the active conformation of the enzyme around the active site are lost. Solvation/desolvation energetic contributions play an important role in the transition from the inactive to the active state, with Phe140 moving from an exposed to a buried environment and Asn142 moving from a buried environment to an exposed environment. In new-inactive Mpro a new cavity is present near the S2′ subsite, and the N-terminal and C-terminal tails, as well as the dimeric interface, are perturbed, with partial destabilization of the dimeric assembly. This novel conformation is relevant both for comprehension of the mechanism of action of Mpro within the catalytic cycle and for the successful structure-based drug design of antiviral drugs.
Self‐Representation, Community Engagement and Decolonisation in the Museums of Indigenous Communities: Perspectives from Meghalaya, India
Authors: Lyngwa Amorette
Published: February 2022

This article is an exploration of the museum practices of the Indigenous communities of Meghalaya, in north‐east India. It uses Bryony Onciul's concept of museums as ‘Engagement Zones’, highlighted in the book Museums, Heritage and Indigenous Voice: Decolonizing Engagement as a conceptual basis for analyses and critique. Presenting a perspective from the Global South, the study aims to locate the limits to self‐representation and community engagement in the museums of Indigenous communities. In doing so, the article aims to make a case for the need for community narratives in museum‐making, particularly for Indigenous communities, in the effort towards decolonised museum practice.
Compromised interhemispheric transfer of information partially mediates cognitive function deficits in adolescents with fetal alcohol syndrome
Authors: Biffen Stevie C. , Dodge Neil C. , Warton Christopher M. R. , Molteno Christopher D. , Jacobson Joseph L. , Meintjes Ernesta M. , Jacobson Sandra W.
Published: February 2022

Background

Prenatal alcohol exposure (PAE) has been associated with compromised interhemispheric transfer of tactile stimuli in childhood and structural changes to the corpus callosum (CC). In this study, we used a finger localization task (FLT) to investigate whether interhemispheric transfer deficits persist in adolescence; whether effects of PAE on perceptual reasoning, working memory, and executive function are mediated by deficits in interhemispheric transfer of information; and whether CC size in childhood predicts FLT performance in adolescence.

Methods

Participants, aged 16 to 17 years, were from the Cape Town Longitudinal Cohort, whose mothers were recruited during pregnancy and interviewed regarding their alcohol use using the timeline follow‐back method. Diagnoses of fetal alcohol syndrome (FAS) and partial FAS (PFAS) were determined by two expert dysmorphologists; nonsyndromal exposed children were designated as heavily exposed (HE); those born to abstainers or light drinkers, as controls. The FLT was administered to 74 participants (12 FAS, 16 PFAS, 14 HE and 32 controls). CC size at age 9 to 12 years was available for 35 participants (7 FAS, 13 PFAS, 5 HE and 10 control).

Results

Although the degree of PAE was similar in the FAS, PFAS, and HE groups, only the adolescents with FAS showed more transfer‐related errors than controls in conditions in which one finger was stimulated. FLT performance mediated the effects of FAS on perceptual reasoning and executive function. In the subsample for which neuroimaging data from childhood were available, there was an association among adolescents with PAE of smaller CC volumes with more transfer‐related errors on the one‐finger/hand hidden condition, suggesting that CC damage previously seen in childhood continues to impact function through adolescence.

Conclusions

This study provides evidence of compromised interhemispheric transfer of information in adolescents with FAS, while those with PFAS or heavy exposed nonsyndromal individuals are apparently spared. It is the first to show that PAE effects on important aspects of cognitive function are partially mediated by deficits in the interhemispheric transfer of information.
Patient‐reported impact of symptoms in schizophrenia scale (PRISS): Development and validation
Authors: Moreno‐Küstner Berta , Fábrega‐Ruz Julia , Gonzalez‐Caballero Juan Luis , Reyes‐Martin Sara , Ochoa Susana , Romero‐Lopez‐Alberca Cristina , Cid Jordi , Vila‐Badia Regina , Frigola‐Capell Eva , Salvador‐Carulla Luis
Published: February 2022

Background

We report the psychometric properties of the Patient‐Reported Impact of Symptoms in Schizophrenia Scale (PRISS), which assesses the impact of subjective experiences or qualia in outpatients with this condition.

Methods

A cross‐sectional study was carried out in 162 patients diagnosed with schizophrenia in Spain. The PRISS measures the presence, frequency, concern and interference with daily life of self‐reported experiences related to the main symptoms observed in these patients. The psychometric analysis included test‐retest reliability, internal consistency and structural and convergent validity.

Results

The 28‐item PRISS showed good test‐retest reliability as 64.3% of the intraclass correlation coefficient values were between 0.40 and 0.79, which were statistically significant (p < 0.01). Analysis of the structural validity revealed a three‐factor structure, (1) productive subjective experiences, (2) affective‐negative subjective experiences and (3) excitation, which accounted for 56.11% of the variance. Of the Pearson's correlation coefficients analysed between the PRISS and the Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms (SANS) and World Health Organization Disability Assessment Schedule (WHO‐DAS), 72.2% were statistically significant (p < 0.05) and ranged from 0.38–0.42, 0.32–0.42 and 0.40–0.42, respectively.

Conclusion

Our results indicate that the PRISS appears to be a brief, reliable and valid scale to measure subjective experiences in schizophrenia and provides valuable information complementary to clinical evaluation.
Reducing opioid prescribing on discharge after orthopaedic surgery: does a guideline and education improve prescribing practice 1 year later?
Authors: Stanley Beata , Collins Lisa , Norman Amanda , Bonomo Anthony , Bonomo Yvonne
Published: February 2022

Background

An intervention Prescription Opioid Practice Improvement (POPI), addressing opioid prescribing on discharge following orthopaedic surgery, demonstrated improved practice. Here we report the sustainability of improved practice at 12 months, and the impact of a booster education intervention, POPI SOS (Safe Opioid Supply).

Methods

Audits were performed using methodology described in previously published studies.

Results

High proportion of patients were discharged on opioids, 89.9% 12 months post‐POPI (n = 149) and 82.2% post‐POPI SOS (n = 169). Twelve months post‐POPI there was a significant reduction in combination immediate (IR) and slow release (SR) opioids, 45.7% at the end of POPI program to 34.3% at 12 months (χ2 (1, N = 364) = 4.47, ρ = 0.034); a significant decrease in opioid‐weaning plans, 87.4% at the end of POPI program to 35.8% at 12 months (χ2 (1, N = 365) = 104.19, ρ = <0.001); and a significant increase in provision of full quantities of SR‐opioids, 6.1% after the POPI program to 15.7% (χ2 (1, N = 364) = 8.95, ρ = 0.003). The POPI SOS booster program significantly improved measures including reduction in combination IR and SR, 34.3–22.3% (χ2 (1, N = 273) = 4.87, ρ = 0.028) and an increase in opioid plans in discharge summaries, from 35.8% to 77.7% (χ2 (1, N = 273) = 48.87, ρ < 0.001).

Conclusion

Better practice in relation to opioid prescribing is achievable but, for sustained improvement, opioid stewardship activities are needed to reduce the potential harms associated with prescription opioids.
Effects of a comprehensive medication review intervention on health‐related quality of life and other clinical outcomes in geriatric outpatients with polypharmacy: A pragmatic randomized clinical trial
Authors: Kornholt Jonatan , Feizi Shafika Tapia , Hansen Alexandra Storm , Laursen Jannie Thaysen , Reuther Lene Ørskov , Petersen Tonny Studsgaard , Pressel Eckart , Christensen Mikkel Bring
Published: February 2022

Aim

To investigate the effects of a comprehensive medication review intervention on health‐related quality of life (HRQoL) and clinical outcomes in geriatric outpatients exposed to polypharmacy.

Methods

Pragmatic, nonblinded, randomized clinical trial with follow‐up after 4 and 13 months. Participants were geriatric outpatients taking ≥9 medicines. The intervention was an additional consultation with a physician focusing on reviewing medication, informing patients about their medicines and increasing cross‐sectoral communication as supplement to and compared with usual care. The primary outcome was change in HRQoL after 4 months measured with the EuroQoL 5‐dimension 5‐level (EQ‐5D‐5L) questionnaire. Secondary outcomes were HRQoL after 13 months, mortality, admissions, falls and number of medicines after 4 and 13 months.

Results

Of 785 eligible patients, 408 were included (age: mean 80.6 [standard deviation 7.22] years; number of medicines: median 12 [interquartile range 10–14]; females 71%). After 4 months, the adjusted between‐group difference in EQ‐5D‐5L index score was 0.066 in favour of the medication consultation (95% confidence interval 0.01 to 0.12, P = .02). After 4 months, two (1%) participants had died in the medication‐consultation group and nine (4%) in the usual‐care group (log‐rank test, P = .045). The medication consultation reduced the number of medicines by 2.0 (15.8%) after 4 months and 1.3 (10.7%) after 13 months. There were no statistically significant differences in mortality or HRQoL after 13 months, and no differences in falls or admissions.

Conclusions

An additional consultation with medication review and increased communication as supplement to usual geriatric outpatient care improved HRQoL and reduced mortality after 4 months.
Prevalence and management of drug interactions between nonsteroidal anti‐inflammatory drugs and antithrombotics in ambulatory care
Authors: Mehuys Els , De Backer Tine , De Keyser Filip , Christiaens Thierry , Van Hees Thierry , Demarche Sophie , Van Tongelen Inge , Boussery Koen
Published: February 2022

Concomitant use of nonsteroidal anti‐inflammatory drugs (NSAIDs) and antithrombotic agents is associated with increased risks of both bleeding and thromboembolism. In this prospective intervention study, community pharmacists screened for NSAID‐antithrombotic interactions and contacted the prescribing physician to discuss interaction management. We included 782 interactions; these were found in an older, polymedicated patient population (mean age: 68 y, median of 5 other drugs). Ibuprofen (in 43.0% of cases) and low‐dose aspirin (78.8%) were the most frequently involved NSAID and antithrombotic, respectively. Anticoagulants were involved in 16.1% of interaction cases. For 61% of cases, the interacting drugs were prescribed by the same physician. The pharmacist–physician discussion about how to manage the interaction mostly resulted in no change of pharmacotherapy (60.7%); the most frequent reason given by physicians was that the NSAID was for short‐term use only. In 39.3% of cases the discussion resulted in a pharmacotherapy change; replacing the NSAID by paracetamol was the most common change.
Everyday dehumanization: Negative contact, humiliation, and the lived experience of being treated as ‘less than human’
Authors: Murray Amy Jo , Durrheim Kevin , Dixon John
Published: February 2022

Developing work on the nature and consequences of negative intergroup contact, this study explores its potential role in sustaining everyday experiences of dehumanization; that is, experiences in which participants report feeling deprived of full human status. As a case study, we explore domestic service relations in a neighbourhood of Pietermaritzburg, South Africa, analysing interviews (n = 22) conducted with Black domestic workers and their families (n = 64 participants in total) about their day‐to‐day interactions with Indian employers. Drawing on thematic analysis of accounts of paid domestic labour and food‐sharing practices, we argue that negative contact experiences may cumulatively engender a sense of dehumanization and associated feelings of humiliation: a response marked by intertwined constructions of shame and injustice. Implications for understanding wider problems of intergroup conflict and political solidarity are discussed and avenues for future research proposed.
Caregiver experiences with transitions from pediatric to adult healthcare for children with complex care needs
Authors: MacNeill Lillian , Doucet Shelley , Luke Alison
Published: February 2022

Background

Caring for a youth with complex care needs (CCN) who is transitioning from paediatric to adult healthcare can produce many challenges. For example, caregivers must often manage their youth's care at home, coordinate care and advocate for their youth. Experiences of fragmented and uncoordinated care often result in caregivers feeling ill‐prepared and uncertain about the transition process. The current study explores caregiver experiences with the transition from paediatric to adult healthcare for youth with CCN in a semi‐rural Canadian province.

Methods

This study used a cross‐sectional qualitative descriptive design, involving semi‐structured interviews with caregivers of youth with CCN who were preparing for, in the process of, or completed a transition from paediatric to adult healthcare within the province of New Brunswick, Canada. Thematic analysis focused on describing caregiver experiences with the transition from paediatric to adult healthcare.

Results

Seventeen caregivers completed interviews for this study. Four key themes emerged relating to caregiver experiences with the transition from paediatric to adult healthcare for these youth: (1) lack of caregiver support, (2) lack of continuity of care, (3) need for collaborative care and (4) difficulty navigating transition.

Conclusion

There is a clear need to address the challenges experienced by youth with CCN and their caregivers throughout the transition from paediatric to adult healthcare. An effective transition strategy should involve early and coordinated planning between the paediatric and adult care team; continued communication across the care team throughout the transition process; and coordination among health, education and social services.
The Presence of Background Noise Extends the Competitor Space in Native and Non‐Native Spoken‐Word Recognition: Insights from Computational Modeling
Authors: Karaminis Themis , Hintz Florian , Scharenborg Odette
Published: February 2022

Oral communication often takes place in noisy environments, which challenge spoken‐word recognition. Previous research has suggested that the presence of background noise extends the number of candidate words competing with the target word for recognition and that this extension affects the time course and accuracy of spoken‐word recognition. In this study, we further investigated the temporal dynamics of competition processes in the presence of background noise, and how these vary in listeners with different language proficiency (i.e., native and non‐native) using computational modeling. We developed ListenIN (Listen‐In‐Noise), a neural‐network model based on an autoencoder architecture, which learns to map phonological forms onto meanings in two languages and simulates native and non‐native spoken‐word comprehension. We also examined the model's activation states during online spoken‐word recognition. These analyses demonstrated that the presence of background noise increases the number of competitor words, which are engaged in phonological competition and that this happens in similar ways intra and interlinguistically and in native and non‐native listening. Taken together, our results support accounts positing a “many‐additional‐competitors scenario” for the effects of noise on spoken‐word recognition.
Immunogenicity of LY2963016 insulin glargine and Lantus® insulin glargine in Chinese patients with type 1 or type 2 diabetes mellitus
Authors: Wang Weimin , Song Xiang , Lou Ying , Du Liying , Zhu Dalong , Zhou Zhiguang
Published: February 2022

Aims

To evaluate the immunogenicity of LY2963016 insulin glargine (LY IGlar) versus originator insulin glargine (IGlar [Lantus®]) in Chinese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM).

Materials and Methods

ABES and ABET were prospective, randomized, active control, open‐label, phase III studies, which enrolled Chinese patients with T1DM (N = 272) and T2DM (N = 536), respectively. Using data from these trials, immunogenicity of LY IGlar and IGlar was evaluated by comparing the proportion of patients with detectable anti‐insulin glargine antibodies and the median antibody levels (percent binding) between the treatment groups. The incidence of anti‐insulin antibodies and treatment‐emergent antibody response (TEAR) were compared using Fisher's exact test or Pearson's chi‐squared test. Levels of anti‐insulin antibodies were compared using the Wilcoxon rank‐sum test. We also evaluated the relationship between antibody formation or TEAR and clinical outcomes using analysis of covariance, negative binomial regression, or partial correlations.

Results

There were no significant treatment differences in the incidence of detectable anti‐insulin antibodies, median antibody levels or TEAR, overall or at Week 24 with last observation carried forward, and median antibody levels were low (<5%) after 24 weeks of treatment, in patients with T1DM or T2DM. Levels of anti‐insulin antibodies and development of TEAR were not associated with efficacy (glycated haemoglobin, insulin dose [U/kg/d] and hypoglycaemia) or safety outcomes.

Conclusions

The immunogenicity profiles of LY IGlar and IGlar are similar, with low levels of anti‐insulin antibodies observed for both insulins. No association was observed between antibody levels or TEAR status and clinical outcomes.