bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human organoid modeling of congenital malformations caused by RFX6 mutations reveal an essential role for this transcription factor in establishing and maintaining duodenal identity upstream of PDX1
Authors: Sanchez J. Guillermo , Rankin Scott , Paul Emily , McCauley Heather A. , Kechele Daniel O. , Enriquez Jacob R. , Jones Nana-Hawa , Greeley Siri AW , Letourneau-Friedberg Lisa , Zorn Aaron M. , Krishnamurthy Mansa , Wells James M. 
Published: November 2023

AbstractThe gastrointestinal (GI) tract consists of highly specialized organs from the proximal esophagus to the distal colon, each with unique functions. Rare congenital malformations of the GI tract, including organ atresia, agenesis or mis-patterning are linked to gene mutations although the molecular basis of these malformations has been poorly studied due to lack of model systems to study human development. We identified a patient with compound heterozygous mutations in the transcription factor RFX6 with pancreatic agenesis as previously described. In addition, the patient had duodenal mal-rotation and atresia suggesting that establishment of the proximal small intestine was impaired in these patients. To identify the molecular basis of the intestinal malformation we generated induced pluripotent stem cell lines from this patient, and derived human intestinal organoid (HIOs) to identify how mutations in RFX6 impact intestinal patterning and function. We identified that the duodenal identity of HIOs and patient tissues had adopted a more distal small intestinal signature, including expression of SATB2, normally expressed in the ileum and colon. CRISPR-mediated correction of RFX6 restored duodenal identity, including expression of PDX1, which is required for duodenal development. Using transcriptomic approaches in HIOs and Xenopus embryos we identified that PDX1 is a downstream transcriptional target of RFX6 and that PDX1 expression in a RFX6 mutant background was sufficient to rescue duodenal identity. However, RFX6 had a PDX1-independent role in regulating expression of components of WNT, HH, and BMP signaling pathways that are critical for establishing early regional identity in the GI tract. In summary, we have identified that RFX6 is one of the most upstream regulators early intestinal patterning in vertebrates and that it acts by regulating key transcriptional and signaling pathways.
Initial clinical evidence on biperiden as antiepileptogenic after traumatic brain injury. A Randomized Clinical Trial
Authors: Foresti Maira Licia , Garzon Eliana , de Moraes Mariana Teichner , Valeriano Rafael PS , Santiago João Paulo , dos Santos Gustavo Mercenas , Longo Natália Mata , Baise Carla , Andrade Joaquina CQF , Susemihl Maria Alice , Naffah Mazzacoratti Maria da Graça , Paiva Wellingson Silva , de Andrade Almir Ferreira , Teixeira Manuel Jacobsen , Mello Luiz E 
Published: November 2023

AbstractThere is currently no available drug to prevent the development of post-traumatic epilepsy. insufficient evidence regarding the effect of biperiden in preventing post-traumatic epilepsy after TBI. The combined effect of variables known to have an impact on the likelihood of developing late post-traumatic seizures and its unbalanced frequency in the different groups is an aspect to be considered and underpins the need for larger studies.HighlightsPrior research suggests anticholinergics may prevent post-traumatic epilepsyThere was insufficient evidence on biperiden’s role in preventing PTE after TBIVariable impact on post-traumatic epilepsy underscores need for broader studiesGraphical Abstract
Secreted protein profiling of human aortic smooth muscle cells identifies vascular disease associations
Authors: Aherrahrou Rédouane , Baig Ferheen , Theofilatos Konstantinos , Lue Dillon , Beele Alicia , Örd Tiit , Kaikkonen Minna U , Aherrahrou Zouhair , Cheng Qi , Ghosh Saikat , Karnewar Santosh , Karnewar Vaishnavi , Finn Aloke , Owens Gary K. , Joner Michael , Mayr Manuel , Civelek Mete 
Published: November 2023

ABSTRACTBackgroundSmooth muscle cells (SMCs), which make up the medial layer of arteries, are key cell types involved in cardiovascular diseases (CVD), the leading cause of mortality and morbidity worldwide. In response to microenvironment alterations, SMCs dedifferentiate from a “contractile” to a “synthetic” phenotype characterized by an increased proliferation, migration, production of extracellular matrix (ECM) components, and decreased expression of SMC-specific contractile markers. These phenotypic changes result in vascular remodeling and contribute to the pathogenesis of CVD, including coronary artery disease (CAD), stroke, hypertension, and aortic aneurysms. Here, we aim to identify the genetic variants that regulate ECM secretion in SMCs and predict the causal proteins associated with vascular disease-related loci identified in genome-wide association studies (GWAS).MethodsUsing human aortic SMCs from 123 multi-ancestry healthy heart transplant donors, we collected the serum-free media in which the cells were cultured for 24 hours and conducted Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analysis of the conditioned media.ResultsWe measured the abundance of 270 ECM and related proteins. Next, we performed protein quantitative trait locus mapping (pQTL) and identified 20 loci associated with secreted protein abundance in SMCs. We functionally annotated these loci using a colocalization approach. This approach prioritized the genetic variant rs6739323-A at the 2p22.3 locus, which is associated with lower expression of LTBP1 in SMCs and atherosclerosis-prone areas of the aorta, and increased risk for SMC calcification. We found that LTBP1 expression is abundant in SMCs, and its expression at mRNA and protein levels was reduced in unstable and advanced atherosclerotic plaque lesions.ConclusionsOur results unravel the SMC proteome signature associated with vascular disorders, which may help identify potential therapeutic targets to accelerate the pathway to translation.
Prenatal exposure to environmental contaminants is associated with altered cord serum metabolite profiles in future immune-mediated diseases
Authors: Karthikeyan Bagavathy Shanmugam , Hyötyläinen Tuulia , Ghaffarzadegan Tannaz , Triplett Eric , Orešič Matej , Ludvigsson Johnny 
Published: November 2023

AbstractPrenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases. In this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases. We selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohn’s disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of contaminants and metabolites. Differences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite levels and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS). Our study suggests that prenatal exposure to specific environmental contaminants alters the cord serum metabolomes, which, in turn, might increase the risk of various immune-mediated disease later in life.
Characterization of Per- and Polyfluoroalkyl Substance (PFAS) concentrations in a community-based sample of infants from Samoa
Authors: Heinsberg Lacey W. , Niu Shan , Arslanian Kendall J. , Chen Ruiwen , Bedi Megha , Unasa-Apelu Folla , Fidow Ulai T. , Soti-Ulberg Christina , Conley Yvette P. , Weeks Daniel E. , Ng Carla A. , Hawley Nicola L. 
Published: November 2023

ABSTRACTPer- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa, where there is more recent modernization and potential window to examine earlier stages of PFAS exposure and consequences. Using data and biosamples collected through theFoafoaga o le Ola(“Beginning of Life”) Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n=66) and dried blood spots (DBS) collected at 4 months post-birth (n=50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 11 detected in >10% of samples (PFBA, PFPeA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); 12 analytes were detected in DBS, with 3 detected in >10% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted associations between higher PFHxS and male sex, higher PFPeA and residence in Northwest ‘Upolu (NWU) compared to the Apia Urban Area (AUA), and lower PFUnA and 9Cl-PF3ONS with greater socioeconomic resources. In DBS, we found associations between higher PFBA and greater socioeconomic resources, and between lower PFBA and PFHxS and residence in NWU versus AUA. However, the latter association did not hold when controlling for socioeconomic resources. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study presents the first evidence of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.
Associations between regional adipose tissue distribution and skeletal muscle bioenergetics in older men and women
Authors: Brennan Andrea M. , Coen Paul M. , Mau Theresa , Hetherington-Rauth Megan , Toledo Frederico G.S. , Kershaw Erin E. , Cawthon Peggy M. , Kramer Philip A. , Ramos Sofhia V. , Newman Anne B. , Cummings Steven R. , Forman Daniel E. , Yeo Reichelle X. , DiStefano Giovanna , Miljkovic Iva , Justice Jamie N. , Molina Anthony J.A. , Jurczak Michael J. , Sparks Lauren M. , Kritchevsky Stephen B. , Goodpaster Bret H. 
Published: November 2023

AbstractObjectiveExamine the association of ectopic adipose tissue (AT) with skeletal muscle (SM) mitochondrial bioenergetics in older adults.MethodsCross-sectional data from 829 older adults ≥70 years was used. Total abdominal, subcutaneous, and visceral AT; and thigh muscle fat infiltration (MFI) was quantified by MRI. SM mitochondrial energetics were characterized usingin vivo31P-MRS (ATPmax) andex vivohigh-resolution respirometry (maximal oxidative phosphorylation (OXPHOS)). ActivPal was used to measure PA (step count). Linear regression models adjusted for covariates were applied, with sequential adjustment for BMI and PA.ResultsIndependent of BMI, total abdominal (standardized (Std.) β=-0.21; R2=0.09) and visceral AT (Std. β=-0.16; R2=0.09) were associated with ATPmax(p<0.01), but not after further adjustment for PA (p≥0.05). Visceral AT (Std. β=-0.16; R2=0.25) and thigh MFI (Std. β=-0.11; R2=0.24) were negatively associated with carbohydrate-supported maximal OXPHOS independent of BMI and PA (p<0.05). Total abdominal AT (Std. β=-0.19; R2=0.24) and visceral AT (Std. β=-0.17; R2=0.24) were associated with fatty acid-supported maximal OXPHOS independent of BMI and PA (p<0.05).ConclusionsSkeletal MFI and abdominal visceral, but not subcutaneous AT, are inversely associated with SM mitochondrial bioenergetics in older adults independent of BMI. Associations between ectopic AT andin vivomitochondrial bioenergetics are attenuated by PA.
Clinical and Economic impact of updated Fall 2023 COVID-19 vaccines in the Immunocompromised Population in Canada
Authors: Lee Amy , Jayasundara Kavisha , Kohli Michele , Maschio Michael , Fust Kelly , Joshi Keya , van de Velde Nicolas , Beck Ekkehard 
Published: November 2023

ABSTRACTBackgroundImmunocompromised (IC) individuals are at increased risk of COVID-19 infection-related severe outcomes. Moderna and Pfizer-BioNTech COVID-19 mRNA vaccines are available in Canada, and differences in vaccine effectiveness (VE) have been found between the two in IC individuals. The objective of this analysis was to compare the clinical and economic impact of a Moderna XBB.1.5 updated COVID-19 mRNA Fall 2023 vaccine to a Pfizer-BioNTech XBB.1.5 updated COVID-19 mRNA Fall 2023 vaccine in Canadian IC individuals aged ≥18 years.MethodsA static decision-analytic model estimated the number of COVID-19 infections, hospitalizations, deaths, and resulting quality-adjusted life years (QALYs) over a one-year time horizon (September 2023-August 2024) in the Canadian IC adult population (n=894,580). Costs associated with COVID-19 infection were estimated from health care and societal perspectives. The predicted VE of the updated Moderna vaccine was based on prior variant versions, which were well-matched to the circulating variant. Pfizer-BioNTech VE was calculated based on a meta-analysis of comparative effectiveness between both vaccines (relative risk for Moderna vaccine: infection=0.85 [95%CI 0.75-0.97], hospitalization=0.88 [95%CI 0.79-0.97]). The model combined VE estimates with COVID-19 incidence and probability of COVID-19 related severe outcomes. Sensitivity analyses tested the impact of uncertainty surrounding incidence, hospitalization and mortality rates, costs, and QALYs.ResultsGiven the expected higher VE against infection and hospitalizations with the Moderna Fall 2023 vaccine, its use is predicted to prevent an additional 2,411 infections (3.6%), 275 hospitalizations (3.7%), and 47 deaths (4.0%) compared to the Pfizer-BioNTech Fall 2023 vaccine, resulting in 330 QALYs gained, and savings of $7.4M in infection treatment costs, and $0.9M in productivity loss costs. Results were most sensitive to variations in VE parameters, specifically the relative risk of infection and hospitalizations between the vaccines, and waning rates.ConclusionsIf the Moderna and Pfizer-BioNTech Fall 2023 vaccines protect against infection and hospitalizations similar to previous vaccines, using the Moderna Fall 2023 vaccine would result in substantial public health benefits in IC individuals, as well as provide health care and societal cost savings.
Protocol for a Magnetic Resonance Imaging (MRI) Study of Participants in the Fever Randomized Controlled Trial: Does fever control prevent brain injury in malaria?
Authors: Chilombe Moses B. , Seydel Karl B. , Hammond Colleen , Mwanza Suzanna , Patel Archana A. , Lungu Frank , wa Somwe Somwe , Kampondeni Sam , Potchen Michael J. , McDermott Michael P. , Birbeck Gretchen L. 
Published: November 2023

AbstractBackgroundDespite eradication efforts, ∼135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy.MethodsThis observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury.DiscussionNeuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.
The recent rapid expansion of multidrug resistant strains ofMycobacterium tuberculosisUral lineage 4.2 in the Republic of Moldova
Authors: Chitwood Melanie H. , Colijn Caroline , Yang Chongguang , Crudu Valeriu , Ciobanu Nelly , Codreanu Alexandru , Kim Jaehee , Rancu Isabel , Rhee Kyu , Cohen Ted , Sobkowiak Benjamin 
Published: November 2023

AbstractThe projected trajectory of multidrug resistant tuberculosis (MDR-TB) epidemics depends on the reproductive fitness of circulating strains of MDRM. tuberculosis (Mtb). Previous efforts to characterize the fitness of MDRMtbhave found thatMtbstrains of the Beijing sublineage (Lineage 2.2.1) may be more prone to develop resistance and retain fitness in the presence of resistance-conferring mutations than other lineages. UsingMtbgenome sequences from all culture-positive cases collected over two years in Moldova, we estimate the fitness of Ural (Lineage 4.2) and Beijing strains, the two lineages in which MDR is concentrated in the country. We estimate that the fitness of MDR Ural strains substantially exceeds that of other susceptible and MDR strains, and we identify several mutations specific to these MDR Ural strains. Our findings suggest that MDR UralMtbhas been transmitting efficiently in Moldova and poses a substantial risk of spreading further in the region.
Management of patients with occupational burnout in Switzerland: some insights on the heterogeneity in current practices
Authors: Canu Irina Guseva , Getzmann Roger , Shoman Yara , Rota Fulvia , Saillant Stéphane , von Känel Roland , Cohidon Christine , Lazor-Blanchet Catherine , Rochat Lysiane , Weissbrodt Rafaël , Droz Nadia , Wahlen Anny 
Published: November 2023

ABSTRACTWe aimed to describe the characteristics and current practices of Swiss health professionals who manage patients with occupational burnout (POB), namely the general practitioners (GP), psychiatrist-psychotherapists (PP), occupational physicians (OP) and psychologists. Among 3216 respondents, 2951 reported to consult POB, and 1130 (713 physicians and 410 psychologists) to treat them. The study showed that POB management constitutes 5 to 25% of health care professionals’ consultations, with an inequal distribution of POBs across professionals’ specialties and specializations, but also across geographic regions. The profile of POB consulted also differs across professionals. Work psychologists see more often POB at early burnout stage, GPs have most patients with moderate burnout, while PPs report the largest proportion of patients with severe burnout.The treatment practices depend on burnout severity. Psychiatrists and physicians with double specialty (GP-OPs and GP-PPs) treat patients with more severe burnout than GPs. Psychologists treating patients with severe burnout collaborate with other health professionals and contact the POB’s employer and/or health insurance. Treatment practices and burnout severity are not associated with the proportion of relapsed patients and patients who return to work. Yet, the former is associated with professionals’ age, sex, and specialty. Physicians with waiting time >3 months have a higher proportion of relapsed patients. GPs prescribe most often sick leaves, while PPs are the most frequent prescribers of pharmacological treatment. PPs collaborate significantly more often than GPs with pharmacologists and contact POB’s employer and health insurance. Among psychologists, work psychologists differ from other psychologists by a more frequent POB (psycho)education and coaching, namely on how to negotiate with employer and family, as well as on physical exercise. They also more often contact POB’s employer. Besides profession and specialization, we observed important regional variation in treatment modalities chosen by both physicians and psychologists.
Neural Mechanisms Underlying Attention Control In Relation To Anxiety And Depressive Symptoms
Authors: Loh Raye Fion , Hui Savannah Siew Kiah , Yu Junhong 
Published: November 2023

AbstractPoor attention control has been implicated in the development of anxiety and depression-related disorders and it is a key diagnostic criterion. This study aims to understand the possible neural mechanisms behind this.191 German participants aged 20-80 were assessed on their level of attention control, depression and anxiety as part of the Leipzig Study for Mind-Body-Emotion Interactions. Network-based statistics were applied to their resting-state functional connectivity (rsFC) data to identify networks positively and negatively associated with attention control. Mediation analyses were then performed with these two networks as mediators.Attention control correlated negatively with both anxiety and depression. The frontoparietal- or dorsal attention-somatomotor connections featured prominently in the attention control-positive network (ACPN). This network correlated positively with attention control, and negatively with both anxiety and depression. The attention control-negative network (ACNN) was largely represented by the ventral attention- or dorsal attention-visual connections. The ACPN was a significant and partial mediator between attention control and anxiety and a complete mediator for the relationship between attention control and depression. These findings could prove useful as neuroeducation in anxiety- and depression-related disorders, and as evidence for attention-based therapy.
Abstract representations emerge in human hippocampal neurons during inference behavior
Authors: Courellis Hristos S. , Mixha Juri , Cardenas Araceli R. , Kimmel Daniel , Reed Chrystal M. , Valiante Taufik A. , Salzman C. Daniel , Mamelak Adam N. , Fusi Stefano , Rutishauser Ueli 
Published: November 2023

AbstractHumans have the remarkable cognitive capacity to rapidly adapt to changing environments. Central to this capacity is the ability to form high-level, abstract representations that take advantage of regularities in the world to support generalization1. However, little is known about how these representations are encoded in populations of neurons, how they emerge through learning, and how they relate to behavior2,3. Here we characterized the representational geometry of populations of neurons (single-units) recorded in the hippocampus, amygdala, medial frontal cortex, and ventral temporal cortex of neurosurgical patients who are performing an inferential reasoning task. We find that only the neural representations formed in the hippocampus simultaneously encode multiple task variables in an abstract, or disentangled, format. This representational geometry is uniquely observed after patients learn to perform inference, and consisted of disentangled directly observable and discovered latent task variables. Interestingly, learning to perform inference by trial and error or through verbal instructions led to the formation of hippocampal representations with similar geometric properties. The observed relation between representational format and inference behavior suggests that abstract/disentangled representational geometries are important for complex cognition.