bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting the effect of CRISPR-Cas9-based epigenome editing
Authors: Batra Sanjit Singh , Cabrera Alan , Spence Jeffrey P. , Goell Jacob , Anand Selvalakshmi S. , Hilton Isaac , Song Yun S
Published: October 2023

Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ~0.70-0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.
Palatal segment contributions to midfacial anterior-posterior growth
Authors: Welsh Ian C. , Feiler Maria E. , Lipman Danika , Mormile Isabel , Hansen Karissa , Percival Christopher J.
Published: October 2023

Anterior-posterior (A-P) elongation of the palate is a critical aspect of integrated midfacial morphogenesis. Reciprocal epithelial-mesenchymal interactions drive secondary palate elongation that is coupled to the periodic formation of signaling centers within the rugae growth zone (RGZ). However, the relationship between RGZ-driven morphogenetic processes, the differentiative dynamics of underlying palatal bone mesenchymal precursors, and the segmental organization of the upper jaw has remained enigmatic. A detailed ontogenetic study of these relationships is important because palatal segment growth is a critical aspect of normal midfacial growth, can produce dysmorphology when altered, and is a likely basis for evolutionary differences in upper jaw morphology. We completed a combined whole mount gene expression and morphometric analysis of normal murine palatal segment growth dynamics and resulting upper jaw morphology. Our results demonstrated that the first formed palatal ruga (ruga 1), found just posterior to the RGZ, maintained an association with important nasal, neurovascular and palatal structures throughout early midfacial development. This suggested that these features are positioned at a proximal source of embryonic midfacial directional growth. Our detailed characterization of midfacial morphogenesis revealed a one-to-one relationship between palatal segments and upper jaw bones during the earliest stages of palatal elongation. Growth of the maxillary anlage within the anterior secondary palate is uniquely coupled to RGZ-driven morphogenesis. This may help drive the unequaled proportional elongation of the anterior secondary palate segment prior to palatal shelf fusion. Our results also demonstrated that the future maxillary-palatine suture, approximated by the position of ruga 1 and consistently associated with the palatine anlage, formed predominantly via the posterior differentiation of the maxilla within the expanding anterior secondary palate. Our ontogenetic analysis provides a novel and detailed picture of the earliest spatiotemporal dynamics of intramembranous midfacial skeletal specification and differentiation within the context of the surrounding palatal segment A-P elongation and associated rugae formation.
CRWN nuclear lamina components maintain the H3K27me3 landscape and promote successful reproduction in Arabidopsis
Authors: Choi Junsik , Gehring Mary
Published: October 2023

The nuclear lamina, a sub-nuclear protein matrix, maintains nuclear structure and genome function. Here, we investigate the role of Arabidopsis lamin analogs CROWDED NUCLEIs during gametophyte and seed development. We observed defects incrwnmutant seeds, including seed abortion and reduced germination rate. Quadruplecrwnnull genotypes were rarely transmitted through gametophytes. We focused on thecrwn1 crwn2(crwn1/2) endosperm, which exhibited enlarged chalazal cysts and increased expression of stress-related genes and the MADS-box transcription factorPHERES1and its targets. Previously, it was shown thatPHERES1is regulated by H3K27me3 and that CRWN1 interacts with the PRC2 interactor PWO1. Thus, we tested whethercrwn1/2alters H3K27me3 patterns. We observed a mild loss of H3K27me3 at several hundred loci, which differed between endosperm and leaves. These data indicate that CRWNs are necessary to maintain the H3K27me3 landscape, with tissue-specific chromatin and transcriptional consequences.
Voluntary alcohol consumption during distinct phases of adolescence differentially alters adult fear acquisition, extinction and renewal in male and female rats
Authors: Grizzell J Alex , Vanbaelinghem Maryam , Westerman Jessica , Saddoris Michael P
Published: October 2023

Alcohol use during adolescence coincides with elevated risks of stress-related impairment in adults, particularly via disrupted developmental trajectories of vulnerable corticolimbic and mesolimbic systems involved in fear processing. Prior work has investigated the impact of binge-like alcohol consumption on adult fear and stress, but less is known about whether voluntarily consumed alcohol imparts differential effects based on adolescence phases and biological sex. Here, adolescent male and female Long Evans rats were granted daily access to alcohol (15%) during either early (Early-EtOH; P25-45) or late adolescence (Late-EtOH; P45-55) using a modified drinking-in-the-dark design. Upon adulthood (P75-80), rats were exposed to a three-context (ABC) fear renewal procedure. We found that male and female Early-EtOH rats showed faster acquisition of fear but less freezing during early phases of extinction and throughout fear renewal. In the extinction period specifically, Early-EtOH rats showed normal levels of freezing in the presence of fear-associated cues, but abnormally low freezing immediately after cue offset, suggesting a key disruption in contextual processing and/or novelty seeking brought by early adolescent binge consumption. While the effects of alcohol were most pronounced in the Early-EtOH rats (particularly in females), Late-EtOH rats displayed some changes in fear behavior including slower fear acquisition, faster extinction, and reduced renewal compared with controls, but primarily in males. Our results suggest that early adolescence in males and females and, to a lesser extent, late adolescence in males is a particularly vulnerable period wherein alcohol use can promote stress-related dysfunction in adulthood. Furthermore, our results provide multiple bases for future research focused on developmental correlates of alcohol mediated disruption in the brain.
Whole genome assembly and annotation of the clover root weevil (Sitona obsoletus) using a combination of Illumina, 10X Genomics and MinION sequencing
Authors: Katuwal Mandira , Phillips Craig B. , Gemmell Neil J. , Dowle Eddy
Published: October 2023

Weevils are a highly diversified taxon, comprising about 70,000 described species that include many agricultural pests, biological control agents, and nutrient recyclers. Despite their importance and vast diversity, the number of sequenced genomes for the weevil family is still low (n=15). Here, we present a high-quality and contiguous genome assembly ofSitona obsoletus(Coleoptera: Curculionidae: Entiminae), a widespread invasive forage pest that infests clover species (Trifoliumspp.) worldwide. We sequenced, assembled, and annotated theS. obsoletusgenome using a hybrid approach that employed Nanopore long reads, 10X Chromium linked reads, Illumina short reads for assembly, and mRNA short read sequencing of various developmental stages for annotation. Our final annotated genome has a size of 1.2 Gb, with an N50 length of 313.85 kb. Benchmarking analyses against conserved single-copy Orthologs (BUSCO) found that over 94% of the genes were complete from each of the three BUSCO databases (Eukaryota, Insecta, and Arthropoda). A total of 9,777 protein-coding genes were annotated using the MAKER2 pipeline, of which 65% were functionally annotated. The annotated repeat elements make up 84.26% of the genome. The high-quality annotated genome of the weevil will facilitate a wide range of genetic, genomic, and phylogenetic studies on invasive weevils, as well as other weevil species in the subfamily Entiminae.
Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma
Authors: Prakash Ajay , Rubin Nathan , Staley Christopher , Onyeaghala Guillaume , Wen Ya-Feng , Shaukat Aasma , Milne Ginger , Straka Robert J. , Church Timothy R. , Prizment Anna
Published: October 2023

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the generaAkkermansia(p<0.001),Bacteroides(p=0.018), andRuminococcus(p=0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances ofAkkermansiaandBacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas.
The role of cytomegalovirus in prostate cancer incidence and mortality
Authors: Classon Johanna , Britten Abigail , Alkass Kanar , Druid Henrik , Brenner Nicole , Waterboer Tim , Wareham Nicholas J , Gkrania-Klotsas Effrossyni , Frisén Jonas
Published: October 2023

Prostate cancer is one of the most common cancers in men with over 350 000 prostate cancer deaths reported worldwide every year. Current risk stratification models are insufficient to predict prostate cancer and prostate cancer death. New biomarkers are needed to identify those at increased risk of lethal prostate cancer. Cytomegalovirus (CMV) infection is common in the healthy prostate epithelium and promotes cell proliferation and viability in prostate cancer. Analyzing matched serum and tissue samples from post-mortem donors (n=41) and prostate cancer patients (n=40), we report that CMV seropositivity predicts high CMV abundance in prostate tissue. We studied if CMV seropositive men had increased prostate cancer incidence and cancer mortality in the European Prospective Investigation of Cancer (EPIC)–Norfolk population-based cohort study. CMV IgG serostatus was determined between 1993 and 2000 in 7,655 men aged 40-81 years, of which 57% were CMV seropositive. Study participants were followed for 18±6.0 years (mean±SD). We used Cox proportional hazard models, adjusted for age and potential confounders to estimate hazard ratios (HR) with 95% confidence intervals (CI). CMV serostatus was not associated with prostate cancer incidence (adjusted HR 1.03, 95% CI 0.89-1.19, p=0.687, 138,652 person-years). However, among prostate cancer patients, CMV seropositivity was associated with increased risk of prostate cancer-associated mortality (adjusted HR 2.26, CI 95% 1.02-4.99, p=0.044, 4639 person-years), with 25% of seropositive and 18% of seronegative prostate cancer patients dying from their disease during follow up. These results show that CMV seropositivity is associated with increased risk of prostate cancer death and suggest that CMV infection may contribute to prostate cancer lethality.
Development and validation of automated methods for COVID-19 PCR MasterMix preparation
Authors: Fedele Giorgio , Hill Graham , Sweetford Amelia , Lee Suki , Yau Bobby , Caputo Domenico R. , Grovewood Denise , Dahir Rowda , Ruiz-Dana Paula Esquivias , Wisniewska Anika , Di Biase Anna , Gibson Miles , Percival Benita , Grujic Stefan , Fraser Donald P.
Published: October 2023

Polymerase Chain Reaction (PCR)-based assays were widely deployed during the SARS-CoV-2 pandemic for population-scale testing. High-throughput molecular diagnostic labora-tories required a high degree of process automation to cope with huge testing demand, fast turn-around times and quality requirements. However, the critical step of preparing a PCR MasterMix has often been neglected by process developers and optimisers, and is largely dependent upon operator skill for the manual pipetting of reagents to construct the PCR MasterMix. Dependence on manual procedures introduces variation, inconsistency, wastage and potentially risks data integrity. To address this issue, we developed a liquid-handler based solution for automated, traceable and compliant PCR MasterMix preparation. Here, we show that a fully automated PCR MasterMix protocol can substitute manual pipetting, without affecting clinical calling, accuracy or precision. Ultimately, this method reduced cost-per-test at a high-throughput laboratory by eliminating operator-induced wastage while improving the quality of results.
Humoral and cellular immune responses following BNT162b2 XBB.1.5 vaccination
Authors: Stankov Metodi V. , Hoffmann Markus , Jauregui Rodrigo Gutierrez , Cossmann Anne , Ramos Gema Morillas , Graalmann Theresa , Friedrichsen Michaela , Ravens Inga , Ilievska Tamara , Ristenpart Jasmin , Schimrock Anja , Willenzon Stefanie , Ahrenstorf Gerrit , Witte Torsten , Förster Reinhold , Kempf Amy , Pöhlmann Stefan , Hammerschmidt Swantje I. , Alexandra Dopfer-Jablonka , Behrens Georg M. N.
Published: October 2023

SARS-CoV-2 Omicron XBB subvariants efficiently evade immunity from prior infection or vaccination, requiring vaccine adaptation. Here, we analyzed immunogenicity of an adapted vaccine, BNT162b2 Omicron XBB.1.5, which is currently used for booster vaccination. Booster vaccination significantly increased anti-Spike IgG, accompanied by expansion of cross-reactive memory B cells recognizing Wuhan and Omicron XBB.1.5 spike variants. Geometric mean neutralizing titers against XBB.1.5, XBB.1.16 and XBB.2.3, as well as cross-reactive responses against EG.5.1 and BA.2.86 increased significantly relative to pre-booster titers. Finally, the number of Wuhan and XBB.1.5 spike reactive IFN-γ-producing T cells significantly increased after booster vaccination. In summary, BNT162b2 Omicron XBB.1.5 vaccination resulted in potent neutralizing antibody responses against Omicron XBB variants, including the recent Omicron variants EG.5.1 (Eris) and BA.2.86 (Pirola), as well as XBB.1.5 reactive T cell responses, suggesting that booster vaccination will augment protection against these emerging variants.
Modelling the effectiveness of isolation strategies for managing mpox outbreaks with variable infectiousness profiles
Authors: Jeong Yong Dam , Nishiyama Takara , Park Hyeongki , Ishikane Masahiro , Iwamoto Noriko , Aihara Kazuyuki , Watashi Koichi , Op de Coul Eline , Hart William S , Thompson Robin N , Ohmagari Norio , Wallinga Jacco , Iwami Shingo , Miura Fuminari
Published: October 2023

The global outbreak of mpox (formerly monkeypox) in 2022 raised public awareness about the disease. The ensuing sporadic outbreaks in 2023 highlighted the importance of sustaining nonpharmaceutical interventions, such as case isolation and contact tracing. Using viral load data, we developed a modelling framework to characterize the various infectiousness profiles of infected individuals. We used this model to examine the potential effectiveness of two different possible isolation rules: specifically, rules permitting infected individuals to stop isolating after either a fixed-duration or following negative tests for infection. Our analysis showed large individual variations in the duration of viral shedding, ranging from about 23 to 50 days. The risk of infected individuals ending isolation too early (i.e., while they remained an infection risk) was estimated to be about 5% after 3 weeks of isolation. Unnecessary isolation after the end of the infectious period could be reduced by use of a testing-based rule. These findings support the choice of a 3-week isolation period following symptom onset if a fixed-duration rule is used, but also demonstrate how testing can mitigate unnecessarily prolonged isolation for those who have shorter infectious periods.
Sexual violence, PrEP discussion, and PrEP use among HIV-negative men who have sex with men in 23 U.S. urban areas – National HIV Behavioral Surveillance, 2017
Authors: Freeman Jincong Q. , Chapin-Bardales Johanna , Cha Susan , Wejnert Cyprian , Baugher Amy R. ,   the NHBS Study Group
Published: October 2023

Background

Men who have sex with men (MSM) who experience sexual violence are at increased risk for HIV. Pre-exposure prophylaxis (PrEP) is effective in preventing HIV infection. Associations between sexual violence and PrEP discussion or PrEP use among MSM are not well-understood.

Methods

National HIV Behavioral Surveillance used venue-based sampling methods to recruit and interview MSM in 23 U.S. urban areas in 2017. We estimated the prevalence of sexual violence and examined associations between sexual violence and PrEP discussion with a health care provider (HCP) or PrEP use among HIV-negative MSM in the past 12 months. We reported weighted percentages and 95% confidence intervals (CI). Adjusted prevalence ratios (aPR) with 95% CIs were calculated using logistic regression with predicted margins to compare groups.

Results

Among 7,121 HIV-negative MSM, 4.2% (95% CI: 3.6%-4.8%) experienced sexual violence in the past 12 months. Sexual violence was not independently associated with PrEP discussion with HCP (47.6% vs. 40.0%; aPR = 1.16, 95% CI: 0.98-1.37). MSM who experienced sexual violence were more likely to use PrEP than those who did not experience sexual violence, even after adjusting for demographic differences (34.9% vs. 25.7%; aPR = 1.34, 95% CI: 1.07-1.67).

Conclusions

Overall PrEP discussion and PrEP use were low among HIV-negative MSM. PrEP use was higher among MSM who experienced sexual violence. Supportive patient-provider relationships that foster PrEP discussion and sexual violence screening in healthcare settings may be important to identifying HIV risk and PrEP needs while assessing MSM’s safety.
Oleic acid differentially affectsde novolipogenesis in adipocytes and hepatocytes
Authors: Castillo Hannah B. , Shuster Sydney O. , Tarekegn Lydia H. , Davis Caitlin M.
Published: October 2023

Lipogenesis is a vital but often dysregulated metabolic pathway. We report super-resolution multiplexed vibrational imaging of lipogenesis rates and pathways using isotopically labelled oleic acid and glucose as probes in live adipocytes and hepatocytes. These findings suggest oleic acid inhibitsde novolipogenesis (DNL), but not total lipogenesis, in hepatocytes. No significant effect is seen in adipocytes. These differential effects may be due to alternate regulation of DNL between cell types and could help explain the complicated role oleic acid plays in metabolism.
Reading reshapes stimulus selectivity in the visual word form area
Authors: Chauhan Vassiki S. , McCook Krystal C. , White Alex L.
Published: October 2023

Reading depends on a brain region known as the “visual word form area” (VWFA) in left ventral occipito-temporal cortex. This region’s function is debated because its stimulus selectivity is not absolute, it is modulated by a variety of task demands, and it is inconsistently localized. We used fMRI to characterize the combination of sensory and cognitive factors that activate word-responsive regions that we precisely localized in 16 adult humans (4 male). We then presented three types of character strings: English words, pseudowords, and unfamiliar characters with matched visual features. Participants performed three different tasks while viewing those stimuli: detecting real words, detecting color in the characters, and detecting color in the fixation mark. There were three primary findings about the VWFA’s response: (1) It preferred letter strings over unfamiliar characters even when the stimuli were ignored during the fixation task; (2) Compared to those baseline responses, engaging in the word reading taskenhancedthe response to words butsuppressedthe response to unfamiliar characters. (3) Attending to the stimuli to judge their font color had little effect on the response magnitudes. Thus, the VWFA is uniquely modulated by a cognitive signal that is specific to voluntary linguistic processing and is not additive. Functional connectivity analyses revealed that communication between the VWFA and a left frontal language area increased when the participant engaged in the linguistic task. We conclude that the VWFA is inherently selective for familiar orthography, but it falls under control of the language network when the task demands it.

Significance Statement

The function of the “visual word form area” (VWFA) is controversial. Some researchers emphasize its bottom-up visual selectivity for words, hence the region’s common name. Others argue that its activity is explained by feedback from regions that control attention or language. To seek clarity, we investigated what drives the VWFA: seeing words, attending visually to words, or trying to read words. None of those factors was sufficient on its own. Our results support a hybrid model: the VWFA has inherent selectivity for words, but its function is reshaped by voluntary language processing. Thus, with an integrated analysis of sensory inputs, task demands, and network connectivity, we provide some resolution to debates about this important region.
Synaptic Basis of Behavioral Timescale Plasticity
Authors: Gonzalez Kevin C. , Negrean Adrian , Liao Zhenrui , Polleux Franck , Losonczy Attila
Published: October 2023

Learning and memory are fundamental to adaptive behavior and cognition. Various forms of synaptic plasticity have been proposed as cellular substrates for the emergence of feature selectivity in neurons underlying episodic memory. However, despite decades of work, our understanding of how synaptic plasticity underlies memory encoding remains limited, largely due to a shortage of tools and technical challenges associated with the visualization of synaptic plasticity at single-neuron resolution in awake-behaving animals. Behavioral Timescale Synaptic Plasticity (BTSP) postulates that synaptic inputs active during a seconds-long time window preceding and immediately following a large depolarizing plateau spike are potentiated, while synaptic inputs active outside this time window are depressed. We experimentally tested this modelin vivoin awake-behaving mice using an all-optical approach by inducing place fields (PFs) in single CA1 pyramidal neurons (CA1PNs) while monitoring the spatiotemporal tuning of individual dendritic spines and changes in their corresponding synaptic weights. We identified an asymmetric synaptic plasticity kernel resulting from bidirectional modifications of synaptic weights around plateau burst induction. Surprisingly, our work also uncovered compartment-specific differences in the magnitude and temporal expression of synaptic plasticity between basal and oblique dendrites of CA1PNs. Our results provide the first experimental evidence linking synaptic plasticity to the rapid emergence of spatial selectivity in hippocampal neurons, a critical prerequisite for episodic memory.
NOTCH3p.Arg1231Cys is Markedly Enriched in South Asians and Associated with Stroke
Authors: Rodriguez-Flores Juan L. , Khalid Shareef , Parikshak Neelroop , Rasheed Asif , Ye Bin , Kapoor Manav , Backman Joshua , Sepehrband Farshid , DiGioia Silvio Alessandro , Gelfman Sahar , De Tanima , Banerjee Nilanjana , Sharma Deepika , Martinez Hector , Castaneda Sofia , D’Ambrosio David , Zhang Xingmin A. , Xun Pengcheng , Tsai Ellen , Tsai I-Chun ,   Regeneron Genetics Center, Khan Maleeha Zaman , Jahanzaib Muhammad , Mian Muhammad Rehan , Liaqat Muhammad Bilal , Mahmood Khalid , Salam Tanvir Us , Hussain Muhammad , Iqbal Javed , Aslam Faizan , Cantor Michael N. , Tzoneva Gannie , Overton John , Marchini Jonathan , Reid Jeff , Baras Aris , Verweij Niek , Lotta Luca A. , Coppola Giovanni , Karalis Katia , Economides Aris , Fazio Sergio , Liedtke Wolfgang , Danesh John , Kamal Ayeesha , Frossard Philippe , Coleman Thomas , Shuldiner Alan R. , Saleheen Danish
Published: October 2023

The genetic factors of stroke in South Asians are largely unexplored. Exome-wide sequencing and association analysis (ExWAS) in 75 K Pakistanis identified NM_000435.3(NOTCH3):c.3691C>T, encoding the missense amino acid substitution p.Arg1231Cys, enriched in South Asians (alternate allele frequency = 0.58% compared to 0.019% in Western Europeans), and associated with subcortical hemorrhagic stroke [odds ratio (OR) = 3.39, 95% confidence interval (CI) = [2.26, 5.10], p value = 3.87×10-9), and all strokes (OR [CI] = 2.30 [1.77, 3.01], p value = 7.79×10-10).NOTCH3p.Arg231Cys was strongly associated with white matter hyperintensity on MRI in United Kingdom Biobank (UKB) participants (effect [95% CI] in SD units = 1.1 [0.61, 1.5], p value = 3.0×10-6). The variant is attributable for approximately 2.0% of hemorrhagic strokes and 1.1% of all strokes in South Asians. These findings highlight the value of diversity in genetic studies and have major implications for genomic medicine and therapeutic development in South Asian populations.
Real World Performance of the 21st Century Cures Act Population Level Application Programming Interface
Authors: Jones James R. , Gottlieb Daniel , McMurry Andrew J. , Atreja Ashish , Desai Pankaja M. , Dixon Brian E. , Payne Philip R.O. , Saldanha Anil J. , Shankar Prabhu , Solad Yauheni , Wilcox Adam B. , Ali Momeena S. , Kang Eugene , Martin Andrew M. , Sprouse Elizabeth , Taylor David , Terry Michael , Ignatov Vladimir ,   the SMART Cumulus Network, Mandl Kenneth D.
Published: October 2023

Objective

To evaluate the real-world performance in delivering patient data on populations, of the SMART/HL7 Bulk FHIR Access API, required in Electronic Health Records (EHRs) under the 21st Century Cures Act Rule.

Materials and Methods

We used an open-source Bulk FHIR Testing Suite at five healthcare sites from April to September 2023, including four hospitals using EHRs certified for interoperability, and one Health Information Exchange (HIE) using a custom, standards-compliant API build. We measured export speeds, data sizes, and completeness across six types of FHIR resources.

Results

Among the certified platforms, Oracle Cerner led in speed, managing 5-16 million resources at over 8,000 resources/min. Three Epic sites exported a FHIR data subset, achieving 1-12 million resources at 1,555-2,500 resources/min. Notably, the HIE’s custom API outperformed, generating over 141 million resources at 12,000 resources/min.

Discussion

The HIE’s custom API showcased superior performance, endorsing the effectiveness of SMART/HL7 Bulk FHIR in enabling large-scale data exchange while underlining the need for optimization in existing EHR platforms. Agility and scalability are essential for diverse health, research, and public health use cases.

Conclusion

To fully realize the interoperability goals of the 21st Century Cures Act, addressing the performance limitations of Bulk FHIR API is critical. It would be beneficial to include performance metrics in both certification and reporting processes.
Prevalence and correlates of age at first birth and utilization of maternal health care services among pregnant women in four Asian-Pacific Island countries
Authors: Myint Wah W. , Washburn David J. , Lee Shinduk , Colwell Brian , Ahenda Petronella , Maddock Jay E.
Published: October 2023

BACKGROUND

Maternal mortality is still high among adolescent women worldwide. This study explores the influence of socio-demographic characteristics on having four or more antenatal care (ANC4+) visits and use of Skilled Birth Attendants (SBA) among women in four island countries: Indonesia, the Philippines, Papua New Guinea, and Timor-Leste.

METHODS

Data from Demographic and Health Surveys of Indonesia, the Philippines, Papua New Guinea, and Timor-Leste were used. We studied the relationship of utilization of ANC4+ visits and SBA among women aged 15-49 years with socio-demographic variables including women’s age at first birth, age at first cohabitation, age at last birth, age groups, place of residence, education, wealth, birth order, number of living children, household ownership of a vehicle, and reproductive health knowledge. Descriptive, bivariate, and multivariable logistic regression analyses were performed.

RESULTS

Women at first birth before age 18 ranged from 18% in Indonesia to 31% in Papua New Guinea. In all countries, wealth status and having knowledge on modern contraceptives were significant predictors for having ANC4+ visits and SBA use. In Indonesia, women older than 25 were 1.38 times (95% CI=1.09-1.74) more likely to use SBA than those younger than 19. Each country demonstrated different patterns of ANC4+ visits and use of SBA that varied by education, place of residence, birth order, number of living children, and household ownership of a vehicle.

CONCLUSION

Having a high number of adolescent births highlighted a need for reproductive health knowledge reach to the young women, which can achieve through ANC4+ visits and use of SBA.
Sensitivity of the African Neuropsychology Battery Memory Subtests and Learning Slopes in Discriminating APOE 4 and Amyloid Pathology in Adult Individuals in the Democratic Republic of Congo
Authors: Ikanga Jean , Patrick Sarah D. , Schwinne Megan , Patel Saranya Sundaram , Epenge Emmanuel , Gikelekele Guy , Tshengele Nathan , Kavugho Immaculee , Mampunza Samuel , Yarasheski Kevin E. , Teunissen Charlotte E. , Stringer Anthony , Levey Allan , Rojas Julio C. , Chan Brandon , Lago Argentina Lario , Kramer Joel H. , Boxer Adam L. , Jeromin Andreas , Alonso Alvaro , Spencer Robert J.
Published: October 2023

Background

The current study examined the sensitivity of two memory subtests and their corresponding learning slope metrics derived from the African Neuropsychology Battery (ANB) to detect amyloid pathology and APOEε4 status in adults from Kinshasa, the Democratic Republic of the Congo.

Methods

85 participants were classified for the presence of β-amyloid pathology and based on allelic presence of APOEε4. All participants were screened using CSID and AQ, underwent verbal and visuospatial memory testing from ANB, and provided blood samples for plasma Aβ42, Aβ40, and APOE proteotype. Pearson correlation, linear and logistic regression were conducted to compare amyloid pathology and APOEε4 status with derived learning scores, including initial learning, raw learning score, learning over trials, and learning ratio.

Results

Our sample included 35 amyloid positive and 44 amyloid negative individuals as well as 42 without and 39 with APOEε4. All ROC AUC ranges for the prediction of amyloid pathology based on learning scores were low, ranging between 0.56-0.70 (95% CI ranging from 0.44-0.82). The sensitivity of all the scores ranged between 54.3-88.6, with some learning metrics demonstrating good sensitivity. Regarding APOEε4 prediction, all AUC values ranged between 0.60-0.69, with all sensitivity measures ranging between 53.8-89.7. There were minimal differences in the AUC values across learning slope metrics, largely due to the lack of ceiling effects in this sample.

Discussion

This study demonstrates that some ANB memory subtests and learning slope metrics can discriminate those that are normal from those with amyloid pathology and those with and without APOEε4, consistent with findings reported in Western populations.
Premature deaths attributable to the consumption of ultra-processed foods: a comparative assessment modelling study in eight countries
Authors: Nilson Eduardo A. F. , Delpino Felipe Mendes , Batis Carolina , Machado Priscila Pereira , Moubarac Jean-Claude , Cediel Gustavo , Corvalan Camila , Ferrari Gerson , Rauber Fernanda , Martinez-Steele Euridice , da Costa Louzada Maria Laura , Levy Renata Bertazzi , Monteiro Carlos A. , Rezende Leandro F.M.
Published: October 2023

Background

Ultra-processed foods (UPFs) are becoming dominant in the global food and supply. Prospective cohort studies have found an association between UPF dietary pattern and increased risk of several non-communicable diseases and all-cause mortality. In this study, we (1) estimated the risk of all-cause mortality associated for each 10% increase in the share of UPF consumption in the total energy intake; (2) estimated the population attributable fractions (PAF) and the total number of premature deaths attributable to the consumption of UPF in adults (30-69 years) from 8 selected countries.

Methods

First, we performed a dose-response meta-analysis of observational cohort studies assessing the association between UPFs dietary pattern and all-cause mortality. As we found evidence of linearity, we estimated the pooled RR (and its 95% CI) for all-cause mortality per each 10% increment in the % UPF. Then, we estimated the population attributable fraction (PAF) of premature all-cause mortality attributable to UPF in 8 selected countries with relatively low (Colombia and Brazil), intermediate (Chile and Mexico), and high (Australia, Canada, UK, and US) UPF consumption.

Results

We found a linear dose-response association between UPF intake and all-cause mortality, with a 2.7% increased risk of all-cause mortality per 10% increase in the % UPF. Considering the magnitude of the association between UPFs intake and all-cause mortality, and the dietary share of UPF in each of the 8 selected countries, we estimated that 4% (Colombia) to 14% (United Kingdom and United States) of premature deaths were attributable to UPF intake.

Conclusions

Our findings support that UPF intake contributes significantly to the overall burden of disease in many countries and its reduction should be included in national dietary guideline recommendations and addressed in public policies.
Optimal cell length for exploration and exploitation in chemotactic planktonic bacteria
Authors: Guadayol Oscar , Schuech Rudi , Humphries Stuart
Published: October 2023

Elongated morphologies are prevalent among marine motile bacterioplankton. This is often attributed to enhanced chemotactic ability, but how long is best? We hypothesized the existence of an optimal cell length for efficient chemotaxis resulting from shape-imposed physical constraints acting on the trade-off between rapid exploration versus efficient exploitation of nutrient sources. To test this hypothesis, we first evaluated the chemotactic performance of elongated cephalexin-treated Escherichia coli towards alpha-methyl-aspartate in an agarose-based microfluidic device that creates linear, stable and quiescent chemical gradients. Our experiments showed that cells of intermediate lengths aggregated most tightly to the chemoattractant source. We then replicated these experimental results with Individual Based Model (IBM) simulations. A sensitivity analysis of the IBM allowed us to gain mechanistic insights into which parameters drive this trend and showed that the poor chemotactic performance of very short cells is caused by loss of directionality, whereas long cells are penalized by brief, slow runs. Finally, we evaluated the chemotactic performance of cells of different length with IBM simulations of a phycosphere - a hotspot of microbial interactions in the ocean. Results indicated that long cells swimming in a run-and-reverse pattern with extended runs and moderate speeds are most efficient at harvesting nutrients in this microenvironment. The combination of microfluidic experiments and IBMs proves thus to be a powerful tool for untangling the physical constraints that motile bacteria are facing in the ocean.
A murine model ofTrypanosoma brucei-induced myocarditis and cardiac dysfunction
Authors: Crilly Nathan P. , Zita Marcelle Dina , Beaver Alexander K. , Sysa-Shah Polina , Bhalodia Aashik , Gabrielson Kathy , Adamo Luigi , Mugnier Monica R.
Published: October 2023

Trypanosoma bruceiis a protozoan parasite that causes human and animal African trypanosomiases (HAT and AAT). Cardiac symptoms are commonly reported in HAT patients, and intracardiac parasites with accompanying myocarditis have been observed in both natural hosts and animal models ofT. bruceiinfection. Despite the importance ofT. bruceias a cause of cardiac dysfunction and the dramatic socioeconomic impact of African trypanosomiases in sub-Saharan Africa, there are currently no reproducible murine models ofT. brucei-associated cardiomyopathy. We present the first clinically relevant, reproducible murine model of cardiac dysfunction in chronicT. bruceiinfection. Similar to humans, mice showed histological evidence of myocarditis and elevation of serum NT-proBNP with electrocardiographic abnormalities. Serum NT-proBNP levels were elevated prior to the development of severe ventricular dysfunction. On flow cytometry, myocarditis was associated with an increase of most myocardial immune cell populations, including multiple T cell and macrophage subsets, corroborating the notion thatT. brucei-associated cardiac damage is an immune-mediated event. This novel mouse model represents a powerful and practical tool to investigate the pathogenesis ofT. brucei-mediated heart damage and supports the development of therapeutic options forT. brucei-associated cardiac disease.
Effect of antiretroviral protease inhibitors onPlasmodium falciparumerythrocyte egress and invasion
Authors: Wilson Danny W. , Frolich Sonja , Andrews Katherine T. , Skinner-Adams Tina S.
Published: October 2023

Background

Anti-retroviral protease inhibitors directly inhibit the growth of asexual blood stage malaria parasites, however, this activity is not fully understood. While mode of action hypotheses have included parasite aspartic protease (plasmepsin) inhibition, current data suggest that digestive vacuole plasmepsins I-IV are not essential for asexual parasite survival, that plasmepsins VI-VIII are not expressed in these parasites and that antiretroviral protease inhibitors are poor inhibitors of plasmepsin V. The remaining plasmepsins, IX and X, have recently been shown to be essential for merozoite egress and invasion, playing important roles in the processing of key proteins including the rhoptry bulb proteinPfRAP1, and subtilisin-like serine proteasePfSUB1, respectively. To further understand the antiplasmodial activity of antiretroviral protease inhibitors, here we investigated the impact of tipranavir, lopinavir, ritonavir and saquinavir on the processing ofPfRAP1, thePfSUB1-processedPfMSP1, and the egress and invasion ofP. falciparumparasites from human erythrocytes.

Methods

The effect of tipranavir, lopinavir, ritonavir and saquinavir onP. falciparumparasite egress and invasion was assessed using synchronized asexual blood stageP. falciparumparasites. Schizont rupture and purified merozoite invasion were performed with and without drug and quantified by flow cytometry analysis. The impact of selected antitretroviral protease inhibitors onPfRAP1 andPfMSP1 processing was assessed by Wesstern blot.

Results

The effect of tipranavir, lopinavir, ritonavir and saquinavir on the egress and invasion ofP. falciparumparasites from human erythrocytes varied considerably, but was low at concentrations shown to inhibitP. falciparumasexual parasite growthin vitroand negligible at clinically relevant concentrations. While the treatment of parasites with the antiretrovial protease inhibitors appeared to reduce the overall expression ofPfRAP1 andPfMSP1, the processing of these proteins was not inhibited by concentrations known to inhibit parasite growthin vitro.

Conclusions

The limited activity of tipranavir, lopinavir, ritonavir and saquinavir on the egress and invasion ofP. falciparumparasites from human erythrocytes and the processing ofPfRAP1 andPfMSP1 suggests that plasmepsin IX and X are unlikely to be the primary targets of these drugs in these parasites.
Investigating the Rescue Potential of Fecal Microbiota Transplants in Anorexia Nervosa using Antibiotic-treated Mice in a Split Group Cross-Over Study
Authors: Maschek Sina , Østergaard Theresa Helena , Krych Lukasz , Zachariassen Line Fisker , Sørensen Dorte Bratbo , Mentzel Caroline M. Junker , Hansen Axel Kornerup , Sjögren Jan Magnus , Barfod Kenneth Klingenberg
Published: October 2023

Anorexia nervosa (AN) is a complex and serious mental disorder, which may affect individuals of all ages and sex, but primarily affecting young women. The disease is characterized by a disturbed body image, restrictive eating behavior, and a lack of acknowledgment of low body weight. The underlying causes of AN remain largely unknown, and current treatment options are limited to psychotherapy and nutritional support. This paper investigates the impact of Fecal Microbiota Transplants (FMT) from AN patients on food intake, body weight, behavior, and gut microbiota in antibiotic-treated mice. Two rounds of FMT were performed using AN and control (CO) donors. During the second round of FMT, a subset of mice received FMT from a different donor type. This split-group cross-over design was chosen to demonstrate any recovery effect of FMT from a healthy donor. The first FMT, from AN donors, resulted in lower food intake in mice without affecting body weight. After FMT2, serum analysis revealed higher levels of appetite-influencing hormones (PYY and leptin) in mice receiving AN-GM. Gut microbiota analysis showed significant differences between AN and CO mice after FMT1, before cross-over. Specific bacterial genera and familiesRuminococcaceae, Lachnospiraceae,andFaecalibacteriumshowed different abundances in AN and CO receiving mice. Behavioral tests showed decreased locomotor activity in AN mice after FMT1. Overall, the results suggest that AN-GM may contribute to altered food intake and appetite regulation, which can be ameliorated with FMT from a healthy donor potentially offering FMT as a supportive treatment for AN.
Occurrence of Salmonella species in local and commercial chickens slaughtered at Samaru and Sabon-gari live bird markets, Kaduna State
Authors: Ashar Saaondo James , Ameh Anthony Oche , Adamu Jibril , Kwaga Jacob Kwaga Paghi
Published: October 2023

Salmonellosis is a bacterial infection caused by members of the genusSalmonella. It is one of the most common and important zoonotic diseases. The route of infection from animals to humans is usually through contaminated food, water and environment. Bacteriological investigation on 303 cloacal swab samples collected from local (139) and commercial (164) chickens slaughtered at Samaru and Sabon-gari live bird markets, Kaduna State was carried out to determine the occurrence ofSalmonellaspecies. Cultural isolation and identification using conventional biochemical tests, microgen test kit™ and Polymerase Chain Reaction (PCR) amplification ofinvA gene of theSalmonellaisolates was carried out. Isolates were subjected to antimicrobial susceptibility tests, phenotypic detection of Extended Spectrum Beta Lactamases (ESBLs) producingSalmonellaisolates using the modified Clinical and Laboratory Standards Institute (CLSI) ESBL confirmatory test. The occurrence ofSalmonellaspecies based on cultural and biochemical tests was found to be 13 (4.29%), microgen kit identified 7 (53.8%) of the 13Salmonellaspecies while PCR based oninvA gene confirmed 9 (69.2%) as the overall occurrence rate ofSalmonellaspecies. Meanwhile, the study also revealed rate of occurrence ofSalmonellaspecies in local chickens 8 (61.5%) which was higher compared to commercial chickens 1 (7.69%) with a statistical significant association (χ2= 8.775, P = 0.003) between the occurrence ofSalmonellaspecies in local and commercial chickens. Antimicrobial susceptibility testing was carried out using panel of 12 antibiotics from 8 different antibiotic classes. Highest rate of sensitivity of the isolates to antibiotics was observed for Ofloxacin with 90%, while all the isolates (100%) were resistant to Nalidixic Acid, Cefazolin, Amoxicillin + Clavulanic Acid, Oxacillin and Penicillin. This study revealed multidrug-resistance (MDR) profile ofSalmonellawith a total of (25%) ofSalmonellaisolates being resistant to 5 antibiotics belonging to 4 different classes of antimicrobials with the highest multiple antibiotic-resistant (MAR) indices ranging from 0.58 to 0.91. All the nine (9) isolates ofSalmonellatested were found to be negative for ESBLs production. Therefore, it is concluded thatSalmonellaspecies are present in local and commercial chickens slaughtered at Samaru and Sabon-gari live bird markets, Kaduna State and could pose serious public health risks to handlers and to consumers of poultry meat and its products.