bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association Between Increased Linezolid Plasma Concentrations and the Development of Severe Toxicity in Multidrug-Resistant Tuberculosis Treatment
Authors: Eimer Johannes , Fréchet-Jachym Mathilde , Le Dû Damien , Caumes Eric , El-Helali Najoua , Marigot-Outtandy Dhiba , Mechai Frédéric , Peytavin Gilles , Pourcher Valérie , Rioux Christophe , Yazdanpanah Yazdan , Robert Jérôme , Guglielmetti Lorenzo ,   for the LZDM group, Aubry Alexandra , Bonnet Isabelle , Morel Florence , Veziris Nicolas , Lecorché Emmanuel , Mougari Faiza , Andrejak Claire , Bourgarit Anne , Klement Elise , Rivoire Bénédicte , Thouvenin Guillaume , Tunesi Simone , Wicky Marie , Jaspard Marie , Alauzet Corentine , Escaut Lelia , Ellis-Corbet Sophie , Bernard Christine , Roux Anne-Laure 
Published: June 2022

Abstract

Background
Treatment of multidrug-resistant (MDR) tuberculosis with linezolid is characterized by high rates of adverse events. Evidence on therapeutic drug monitoring to predict drug toxicity is scarce. This study aimed to evaluate the association of linezolid trough concentrations with severe toxicity.

Methods
We retrospectively assessed consecutive patients started on linezolid for MDR tuberculosis between 2011 and 2017. The primary outcome was severe mitochondrial toxicity (SMT) due to linezolid, defined as neurotoxicity or myelotoxicity leading to drug discontinuation. The impact of plasma linezolid trough concentrations &gt;2 mg/L was assessed in multivariate Cox proportional hazards models including time-varying covariates.

Results
SMT occurred in 57 of 146 included patients (39%) at an incidence rate of 0.38 per person-year (95% confidence interval, .30–.49). A maximum linezolid trough concentration &gt;2 mg/L was detected in 52 patients (35.6%), while the mean trough concentration was &gt;2 mg/L in 22 (15%). The adjusted hazard ratio for SMT was 2.35 (95% confidence interval, 1.26–4.38; P = .01) in patients with a mean trough concentration &gt;2 mg/L and 2.63 (1.55–4.47; P &lt; .01) for SMT after the first detection of a trough concentration &gt;2 mg/L. In an exploratory analysis, higher maximum trough concentrations were dose-dependently associated with toxicity, while lowering elevated trough concentrations did not restore baseline risk.

Conclusions
Linezolid trough concentrations &gt;2 mg/L are strongly associated with the development of severe treatment-emergent toxicity in patients treated for MDR tuberculosis. Pending further prospective evidence, an individual risk-benefit assessment on the continuation of linezolid treatment is warranted in any patient with trough concentrations &gt;2 mg/L.
Reported Exposures Among In-Person Workers With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in 6 States, September 2020–June 2021
Authors: Free Hannah , Luckhaupt Sara E , Billock Rachael M , Groenewold Matthew R , Burrer Sherry , Sweeney Marie Haring , Wong Jessie , Gibb Kathryn , Rodriguez Andrea , Vergara Ximena P , Cummings Kristin J , Lavender Antionette , Argueta Gabriel , Crawford Hannah Leigh , Erukunuakpor Kimberly , Karlsson Nicole D , Armenti Karla , Thomas Hannah , Gaetz Kim , Dang Gialana , Harduar-Morano Laurel , Modji Komi 
Published: June 2022

Abstract

Background
Surveillance systems lack detailed occupational exposure information from workers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The National Institute for Occupational Safety and Health partnered with 6 states to collect information from adults diagnosed with SARS-CoV-2 infection who worked in person (outside the home) in non-healthcare settings during the 2 weeks prior to illness onset.

Methods
The survey captured demographic, medical, and occupational characteristics and work- and non–work-related risk factors for SARS-CoV-2 infection. Reported close contact with a person known or suspected to have SARS-CoV-2 infection was categorized by setting as exposure at work, exposure outside of work only, or no known exposure/did not know. Frequencies and percentages of exposure types are compared by respondent characteristics and risk factors.

Results
Of 1111 respondents, 19.4% reported exposure at work, 23.4% reported exposure outside of work only, and 57.2% reported no known exposure/did not know. Workers in protective service occupations (48.8%) and public administration industries (35.6%) reported exposure at work most often. More than one third (33.7%) of respondents who experienced close contact with ≥10 coworkers per day and 28.8% of respondents who experienced close contact with ≥10 customers/clients per day reported exposures at work.

Conclusions
Exposure to occupational SARS-CoV-2 was common among respondents. Examining differences in exposures among different worker groups can help identify populations with the greatest need for prevention interventions. The benefits of recording employment characteristics as standard demographic information will remain relevant as new and reemerging public health issues occur.
Vaccine Effectiveness of CanSino (Adv5-nCoV) Coronavirus Disease 2019 (COVID-19) Vaccine Among Childcare Workers—Mexico, March–December 2021
Authors: Richardson Vesta L , Camacho Franco Martín Alejandro , Bautista Márquez Aurora , Martínez Valdez Libny , Castro Ceronio Luis Enrique , Cruz Cruz Vicente , Gharpure Radhika , Lafond Kathryn E , Yau Tat S , Azziz-Baumgartner Eduardo , Hernández Ávila Mauricio 
Published: June 2022

Abstract

Background
Beginning in March 2021, Mexico vaccinated childcare workers with a single-dose CanSino Biologics (Adv5-nCoV) coronavirus disease 2019 (COVID-19) vaccine. Although CanSino is currently approved for use in 10 Latin American, Asian, and European countries, little information is available about its vaccine effectiveness (VE).

Methods
We evaluated CanSino VE within a childcare worker cohort that included 1408 childcare facilities. Participants were followed during March–December 2021 and tested through severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse-transcription polymerase chain reaction or rapid antigen test if they developed any symptom compatible with COVID-19. Vaccination status was obtained through worker registries. VE was calculated as 100% × (1 − hazard ratio for SARS-CoV-2 infection in fully vaccinated vs unvaccinated participants), using an Andersen-Gill model adjusted for age, sex, state, and local viral circulation.

Results
The cohort included 43 925 persons who were mostly (96%) female with a median age of 32 years; 37 646 (86%) were vaccinated with CanSino. During March–December 2021, 2250 (5%) participants had laboratory-confirmed COVID-19, of whom 25 were hospitalized and 6 died. Adjusted VE was 20% (95% confidence interval [CI], 10%–29%) against illness, 76% (95% CI, 42%–90%) against hospitalization, and 94% (95% CI, 66%–99%) against death. VE against illness declined from 48% (95% CI, 33%–61%) after 14–60 days following full vaccination to 20% (95% CI, 9%–31%) after 61–120 days.

Conclusions
CanSino vaccine was effective at preventing COVID-19 illness and highly effective at preventing hospitalization and death. It will be useful to further evaluate duration of protection and assess the value of booster doses to prevent COVID-19 and severe outcomes.
Increased Deaths From Fungal Infections During the Coronavirus Disease 2019 Pandemic—National Vital Statistics System, United States, January 2020–December 2021
Authors: Gold Jeremy A W , Ahmad Farida B , Cisewski Jodi A , Rossen Lauren M , Montero Alejandro J , Benedict Kaitlin , Jackson Brendan R , Toda Mitsuru 
Published: June 2022

Abstract

Background
Coronavirus disease 2019 (COVID-19)–associated fungal infections cause severe illness, but comprehensive data on disease burden are lacking. We analyzed US National Vital Statistics System (NVSS) data to characterize disease burden, temporal trends, and demographic characteristics of persons dying of fungal infections during the COVID-19 pandemic.

Methods
Using NVSS’s January 2018–December 2021 Multiple Cause of Death Database, we examined numbers and age-adjusted rates (per 100 000 population) of deaths due to fungal infection by fungal pathogen, COVID-19 association, demographic characteristics, and year.

Results
Numbers and age-adjusted rates of deaths due to fungal infection increased from 2019 (n = 4833; rate, 1.2 [95% confidence interval, 1.2–1.3]) to 2021 (n = 7199; rate, 1.8 [1.8–1.8] per 100 000); of 13 121 such deaths during 2020–2021, 2868 (21.9%) were COVID-19 associated. Compared with non–COVID-19–associated deaths (n = 10 253), COVID-19–associated deaths more frequently involved Candida (n = 776 [27.1%] vs n = 2432 [23.7%], respectively) and Aspergillus (n = 668 [23.3%] vs n = 1486 [14.5%]) and less frequently involved other specific fungal pathogens. Rates of death due to fungal infection were generally highest in nonwhite and non-Asian populations. Death rates from Aspergillus infections were approximately 2 times higher in the Pacific US census division compared with most other divisions.

Conclusions
Deaths from fungal infection increased during 2020–2021 compared with previous years, primarily driven by COVID-19–associated deaths, particularly those involving Aspergillus and Candida. Our findings may inform efforts to prevent, identify, and treat severe fungal infections in patients with COVID-19, especially in certain racial/ethnic groups and geographic areas.
Antibody Binding and Angiotensin-Converting Enzyme 2 Binding Inhibition Is Significantly Reduced for Both the BA.1 and BA.2 Omicron Variants
Authors: Junker Daniel , Becker Matthias , Wagner Teresa R , Kaiser Philipp D , Maier Sandra , Grimm Tanja M , Griesbaum Johanna , Marsall Patrick , Gruber Jens , Traenkle Bjoern , Heinzel Constanze , Pinilla Yudi T , Held Jana , Fendel Rolf , Kreidenweiss Andrea , Nelde Annika , Maringer Yacine , Schroeder Sarah , Walz Juliane S , Althaus Karina , Uzun Gunalp , Mikus Marco , Bakchoul Tamam , Schenke-Layland Katja , Bunk Stefanie , Haeberle Helene , Göpel Siri , Bitzer Michael , Renk Hanna , Remppis Jonathan , Engel Corinna , Franz Axel R , Harries Manuela , Kessel Barbora , Lange Berit , Strengert Monika , Krause Gerard , Zeck Anne , Rothbauer Ulrich , Dulovic Alex , Schneiderhan-Marra Nicole 
Published: June 2022

Abstract

Background
The rapid emergence of the Omicron variant and its large number of mutations led to its classification as a variant of concern (VOC) by the World Health Organization. Subsequently, Omicron evolved into distinct sublineages (eg, BA.1 and BA.2), which currently represent the majority of global infections. Initial studies of the neutralizing response toward BA.1 in convalescent and vaccinated individuals showed a substantial reduction.

Methods
We assessed antibody (immunoglobulin G [IgG]) binding, ACE2 (angiotensin-converting enzyme 2) binding inhibition, and IgG binding dynamics for the Omicron BA.1 and BA.2 variants compared to a panel of VOCs/variants of interest, in a large cohort (N = 352) of convalescent, vaccinated, and infected and subsequently vaccinated individuals.

Results
While Omicron was capable of efficiently binding to ACE2, antibodies elicited by infection or immunization showed reduced binding capacities and ACE2 binding inhibition compared to wild type. Whereas BA.1 exhibited less IgG binding compared to BA.2, BA.2 showed reduced inhibition of ACE2 binding. Among vaccinated samples, antibody binding to Omicron only improved after administration of a third dose.

Conclusions
Omicron BA.1 and BA.2 can still efficiently bind to ACE2, while vaccine/infection-derived antibodies can bind to Omicron. The extent of the mutations within both variants prevents a strong inhibitory binding response. As a result, both Omicron variants are able to evade control by preexisting antibodies.
Rare germline deleterious variants increase susceptibility for lung cancer
Authors: Sang Jian , Zhang Tongwu , Kim Jung , Li Mengying , Pesatori Angela C , Consonni Dario , Song Lei , Liu Jia , Zhao Wei , Hoang Phuc H , Campbell Dave S , Feng James , D’Arcy Monica E , Synnott Naoise , Chen Yingxi , Wu Zeni , Zhu Bin , Yang Xiaohong R , Brown Kevin M , Choi Jiyeon , Shi Jianxin , Landi Maria Teresa 
Published: June 2022

Abstract
Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies, they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology study, a homogenous population including 1461 LC cases and 1316 controls. In single-variant analyses, we identified a new RDV, rs77187983 [EHBP1, odds ratio (OR) = 3.13, 95% confidence interval (CI) = 1.34–7.30, P = 0.008] and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25–3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04–13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair [carrier frequency (CF) = 22.9% versus 19.5%, P = 0.017] and Fanconi anemia (CF = 12.5% versus 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing corrections but were enriched in cases versus controls from large scale public biobank resources, including The Cancer Genome Atlas, FinnGen and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair-related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.
De novo non-synonymous CTR9 variants are associated with motor delay and macrocephaly: human genetic and zebrafish experimental evidence
Authors: Suzuki Hisato , Aoki Kana , Kurosawa Kenji , Imagawa Kazuo , Ohto Tatsuyuki , Yamada Mamiko , Takenouchi Toshiki , Kosaki Kenjiro , Ishitani Tohru 
Published: June 2022

Abstract
CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.
Investigating DNA methylation as a mediator of genetic risk in childhood acute lymphoblastic leukemia
Authors: Xu Keren , Li Shaobo , Pandey Priyatama , Kang Alice Y , Morimoto Libby M , Mancuso Nicholas , Ma Xiaomei , Metayer Catherine , Wiemels Joseph L , de Smith Adam J 
Published: June 2022

Abstract
Genome-wide association studies have identified a growing number of single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL), yet the functional roles of most SNPs are unclear. Multiple lines of evidence suggest that epigenetic mechanisms may mediate the impact of heritable genetic variation on phenotypes. Here, we investigated whether DNA methylation mediates the effect of genetic risk loci for childhood ALL. We performed an epigenome-wide association study (EWAS) including 808 childhood ALL cases and 919 controls from California-based studies using neonatal blood DNA. For differentially methylated CpG positions (DMPs), we next conducted association analysis with 23 known ALL risk SNPs followed by causal mediation analyses addressing the significant SNP-DMP pairs. DNA methylation at CpG cg01139861, in the promoter region of IKZF1, mediated the effects of the intronic IKZF1 risk SNP rs78396808, with the average causal mediation effect (ACME) explaining ~30% of the total effect (ACME P = 0.0031). In analyses stratified by self-reported race/ethnicity, the mediation effect was only significant in Latinos, explaining ~41% of the total effect of rs78396808 on ALL risk (ACME P = 0.0037). Conditional analyses confirmed the presence of at least three independent genetic risk loci for childhood ALL at IKZF1, with rs78396808 unique to non-European populations. We also demonstrated that the most significant DMP in the EWAS, CpG cg13344587 at gene ARID5B (P = 8.61 × 10−10), was entirely confounded by the ARID5B ALL risk SNP rs7090445. Our findings provide new insights into the functional pathways of ALL risk SNPs and the DNA methylation differences associated with risk of childhood ALL.
Embryo cryopreservation leads to sex-specific DNA methylation perturbations in both human and mouse placentas
Authors: Mani Sneha , Ghosh Jayashri , Rhon-Calderon Eric A , Lan Yemin , Ord Teri , Kalliora Charikleia , Chan Joe , Schultz Bryant , Vaughan-Williams Elaine , Coutifaris Christos , Sapienza Carmen , Senapati Suneeta , Bartolomei Marisa S , Mainigi Monica 
Published: June 2022

Abstract
In vitro fertilization (IVF) is associated with DNA methylation abnormalities and a higher incidence of adverse pregnancy outcomes. However, which exposure(s), among the many IVF interventions, contributes to these outcomes remains unknown. Frozen embryo transfer (ET) is increasingly utilized as an alternative to fresh ET, but reports suggest a higher incidence of pre-eclampsia and large for gestational age infants. This study examines DNA methylation in human placentas using the 850K Infinium MethylationEPIC BeadChip array obtained after 65 programmed frozen ET cycles, 82 fresh ET cycles and 45 unassisted conceptions. Nine patients provided placentas following frozen and fresh ET from consecutive pregnancies for a paired subgroup analysis. In parallel, eight mouse placentas from fresh and frozen ET were analyzed using the Infinium Mouse Methylation BeadChip array. Human and mouse placentas were significantly hypermethylated after frozen ET compared with fresh. Paired analysis showed similar trends. Sex-specific analysis revealed that these changes were driven by male placentas in humans and mice. Frozen and fresh ET placentas were significantly different from controls, with frozen samples hypermethylated compared with controls driven by males and fresh samples being hypomethylated compared with controls, driven by females. Sexually dimorphic epigenetic changes could indicate differential susceptibility to IVF-associated perturbations, which highlights the importance of sex-specific evaluation of adverse outcomes. Similarities between changes in mice and humans underscore the suitability of the mouse model in evaluating how IVF impacts the epigenetic landscape, which is valuable given limited access to human tissue and the ability to isolate specific interventions in mice.
Acute appendicitis following the COVID-19 vaccine
Authors: Oganesyan Ani , Schäfer Michal , Lesh Caitlyn 
Published: June 2022

Abstract
We report the case of a previously healthy 69-year-old female who developed appendicitis after receiving the third dose of the Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) vaccine; no other triggers were identified. We speculate that an association exists which may be mediated by colonic lymphoid hyperplasia, a condition that might be indicative of an enhanced immunological mucosal response to antigenic stimulation. As widespread vaccination coverage continues, it is crucial to monitor and accurately report the adverse reactions that may otherwise remain unidentified in vaccination trials. Therefore, we suggest that adults experiencing spontaneous, severe abdominal pain following COVID-19 vaccination may benefit from seeking emergent medical care. Likewise, providers should have a low threshold to consider and evaluate patients for appendicitis. If a true causal link is identified, the risk must also be deliberated in context with the millions of patients who have been safely vaccinated and the known morbidity and mortality from COVID-19 infection.
Utilization of Machine Learning Approaches to Predict Mortality in Pediatric Warzone Casualties
Authors: Lammers Daniel , Williams James , Conner Jeff , Francis Andrew , Prey Beau , Marenco Christopher , Morte Kaitlin , Horton John , Barlow Meade , Escobar Mauricio , Bingham Jason , Eckert Matthew 
Published: June 2022

ABSTRACT

Background
Identification of pediatric trauma patients at the highest risk for death may promote optimization of care. This becomes increasingly important in austere settings with constrained medical capabilities. This study aimed to develop and validate predictive models using supervised machine learning (ML) techniques to identify pediatric warzone trauma patients at the highest risk for mortality.

Methods
Supervised learning approaches using logistic regression (LR), support vector machine (SVM), neural network (NN), and random forest (RF) models were generated from the Department of Defense Trauma Registry, 2008-2016. Models were tested and compared to determine the optimal algorithm for mortality.

Results
A total of 2,007 patients (79% male, median age range 7-12 years old, 62.5% sustaining penetrating injury) met the inclusion criteria. Severe injury (Injury Severity Score &gt; 15) was noted in 32.4% of patients, while overall mortality was 7.13%. The RF and SVM models displayed recall values of .9507 and .9150, while LR and NN displayed values of .8912 and .8895, respectively. Random forest (RF) outperformed LR, SVM, and NN on receiver operating curve (ROC) analysis demonstrating an area under the ROC of .9752 versus .9252, .9383, and .8748, respectively.

Conclusion
Machine learning (ML) techniques may prove useful in identifying those at the highest risk for mortality within pediatric trauma patients from combat zones. Incorporation of advanced computational algorithms should be further explored to optimize and supplement the diagnostic and therapeutic decision-making process.