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Effects of Therapeutic Antibiotic Exposure on the Oropharyngeal and Fecal Microbiota in Infants With Cystic Fibrosis
No full textBackground: Systemic antibiotics can impact all microbes inhabiting patients, regardless of the intended target organism(s). We studied the simultaneous effects on respiratory and fecal microbiomes of β-lactam antibiotics administered for respiratory symptoms in infants with cystic fibrosis (IWCF).
Objective: To compare the magnitude and duration of intended (respiratory) and unintended (fecal) antimicrobial action by analyzing oropharyngeal (OP) and fecal microbiota in IWCF.
Design: Shotgun metagenomic sequencing and qPCR were performed on OP and fecal samples collected longitudinally from 14 IWCF (ages 1-17 months) during ("On Antibiotics") and after ("Off Antibiotics") β-lactam therapy, and from 5 IWCF (3-16 months) never treated with antibiotics.
Results: Total bacterial loads (TBL) for On Antibiotics samples were lower than for both Never (OP and fecal) and Off Antibiotics samples (fecal only). α-diversities (within-sample) for OP On Antibiotics samples were lower than for Never and Off Antibiotics samples but did not differ between fecal sample groups. β-diversity (between-sample) differed between all OP sample groups and between fecal On and Never Antibiotics and Off and Never antibiotics samples; however, fecal On and Off Antibiotics sample β-diversities did not differ. Patterns of change in antibiotic resistance gene abundances reflected shifts in microbial community composition.
Conclusions: β-lactam antibiotic exposure was followed by marked alterations in both OP and fecal microbiota. While microbiota appeared to rebound after treatment in both sample types, our results suggest that fecal microbiota recovered less than OP. The clinical consequences of these findings should be studied in IWCF and other populations frequently treated with antibiotics
Utilization of Cannabidiol in Post-Organ-Transplant Care
Full text linkCannabidiol (CBD) is one of the major phytochemical constituents of cannabis, Cannabis sativa, widely recognized for its therapeutic potential. While cannabis has been utilized for medicinal purposes since ancient times, its psychoactive and addictive properties led to its prohibition in 1937, with only the medical use being reauthorized in 1998. Unlike tetrahydrocannabinol (THC), CBD lacks psychoactive and addictive properties, yet the name that suggests its association with cannabis has significantly contributed to its public visibility. CBD exhibits diverse pharmacological properties, most notably anti-inflammatory effects. Additionally, it interacts with key drug-metabolizing enzyme families, including cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT), which mediate phase I and phase II metabolism, respectively. By binding to these enzymes, CBD can inhibit the metabolism of co-administered drugs, which can potentially enhance their toxicity or therapeutic effects. Mild to moderate adverse events associated with CBD use have been reported. Advances in chemical formulation techniques have recently enabled strategies to minimize these effects. This review provides an overview of CBD, covering its historical background, recent clinical trials, adverse event profiles, and interactions with molecular targets such as receptors, channels, and enzymes. We particularly emphasize the mechanisms underlying its anti-inflammatory effects and interaction with drugs relevant to organ transplantation. Finally, we explore recent progress in the chemical formulation of CBD in order to enhance its bioavailability, which will enable decreasing the dose to use and increase its safety and efficacy
Improving Fellow Research Study Design Skills and Confidence Through Gamification
Full text linkIntro:
During Pediatric Emergency Medicine fellowship fellows are required to gain understanding of the whole research process and author substantial scholarship. Despite this, few graduating fellows plan on a research career, and fellows often feel inadequately prepared for a research career upon graduation, reporting challenges of identifying research questions and designing feasible projects as major barriers to choosing a research career.
Purpose/Objective:
We aimed to improve trainee confidence and comfort with identifying research questions and research project design via an engaging, collaborative, table-top research game. We designed a team competition that utilized cards, dice, and play money to give trainees the freedom to explore and experiment with research design while considering the realistic constraints of study completion including funding, time, enrollment challenges, barriers to publication, and more.
Methods:
We performed a pilot of the research game with 8 pediatric emergency medicine fellows in years 1-3 of fellowship early in the academic year. The game took place during 2 hours of a weekly education session, with the assistance of several emergency medicine faculty with varying academic and research interests. Fellows were surveyed immediately before and immediately after the game session to assess comfort and confidence with various aspects of the research process.
Outcomes:
PEM fellows reported overall positive views of the research game. On a 5-point likert scale, 100% reported the game was very fun (4 or 5) and 75% the activity was highly valuable (4 or 5). When asked in which research competencies their comfort most improved, fellows reported “identifying a research question,” “performing a literature review,” and “designing a research study.” 100% recommended repeating the game with future PEM fellows.
Summary:
The pilot implementation of our novel research game demonstrated promise in improving learner comfort and agency with research design and implementation, which are areas identified in previous studies as significant barriers to fellows pursuing careers in research beyond graduation. Our goal is to incorporate this game into our fellow research curriculum to lessen those barriers, and increase the likelihood fellows will consider incorporating research into their careers after graduation. The game was universally regarded as a fun learning experience by participating fellows. While the game was piloted with PEM trainees, it would be easily implemented with a variety of learner groups in the future, including emergency medicine residents and emergency medicine fellows, with the hope of decreasing barriers to trainees considering research careers as faculty.
Our plan is to incorporate this game into our fellow research curriculum moving forward with the hope of decreasing barriers to trainees considering research careers as faculty
Perceived benefits and barriers to the use of long-acting injectable antiretroviral treatment among adolescents and young people living with HIV in Western Kenya: qualitative findings from the KuwaFree! LiveFree! Study
No full textIntroduction: Adolescents and young people living with HIV (AYPLHIV) face significant hurdles in adhering to daily oral antiretroviral therapy (ART). Long-acting (LA) ART, such as injectable cabotegravir and rilpivirine, may help overcome these hurdles. However, little is known about the perceived benefits and barriers to LA ART usage by AYPLHIV in resource-limited settings.
Methods: We conducted focus group discussions (FGDs) with four target groups of adolescents/youth, providers, policymakers, and other advocates in western Kenya from November 2021 to April 2022. The FGDs elicited participants' thoughts on LA ART implementation in Kenya, particularly the benefits and barriers of LA ART use amongst AYPLHIV. Our analysis combined both inductive and deductive approaches, beginning with open coding of the data, then organizing them in predetermined socio-ecological model (SEM) domains.
Results and discussion: We conducted a total of seven FGDs with 58 participants across four stakeholder groups: AYPLHIV (2 FGDs, n = 14), healthcare providers (2 FGDs, n = 19), health/youth advocates (2 FGDs, n = 16), and policymakers (1 FGD, n = 9). We identified several benefits, largely centered around the individual and interpersonal level, as well as barriers, largely centered around the health systems levels. Participants viewed LA ART as a welcome alternative to oral ART due to benefits like improved adherence, reduced pill burden, increased convenience, enhanced privacy, decreased stigma, lower risk of accidental disclosure, and convergence in using LA contraception. At the interpersonal level, LA ART was valued for furthering relationships, especially for AYPLHIV (e.g., dating). At the health systems level, LA ART expanded first-line treatment options. Conversely, barriers to health systems integration included conflicts with service models, increased clinic burden, supply chain issues, and waste disposal. Individual-level barriers included fears of injections, side effects, concerns about a new drug, and reduced effectiveness if mixing LA ART with oral ART.
Conclusions: The perceived benefits of LA ART for AYPLHIV, centering on individual and interpersonal levels of positive impacts, appear in tension with the anticipated barriers for health systems readiness in Kenya. While the prospect of offering LA ART is overwhelming positive, country programs will have to invest in health systems readiness before rolling out LA ART
Sex, racial/ethnic, and APOE‐ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging
No full textBackground:
There is growing recognition that white matter microstructural integrity is affected in Alzheimer’s disease. The goal of this study was to characterize sex, racial/ethnic, and apolipoprotein (APOE)‐ε4 allele differences in white matter integrity.
Methods:
This study included participants from ADNI, BLSA, ROS/MAP/MARS, and VMAP, all longitudinal cohorts of aging. This combined dataset included 6,837 imaging sessions from 2,619 participants age 50+ with diffusion MRI (dMRI) and demographic and clinical data (60% female, 31.4% APOE‐ε4 carriers, 78.9% White). dMRI was preprocessed using the PreQual pipeline. Free‐water (FW) correction was used to generate FW and FW‐corrected intracellular metrics including fractional anisotropy (FAFWcorr), mean diffusivity (MDFWcorr), axial diffusivity (AxDFWcorr), and radial diffusivity (RDFWcorr). Conventional and FW‐corrected metrics were harmonized using the Longitudinal ComBat package. Linear mixed‐effects models related sex, race/ethnicity, and APOE‐ε4 allele status to longitudinal diffusion metrics in 48 white matter tracts, adjusting for age at baseline, sex, education, race/ethnicity, APOE‐ε4 carrier status, cognitive status at baseline, and converter status. All models were corrected for multiple comparisons using the FDR approach.
Result:
Sex differences in white matter were most notable in projection tracts (Figure 1A) and were primarily in FW‐corrected metrics. Females had lower FAFWcorr and higher RDFWcorr, indicative of worse microstructure, but lower AxDFWcorr. This sex difference was most pronounced for FAFWcorr in the ventral premotor projection tract (p=1.53x10‐62). There were global differences in white matter integrity by race/ethnicity (Figure 1B). Non‐Hispanic White participants tended to have higher conventional FA, FAFWcorr and AxDFWcorr and lower RDFWcorr. There was no association between APOE‐ε4 status and white matter integrity and no significant sex x race/ethnicity, sex x APOE‐ε4, or race/ethnicity x APOE‐ε4 interactions for conventional or FW‐corrected metrics when corrected for multiple comparisons.
Conclusion:
There were striking sex and racial/ethnic (but not APOE‐ε4) differences in white matter tract integrity in a large cohort of aging adults. Female participants tended to have measures reflective of worse white matter integrity, and non‐Hispanic White participants tended to have measures reflective of greater integrity. Additional research exploring the etiology of these differences will be important to better understand disparities in Alzheimer’s disease
Spirometry Versus Forced Oscillation to Assess Lung Function Outcome at 5 Years of Age
No full textBackground: Spirometry is the gold standard for assessing airway function for clinical studies; however, obtaining high-quality data in young children remains challenging. Since the forced oscillation technique (FOT) requires less subject cooperations, there has been increasing interest in FOT, particularly in young children. We evaluated whether spirometry and FOT in young children provides comparable ability to detect a treatment effect.
Methods: We recently reported in a randomized controlled trial that vitamin C compared to placebo treatment of mothers who smoked during pregnancy (MSDP) results in the offspring having significantly higher forced expiratory flows (FEFs) at 5-years of age, as well as significantly less wheeze at 4-6 years of age. In these same offspring, we also measured respiratory impedance using FOT at 8-Hz impedance at 3, 4, and 5 years of age.
Results: Although spirometry demonstrated significantly increased FEFs in vitamin C compared to placebo-treatment group at 5 years of age (p < 0.001), we were not able to detect a similar treatment effect using FOT impedance.
Conclusions: It may be challenging to obtain technically successful spirometry in preschool children; however, FEFs may provide a better outcome than single-frequency FOT impedance to assess improvements in airway function in these young subjects
Genetic Testing Resources and Practice Patterns Among Pediatric Cardiomyopathy Programs
No full textThe use of genetic testing has enhanced the diagnostic accuracy of heritable genetic cardiomyopathies. However, it remains unclear how genetic information is interpreted and incorporated into clinical practice for children with cardiomyopathy. The primary aim of this study was to understand how clinical practice differs regarding sequence variant classifications amongst pediatric cardiologists who treat children with cardiomyopathy. A secondary aim was to understand the availability of genetic testing and counseling resources across participating pediatric cardiomyopathy programs. An electronic survey was distributed to pediatric heart failure, cardiomyopathy, or heart transplantation physicians between August and September 2022. A total of 106 individual providers from 68 unique centers responded to the survey. Resources for genetic testing and genetic counseling vary among large pediatric cardiomyopathy programs. A minority of centers reported having a geneticist (N = 16, 23.5%) or a genetic counselor (N = 21, 31%) on faculty within the division of pediatric cardiology. A total of 9 centers reported having both (13%). Few centers (N = 13, 19%) have a formal process in place to re-engage patients who were previously discharged from cardiology follow-up if variant reclassification would alter clinical management. Clinical practice patterns were uniform in response to pathogenic or likely pathogenic variants but were more variable for variants of uncertain significance. Efforts to better incorporate genetic expertise and resources into the clinical practice of pediatric cardiomyopathy may help to standardize the interpretation of genetic information and better inform clinical decision-making surrounding heritable cardiomyopathies
In Vitro Comparison of Direct Attachment Shape and Size on the Orthodontic Forces and Moments Generated by Thermoplastic Aligners During Expansion
No full textObjective: To evaluate the effects of varying direct attachment shape and size on the forces and moments generated by thermoplastic aligners during simulated expansion.
Materials and methods: An in vitro orthodontic force tester (OFT) was used to measure the forces and moments from a typodont where the buccal teeth were translated lingually 0.2 mm to simulate expansion. Hemi-ellipsoid and rectangular attachments with either 0.5 or 1.0 mm thickness were added on upper right first premolar (UR4), second premolar (UR5) and first molar (UR6). Analysis of variance (ANOVA) was used to determine two-way interactions among the factors on the outcomes.
Results: The interactions between group and tooth were significant for all outcomes (p < 0.001). The greatest buccal forces (Fy) were observed with 1 mm rectangular attachment on the UR4 (0.78 ± 0.29 N), with 1 mm hemi-ellipsoid attachment on UR5 (0.28 ± 0.21 N) and with 0.5 mm rectangular attachment on UR6 (1.71 ± 0.18 N). The greatest buccolingual moments (Mx) were obtained with 1 mm rectangular attachment on UR4 (5.61 ± 1.43 Nmm), without any attachments on UR5 (3.33 ± 1.73 Nmm) and with 1 mm hemi-ellipsoid attachment on UR6 (4.18 ± 4.31).
Conclusion: Direct attachment shape and size had a significant effect on the orthodontic forces and moments generated by thermoplastic aligners during simulated expansion. Although loads varied significantly by tooth morphology and its location in the arch, best forces and moments for expansion were obtained with 1 mm rectangular attachments on UR4s, 1 mm hemi-ellipsoid attachments on UR5s and 0.5 mm rectangular attachments on UR6s
Demystifying the black box: A survey on explainable artificial intelligence (XAI) in bioinformatics
Full text linkThe widespread adoption of Artificial Intelligence (AI) and machine learning (ML) tools across various domains has showcased their remarkable capabilities and performance. Black-box AI models raise concerns about decision transparency and user confidence. Therefore, explainable AI (XAI) and explainability techniques have rapidly emerged in recent years. This paper aims to review existing works on explainability techniques in bioinformatics, with a particular focus on omics and imaging. We seek to analyze the growing demand for XAI in bioinformatics, identify current XAI approaches, and highlight their limitations. Our survey emphasizes the specific needs of both bioinformatics applications and users when developing XAI methods and we particularly focus on omics and imaging data. Our analysis reveals a significant demand for XAI in bioinformatics, driven by the need for transparency and user confidence in decision-making processes. At the end of the survey, we provided practical guidelines for system developers
Interaction of genetic variants and methylation in transcript-level expression regulation in Alzheimer's disease by multi-omics data analysis
No full textBackground: Alzheimer's disease (AD) presents a significant public health problem and major cause of dementia. Not only genetic but epigenetic factors contribute to complex and heterogeneous molecular mechanisms underlying AD risk; in particular, single nucleotide polymorphisms (SNPs) and DNA methylation can lead to dysregulation of gene expression in the AD brain. Each of these regulators has been independently studied well in AD progression, however, their interactive roles, particularly when they are located differently, still remains unclear. Here, we aimed to explore the interplay between SNPs and DNA methylation in regulating transcript expression levels in the AD brain through an integrative analysis of whole-genome sequencing, RNA-seq, and methylation data measured from the dorsolateral prefrontal cortex.
Results: We identified 179 SNP-methylation combination pairs that showed statistically significant interactions associated with the expression of 67 transcripts (63 unique genes), enriched in functional pathways, including immune-related and post-synaptic assembly pathways. Particularly, a number of HLA family genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB5, HLA-DPA1, HLA-K, HLA-DQB1, and HLA-DMA) were observed as having expression changes associated with the interplay.
Conclusions: Our findings especially implicate immune-related pathways as targets of these regulatory interactions. SNP-methylation interactions may thus contribute to the molecular complexity underlying immune-related pathogenies in AD patients. Our study provides a new molecular knowledge in the context of the interplay between genetic and epigenetic regulations, in that it concerns transcript expression status in AD