Title: Microbes in Lungs Could Affect COVID-19 Outcomes
Category: Health News
Created: 8/24/2020 12:00:00 AM
Last Editorial Review: 8/25/2020 12:00:00 AM

Title: U.S. Kidney Transplant Outcomes Are Improving
Category: Health News
Created: 8/24/2021 12:00:00 AM
Last Editorial Review: 8/24/2021 12:00:00 AM

Title: AHA News: Obstacles Didn't Stop This Heart Defect Survivor From Competing on 'American Ninja Warrior
Category: Health News
Created: 8/12/2022 12:00:00 AM
Last Editorial Review: 8/15/2022 12:00:00 AM

Title: Common Diabetes Drug May Contain Traces of Carcinogen
Category: Health News
Created: 8/12/2022 12:00:00 AM
Last Editorial Review: 8/12/2022 12:00:00 AM

Title: LSD Is Making a Comeback Among Young Americans
Category: Health News
Created: 8/23/2022 12:00:00 AM
Last Editorial Review: 8/23/2022 12:00:00 AM

Title: 'News Addiction' Is Common and Can Harm Your Mental Health
Category: Health News
Created: 8/24/2022 12:00:00 AM
Last Editorial Review: 8/25/2022 12:00:00 AM

Title: 12 Best Compression Leggings in 2022
Category: Health and Living
Created: 8/16/2022 12:00:00 AM
Last Editorial Review: 8/16/2022 12:00:00 AM

Title: Heat Waves That Threaten Lives Will Be Common by 2100
Category: Health News
Created: 8/26/2022 12:00:00 AM
Last Editorial Review: 8/26/2022 12:00:00 AM

Title: Changes in Menstrual Cycle Can Come After COVID Shot
Category: Health News
Created: 7/18/2022 12:00:00 AM
Last Editorial Review: 7/18/2022 12:00:00 AM

Title: Scotland Becomes 1st Country to Provide Free Period Products
Category: Health News
Created: 8/15/2022 12:00:00 AM
Last Editorial Review: 8/16/2022 12:00:00 AM

Title: Is Syphilis Completely Curable?
Category: Diseases and Conditions
Created: 7/15/2022 12:00:00 AM
Last Editorial Review: 7/15/2022 12:00:00 AM

Title: When Hospital Patient & Doctor Speak Same Language, Outcomes Improve
Category: Health News
Created: 7/11/2022 12:00:00 AM
Last Editorial Review: 7/11/2022 12:00:00 AM

Title: The 8 Most Common Food Allergies
Category: Health and Living
Created: 7/13/2022 12:00:00 AM
Last Editorial Review: 7/13/2022 12:00:00 AM

Background

People living with serious respiratory illness experience a high burden of symptoms. This review aimed to determine whether multicomponent services reduce symptoms in people with serious illness related to respiratory disease.

PWAS (proteome-wide association study) is an innovative genetic association approach that complements widely used methods like GWAS (genome-wide association study). The PWAS approach involves consecutive phases. Initially, machine learning modeling and probabilistic considerations quantify the impact of genetic variants on protein-coding genes’ biochemical functions. Secondly, for each individual, aggregating the variants per gene determines a gene-damaging score. Finally, standard statistical tests are activated in the case-control setting to yield statistically significant genes per phenotype. The PWAS Hub offers a user-friendly interface for an in-depth exploration of gene–disease associations from the UK Biobank (UKB). Results from PWAS cover 99 common diseases and conditions, each with over 10,000 diagnosed individuals per phenotype. Users can explore genes associated with these diseases, with separate analyses conducted for males and females. For each phenotype, the analyses account for sex-based genetic effects, inheritance modes (dominant and recessive), and the pleiotropic nature of associated genes. The PWAS Hub showcases its usefulness for asthma by navigating through proteomic-genetic analyses. Inspecting PWAS asthma-listed genes (a total of 27) provide insights into the underlying cellular and molecular mechanisms. Comparison of PWAS-statistically significant genes for common diseases to the Open Targets benchmark shows partial but significant overlap in gene associations for most phenotypes. Graphical tools facilitate comparing genetic effects between PWAS and coding GWAS results, aiding in understanding the sex-specific genetic impact on common diseases. This adaptable platform is attractive to clinicians, researchers, and individuals interested in delving into gene–disease associations and sex-specific genetic effects.

High-throughput sequencing (HTS) technologies have been instrumental in investigating biological questions at the bulk and single-cell levels. Comparative analysis of two HTS data sets often relies on testing the statistical significance for the difference of two negative binomial distributions (DOTNB). Although negative binomial distributions are well studied, the theoretical results for DOTNB remain largely unexplored. Here, we derive basic analytical results for DOTNB and examine its asymptotic properties. As a state-of-the-art application of DOTNB, we introduce DEGage, a computational method for detecting differentially expressed genes (DEGs) in scRNA-seq data. DEGage calculates the mean of the sample-wise differences of gene expression levels as the test statistic and determines significant differential expression by computing the P-value with DOTNB. Extensive validation using simulated and real scRNA-seq data sets demonstrates that DEGage outperforms five popular DEG analysis tools: DEGseq2, DEsingle, edgeR, Monocle3, and scDD. DEGage is robust against high dropout levels and exhibits superior sensitivity when applied to balanced and imbalanced data sets, even with small sample sizes. We utilize DEGage to analyze prostate cancer scRNA-seq data sets and identify marker genes for 17 cell types. Furthermore, we apply DEGage to scRNA-seq data sets of mouse neurons with and without fear memory and reveal eight potential memory-related genes overlooked in previous analyses. The theoretical results and supporting software for DOTNB can be widely applied to comparative analyses of dispersed count data in HTS and broad research questions.

Mapping transcriptomic variations using either short- or long-read RNA sequencing is a staple of genomic research. Long reads are able to capture entire isoforms and overcome repetitive regions, whereas short reads still provide improved coverage and error rates. Yet, open questions remain, such as how to quantitatively compare the technologies, can we combine them, and what is the benefit of such a combined view? We tackle these questions by first creating a pipeline to assess matched long- and short-read data using a variety of transcriptome statistics. We find that across data sets, algorithms, and technologies, matched short-read data detects ~30% more splice junctions, such that ~10%–30% of the splice junctions included at ≥20% by short reads are missed by long reads. In contrast, long reads detect many more intron-retention events and can detect full isoforms, pointing to the benefit of combining the technologies. We introduce MAJIQ-L, an extension of the MAJIQ software, to enable a unified view of transcriptome variations from both technologies and demonstrate its benefits. Our software can be used to assess any future long-read technology or algorithm and can be combined with short-read data for improved transcriptome analysis.

Asgard archaea are of great interest as the progenitors of Eukaryotes, but little is known about the mobile genetic elements (MGEs) that may shape their ongoing evolution. Here, we describe MGEs that replicate in Atabeyarchaeia, a wetland Asgard archaea lineage represented by two complete genomes. We used soil depth–resolved population metagenomic data sets to track 18 MGEs for which genome structures were defined and precise chromosome integration sites could be identified for confident host linkage. Additionally, we identified a complete 20.67 kbp circular plasmid and two family-level groups of viruses linked to Atabeyarchaeia, via CRISPR spacer targeting. Closely related 40 kbp viruses possess a hypervariable genomic region encoding combinations of specific genes for small cysteine-rich proteins structurally similar to restriction-homing endonucleases. One 10.9 kbp integrative conjugative element (ICE) integrates genomically into the Atabeyarchaeum deiterrae-1 chromosome and has a 2.5 kbp circularizable element integrated within it. The 10.9 kbp ICE encodes an expressed Type IIG restriction-modification system with a sequence specificity matching an active methylation motif identified by Pacific Biosciences (PacBio) high-accuracy long-read (HiFi) metagenomic sequencing. Restriction-modification of Atabeyarchaeia differs from that of another coexisting Asgard archaea, Freyarchaeia, which has few identified MGEs but possesses diverse defense mechanisms, including DISARM and Hachiman, not found in Atabeyarchaeia. Overall, defense systems and methylation mechanisms of Asgard archaea likely modulate their interactions with MGEs, and integration/excision and copy number variation of MGEs in turn enable host genetic versatility.

Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is owing to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.

The human major histocompatibility complex (MHC) is a ~4 Mb genomic segment on Chromosome 6 that plays a pivotal role in the immune response. Despite its importance in various traits and diseases, its complex nature makes it challenging to accurately characterize on a routine basis. We present a novel approach allowing targeted sequencing and de novo haplotypic assembly of the MHC region in heterozygous samples, using long-read sequencing technologies. Our approach is validated using two reference samples, two family trios, and an African-American sample. We achieved excellent coverage (96.6%–99.9% with at least 30x depth) and high accuracy (99.89%–99.99%) for the different haplotypes. This methodology offers a reliable and cost-effective method for sequencing and fully characterizing the MHC without the need for whole-genome sequencing, facilitating broader studies on this important genomic segment and having significant implications in immunology, genetics, and medicine.

We propose a paper that provides education on commonly used long-acting injectable antipsychotics (LAIs) to improve primary care based mental health interventions in patients with severe mental illnesses (SMIs) such as schizophrenia, schizoaffective disorder, and bipolar disorders. With the expanding interface of primary care and psychiatry across all healthcare settings, it has become increasingly important for primary care clinicians to have a broader understanding of common psychiatric treatments, including LAIs. Long-acting injectable antipsychotics have been shown to be helpful in significantly improving treatment adherence, preventing disease progression, improving treatment response, decreasing readmission rates, and reducing social impairment. We discuss evidence-based indications and guidelines for use of long-acting injectable antipsychotics. We provide an overview of the treatment of SMI with LAIs, mainly focusing on the most commonly used long-acting injectable antipsychotics, advantages and disadvantages of each, along with outlining important clinical pearls for ease of practical application. Equipped with increased familiarity and understanding of these essential therapies, primary care clinicians can better facilitate early engagement with psychiatric care, promote more widespread use, and thus significantly improve the wellbeing and quality of life of patients with severe mental illness.

Background:

Discharge communication between hospitalists and primary care clinicians is essential to improve care coordination, minimize adverse events, and decrease unplanned health services use. Health-related social needs are key drivers of health, and hospitalists and primary care clinicians value communicating social needs at discharge.

Purpose:

Colorectal cancer (CRC) screening is recommended starting at age 45, but there has been little research on strategies to promote screening among patients younger than 50. This study assessed the effect of a multicomponent intervention on screening completion in this age group.

BACKGROUND:Opioids are known to cause respiratory depression, aspiration, and to suppress the immune system. This study aimed to investigate the relationship between short- and long-term opioid use and the occurrence and clinical outcomes of pneumonia in South Korea.METHODS:The data for this population-based retrospective cohort analysis were obtained from the South Korean National Health Insurance Service. The opioid user group consisted of those prescribed opioids in 2016, while the non-user group, who did not receive opioid prescriptions that year, was selected using a 1:1 stratified random sampling method. The opioid users were categorized into short-term (1–89 d) and long-term (≥90 d) users. The primary end point was pneumonia incidence from January 1, 2017–December 31, 2021, with secondary end points including pneumonia-related hospitalizations and mortality rates during the study period.RESULTS:In total, 4,556,606 adults were enrolled (opioid group, 2,070,039). Opioid users had a 3% higher risk of pneumonia and an 11% higher risk of pneumonia requiring hospitalization compared to non-users. Short-term users had a 3% higher risk of pneumonia, and long-term users had a 4% higher risk compared to non-users (P < .001). Additionally, short-term users had an 8% higher risk of hospital-treated pneumonia, and long-term users had a 17% higher risk compared to non-users (P < .001).CONCLUSIONS:Both short- and long-term opioid prescriptions were associated with higher incidences of pneumonia and hospital-treated pneumonia. In addition, long-term opioid prescriptions were linked to higher mortality rates due to pneumonia.

BACKGROUND:The use of prone position (PP) has been widespread during the COVID-19 pandemic. Whereas it has demonstrated benefits, including improved oxygenation and lung aeration, the factors influencing the response in terms of gas exchange to PP remain unclear. In particular, the association between baseline quantitative computed tomography (CT) scan results and gas exchange response to PP in invasively ventilated subjects with COVID-19 ARDS is unknown. The present study aimed to compare baseline quantitative CT results between subjects responding to PP in terms of oxygenation or CO2 clearance and those who did not.METHODS:This was a single-center, retrospective observational study including critically ill, invasively ventilated subjects with COVID-19–related ARDS admitted to the ICUs of Niguarda Hospital between March 2020–November 2021. Blood gas samples were collected before and after PP. Subjects in whom the PaO2/FIO2 increase was ≥ 20 mm Hg after PP were defined as oxygen responders. CO2 responders were defined when the ventilatory ratio (VR) decreased during PP. Automated quantitative CT analyses were performed to obtain tissue mass and density of the lungs.RESULTS:One hundred twenty-five subjects were enrolled, of which 116 (93%) were O2 responders and 51 (41%) CO2 responders. No difference in quantitative CT characteristics and oxygen were observed between responders and non-responders (tissue mass 1,532 ± 396 g vs 1,654 ± 304 g, P = .28; density −544 ± 109 HU vs −562 ± 58 HU P = .42). Similar findings were observed when dividing the population according to CO2 response (tissue mass 1,551 ± 412 g vs 1,534 ± 377 g, P = .89; density −545 ± 123 HU vs −546 ± 94 HU, P = .99).CONCLUSIONS:Most subjects with COVID-19–related ARDS improved their oxygenation at the first pronation cycle. The study suggests that baseline quantitative CT scan data were not associated with the response to PP in oxygenation or CO2 in mechanically ventilated subjects with COVID-19–related ARDS.

BACKGROUND:Training in mechanical ventilation is a key goal in critical care fellowship education. Web-based simulators offer a cost-effective and readily available alternative to traditional on-site simulators. However, it is unclear how effective they are as teaching tools. In this study, we evaluated the test scores of fellows who underwent mechanical ventilation training by using a web-based simulator compared with fellows who used an on-site simulator during a mechanical ventilation course.METHODS:This was a nonrandomized controlled trial conducted as part of a mechanical ventilation course that involved 70 first-year critical care fellows. The course was identical except for the simulation technology used. One group of instructors used a traditional on-site simulator, the ASL 5000 Lung Solution (n = 39). The second group was instructed in using a web-based simulator, VentSim (n = 31). Each fellow completed a pre-course test and a post-course test by using a validated, case-based ventilator waveform examination that consisted of 5 questions with a total possible score of 100. The primary outcome was a comparison of the mean scores on the posttest between the 2 groups. The study was designed as a non-inferiority trial with a predetermined margin of 10 points.RESULTS:There was no significant difference in the mean ± SD pretest scores between the web-based and the on-site groups (21.1 ± 12.6 and 26.9 ± 13.6 respectively; P = .11). The mean ± SD posttest scores were 45.6 ± 25.0 for the web-based simulator and 43.4 ± 16.5 for on-site simulator (mean difference 2.2; one-sided 95% CI –7.0 to ∞; Pnon-inferiority = .02 [non-inferiority confirmed]). Changes in mean ± SD scores (posttest – pretest) were 25.9 ± 20.9 for the web-based simulator and 16.5 ± 15.9 for the on-site simulator (mean difference 9.4, one-sided 95% CI 0.9 to ∞; Pnon-inferiority < .001 [non-inferiority confirmed]).CONCLUSIONS:In the education of first-year critical care fellows on mechanical ventilation waveform analysis, a web-based mechanical ventilation simulator was non-inferior to a traditional on-site mechanical ventilation simulator.

Purpose The posterior superior alveolar (PSA) block injection is one of many techniques used to provide profound anesthesia for invasive dental procedures. This technique has a high success rate but is not without complication risks. The purpose of this study was to determine if pulpal anesthesia of the maxillary second molar could be achieved using a reduced needle depth of 10mm or 5mm compared to the traditional needle depth of 16mm.Methods Sixty participants were asked to participate in three sessions. Each session started with a pre neural response test, followed by one randomized needle depth PSA injection, and ending with a post neural response test. The neural response test consisted of two parts, a cold refrigerant and a dental probe, on the buccal and interproximal surface of the maxillary second molar. After receiving a positive neural response, each participant received a posterior superior alveolar block injection using a short (21mm), 27-gauge dental needle with a randomized needle penetration depth of 16mm, 10mm, or 5mm. A post neural response test consisting of the same two parts as the pre-test was conducted on the maxillary second molar to evaluate for profound anesthesia.Results Positive neural responses were obtained from 100% of the participants (n=167) during the pre-tests. Study results demonstrated an 85% success rate at the traditional 16mm needle depth and a 93% and 92% success rates for the reduced needle depths of 10mm and 5mm, respectively. Pulpal anesthesia of the maxillary second molar had been achieved at all three needle depths with no statistically significant difference in the rate of success. Furthermore, there were no adverse events observed.Conclusion The reduced needle depth technique showed promise in achieving desired results of pulpal anesthesia with a reduced risk for complications associated with the PSA block injection. Additional studies are recommended to achieve evidence-based support for this reduced needle depth technique.

Visible particle is an important issue in the biopharmaceutical industry, and it may occur across all the stages in the life cycle of biologics. Upon the occurrence of visible particles, it is often necessary to conduct chemical identification and root cause analysis to safeguard the safety and efficacy of the biotherapeutic products. In this article, we present a number of typical particles and relevant root cause analysis in the categories of extrinsic, intrinsic, and inherent particles that are commonly encountered in the biopharma industry. In particular, the optical images of particles obtained both in situ and after isolation are provided, along with spectral and elemental information. The particle identification was carried out with multiple microscopic and microspectroscopic techniques, including stereo optical microscopy, Fourier-transform infrared microscopy, confocal Raman microscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy. Both commercial and in-house spectral databases were used for comparison and identification. In addition to particle identification, we placed significant efforts on the root cause analysis of the addressed particles with the intention to provide a relatively whole picture of the particle-related issues and practical references to particle mitigation for our peers in the biopharmaceutical industry.

The analysis of extractables and leachables and subsequent risk assessment is an important aspect of the determination of biocompatibility for many medical devices. Leachable chemicals have the potential to pose a toxicological risk to patients, and therefore it is required that they be adequately characterized and assessed for potential safety concerns. One important consideration in the assessment of leachables is the choice of a suitable simulating solvent intended to replicate the use condition for the device and its biological environment. This aspect of study design is especially difficult for blood-contacting medical devices due to the complexity of simulating the biological matrix. This publication reports a comparison of the extracting power of different binary solvent mixtures and saline in comparison with whole blood for a bloodline tubing set connected to a hemodialyzer. Ten different known extractables, spanning a range of physicochemical properties and molecular weights, were quantified. The results indicated that for low-molecular-weight analytes, a suitable exaggeration for whole blood can be obtained using a low-concentration ethanol/water mixture (20%), and in general, extracted quantity increases with the concentration of alcohol cosolvent. For polyvinylpyrrolidone, the opposite trend was observed, as solubility of the polymer was found to decrease with increasing alcohol concentration, resulting in lower extracted quantities at high alcohol concentrations. Analysis of ethanol/water concentrations in the extract solutions post extraction indicated no change in solvent composition.

During B-cell development, cells progress through multiple developmental stages, with the pro-B-cell stage defining commitment to the B-cell lineage. YY1 is a ubiquitous transcription factor that is capable of both activation and repression functions. We found here that knockout of YY1 at the pro-B-cell stage eliminates B lineage commitment. YY1 knockout pro-B cells can generate T lineage cells in vitro using the OP9-DL4 feeder system and in vivo after injection into sublethally irradiated Rag1^–/– mice. These T lineage-like cells lose their B lineage transcript profile and gain a T-cell lineage profile. Single-cell RNA-seq experiments showed that as YY1 knockout pro-B cells transition into T lineage cells in vitro, various cell clusters adopt transcript profiles representing a multiplicity of hematopoietic lineages, indicating unusual lineage plasticity. In addition, YY1 KO pro-B cells in vivo can give rise to other hematopoietic lineages in vivo. Evaluation of RNA-seq, scRNA-seq, ChIP-seq, and scATAC-seq data indicates that YY1 controls numerous chromatin-modifying proteins leading to increased accessibility of alternative lineage genes in YY1 knockout pro-B cells. Given the ubiquitous nature of YY1 and its dual activation and repression functions, YY1 may regulate commitment in multiple cell lineages.

Animal germline development and fertility rely on paralogs of general transcription factors that recruit RNA polymerase II to ensure cell type-specific gene expression. It remains unclear whether gene expression processes downstream from such paralog-based transcription is distinct from that of canonical RNA polymerase II genes. In Drosophila, the testis-specific TBP-associated factors (tTAFs) activate over a thousand spermatocyte-specific gene promoters to enable meiosis and germ cell differentiation. Here, we show that efficient termination of tTAF-activated transcription relies on testis-specific paralogs of canonical polymerase-associated factor 1 complex (PAF1C) proteins, which form a testis-specific PAF1C (tPAF). Consequently, tPAF mutants show aberrant expression of hundreds of downstream genes due to read-in transcription. Furthermore, tPAF facilitates expression of Y-linked male fertility factor genes and thus serves to maintain spermatocyte-specific gene expression. Consistently, tPAF is required for the segregation of meiotic chromosomes and male fertility. Supported by comparative in vivo protein interaction assays, we provide a mechanistic model for the functional divergence of tPAF and the PAF1C and identify transcription termination as a developmentally regulated process required for germline-specific gene expression.

Solid tumors that arise in the body interact with neurons, which influences cancer progression and treatment response. Here, we discuss key questions in the field, including defining the nature of interactions between tumors and neural circuits and defining how neural signals shape the tumor microenvironment. This information will allow us to optimally target neural signaling to improve outcomes for cancer patients.

SEquence Evaluation through k-mer Representation (SEEKR) is a method of sequence comparison that uses sequence substrings called k-mers to quantify the nonlinear similarity between nucleic acid species. We describe the development of new functions within SEEKR that enable end-users to estimate P-values that ascribe statistical significance to SEEKR-derived similarities, as well as visualize different aspects of k-mer similarity. We apply the new functions to identify chromatin-enriched lncRNAs that contain XIST-like sequence features, and we demonstrate the utility of applying SEEKR on lncRNA fragments to identify potential RNA-protein interaction domains. We also highlight ways in which SEEKR can be applied to augment studies of lncRNA conservation, and we outline the best practice of visualizing RNA-seq read density to evaluate support for lncRNA annotations before their in-depth study in cell types of interest.

Introduction

Exacerbation of COPD complicated by respiratory acidaemia is the commonest indication for noninvasive ventilation (NIV). The NIV outcomes (NIVO) score offers the best estimate of survival for those ventilated. Unfortunately, two-thirds of cases of COPD are unrecognised, and patients may present without COPD having been confirmed by spirometry.

Background

Computer-aided detection (CAD) systems hold promise for improving tuberculosis (TB) detection on digital chest radiographs. However, data on their performance in exclusively paediatric populations are scarce.

Background

Halm's clinical stability criteria have long guided antibiotic treatment and hospital discharge decisions for patients hospitalised with community-acquired pneumonia (CAP). Originally introduced in 1998, these criteria were established based on a relatively small and select patient population. Consequently, our study aims to reassess their applicability in the management of CAP in a contemporary real-world setting.

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450’s metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug–processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes.

Organic anion transporting polypeptides (OATP, gene symbol SLCO) are well-recognized key determinants for the absorption, distribution, and excretion of a wide spectrum of endogenous and exogenous compounds including many antineoplastic agents. It was therefore proposed as a potential drug target for cancer therapy. In our previous study, it was found that low-dose X-ray and carbon ion irradiation both upregulated the expression of OATP family member OATP1A2 and in turn, led to a more dramatic killing effect when cancer cells were cotreated with antitumor drugs such as methotrexate. In the present study, the underlying mechanism of the phenomenon was explored in breast cancer cell line MCF-7. It was found that the nonreceptor tyrosine kinase v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1 (YES-1) was temporally coordinated with the change of OATP1A2 after irradiation. The overexpression of YES-1 significantly increased OATP1A2 both at the mRNA and protein level. The signal transducer and activator of transcription 3 (STAT3) pathway is likely the downstream target of YES-1 because phosphorylation and nuclear accumulation of STAT3 were both enhanced after overexpressing YES-1 in MCF-7 cells. Further investigation revealed that there are two possible binding sites of STAT3 localized at the upstream sequence of SLCO1A2, the encoding gene of OATP1A2. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis suggested that these two sites bound to STAT3 specifically and the overexpression of YES-1 significantly increased the association of the transcription factor with the putative binding sites. Finally, inhibition or knockdown of YES-1 attenuated the induction effect of radiation on the expression of OATP1A2.

The CYP3A7 enzyme accounts for ~50% of the total cytochrome P450 (P450) content in fetal and neonatal livers and is the predominant P450 involved in neonatal xenobiotic metabolism. Additionally, it is a key player in healthy birth outcomes through the oxidation of dehydroepiandrosterone (DHEA) and DHEA-sulfate. The amount of the other hepatic CYP3A isoforms, CYP3A4 and CYP3A5, expressed in neonates is low but highly variable, and therefore the activity of individual CYP3A isoforms is difficult to differentiate due to their functional similarities. Consequently, a better understanding of the contribution of CYP3A7 to drug metabolism is essential to identify the risk that drugs may pose to neonates and developing infants. To distinguish CYP3A7 activity from CYP3A4/5, we sought to further characterize the selectivity of the specific CYP3A inhibitors CYP3cide, clobetasol, and azamulin. We used three substrate probes, dibenzylfluorescein, luciferin-PPXE, and midazolam, to determine the IC₅₀ and metabolism-dependent inhibition (MDI) properties of the CYP3A inhibitors. Probe selection had a significant effect on the IC₅₀ values and P450 inactivation across all inhibitory compounds and enzymes. CYP3cide and azamulin were both identified as MDIs and were most specific for CYP3A4. Contrary to previous reports, we found that clobetasol propionate (CP) was not an MDI of CYP3A5 but was more selective for CYP3A5 over CYP3A4/7. We further investigated CYP3cide and CP’s ability to differentiate CYP3A7 activity in an equal mixture of recombinant CYP3A4, CYP3A5, and CYP3A7, and our results provide confidence of CYP3cide’s and CP’s ability to distinguish CYP3A7 activity in the presence of the other CYP3A isoforms.

The precision medicine initiative has driven a substantial change in the way scientists and health care practitioners think about diagnosing and treating disease. While it has long been recognized that drug response is determined by the intersection of genetic, environmental, and disease factors, improvements in technology have afforded precision medicine guided dosing of drugs to improve efficacy and reduce toxicity. Pharmacometabolomics aims to evaluate small molecule metabolites in plasma and/or urine to help evaluate mechanisms that predict and/or reflect drug efficacy and toxicity. In this mini review, we provide an overview of pharmacometabolomic approaches and methodologies. Relevant examples where metabolomic techniques have been used to better understand drug efficacy and toxicity in major depressive disorder and cancer chemotherapy are discussed. In addition, the utility of metabolomics in drug development and understanding drug metabolism, transport, and pharmacokinetics is reviewed. Pharmacometabolomic approaches can help describe factors mediating drug disposition, efficacy, and toxicity. While important advancements in this area have been made, there remain several challenges that must be overcome before this approach can be fully implemented into clinical drug therapy.

ABSTRACTIntroduction:Family Planning 2020 (FP2020) was established in 2012 with the goal of expanding contraceptive access. By 2020, 46 countries had made commitments to FP2020. A sustained focus on adolescents and youth (AY) began in 2016. During the commitment formulation process, substantial support was offered to countries to develop AY commitments based on sound data, research evidence, and programmatic experience. This study assesses how country commitments under FP2020 and FP2030 have evolved over time with respect to improving attention to and focus on the needs of adolescents and youth sexual and reproductive health (AYSRH).Methods:We analyzed the content of FP2020 and FP2030 country commitments focusing on AY (aged 10–24 years) using a scoring guideline we developed to measure the AY commitments in terms of completeness, clarity, and quality.Results:This analysis shows that FP2030 commitments better articulate strategies and activities to reach AY with contraceptive information and services when compared to FP2020 commitments.Conclusion:FP2030 commitments are stronger in some areas on AYSRH, such as commitment to establish national or local policies, strategies, and guidance for AY programming, specifying the target audience of the AY commitment, and partnering with AY or youth-led organizations in commitments. However, more work remains to be done by countries to dedicate a budget for achieving AY objectives, including measurable targets for monitoring progress, identifying and addressing the root causes that impact AY access to and use of contraception, including child marriage and gender-based violence, and reducing financial barriers to access contraception.

ABSTRACTIntroduction:Health risks associated with short interpregnancy intervals, coupled with women’s desires to avoid pregnancy following childbirth, underscore the need for effective postpartum family planning programs. The antenatal period provides an opportunity to intervene; however, evidence is limited on the effectiveness of interventions aimed at reaching women in the antenatal period to increase voluntary postpartum family planning in low- and middle-income countries (LMICs). This systematic review aimed to identify and describe interventions in LMICs that attempted to increase postpartum contraceptive use via contacts with pregnant women in the antenatal period.Methods:Studies published from January 2012 to July 2022 were considered if they were conducted in LMICs, evaluated an intervention delivered during the antenatal period, were designed to affect postpartum contraceptive use, were experimental or quasi-experimental, and were published in French or English. The main outcome of interest was postpartum contraceptive use within 1 year after birth, defined as the use of any method of contraception at the time of data collection. We searched EMBASE, Global Health, and Medline and manually searched the reference lists from studies included in the full-text screening.Results:We double-screened 771 records and included 34 reports on 31 unique interventions in the review. Twenty-three studies were published from 2018 on, with 21 studies conducted in sub-Saharan Africa. Approximately half of the study designs (n=16) were randomized controlled trials, and half (n=15) were quasi-experimental. Interventions were heterogeneous. Among the 24 studies that reported on the main outcome of interest, 18 reported a positive intervention effect, with intervention recipients having greater contraceptive use in the first year postpartum.Conclusion:While the studies in this systematic review were heterogeneous, the findings suggest that interventions that included a multifaceted package of initiatives appeared to be most likely to have a positive effect.

The National Center for Complementary and Integrative Health (NCCIH), which is part of the US National Institutes of Health (NIH), has a broad interest in studying the biologic activities of natural products, especially those for which compelling evidence from preclinical research suggests biologic activities that may be beneficial to health or have a potential role in disease treatment, as well as products used extensively by the American public. As of 2023, use of cannabis for medical purposes is legal in 38 states and Washington, D.C. Such use continues to climb generally without sufficient knowledge regarding risks and benefits. In keeping with NCCIH’s natural product research priorities and recognizing this gap in knowledge, NCCIH formally launched a research program in 2019 to expand research on the possible benefits for pain management of certain substances found in cannabis: minor cannabinoids and terpenes. This Viewpoint provides additional details and the rationale for this research priority at NCCIH. In addition, NCCIH’s efforts and initiatives to facilitate and coordinate an NIH research agenda focused on cannabis and cannabinoid research are described.

Cannabis and its products have been used for centuries for both medicinal and recreational purposes. The recent widespread legalization of cannabis has vastly expanded its use in the United States across all demographics except for adolescents. Meanwhile, decades of research have advanced our knowledge of cannabis pharmacology and particularly of the endocannabinoid system with which the components of cannabis interact. This research has revealed multiple targets and approaches for manipulating the system for therapeutic use and to ameliorate cannabis toxicity or cannabis use disorder. Research has also led to new questions that underscore the potential risks of its widespread use, particularly the enduring consequences of exposure during critical windows of brain development or for consumption of large daily doses of cannabis with high content ⁹-tetrahydrocannabinol. This article highlights current neuroscience research on cannabis that has shed light on therapeutic opportunities and potential adverse consequences of misuse and points to gaps in knowledge that can guide future research.

The phase 3 VISION trial demonstrated that [¹⁷⁷Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]–positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor–signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [¹⁷⁷Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [¹⁷⁷Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [¹⁷⁷Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients.