Title: Being Social May Be Key to 'Sense of Purpose' as You Age
Category: Health News
Created: 7/12/2022 12:00:00 AM
Last Editorial Review: 7/12/2022 12:00:00 AM

Title: U.S. Hospitals Are Getting Safer for Patients, Study Finds
Category: Health News
Created: 7/20/2022 12:00:00 AM
Last Editorial Review: 7/20/2022 12:00:00 AM

Title: You Could Live 9 Years Longer in Hawaii Than in Mississippi, New Data Shows
Category: Health News
Created: 8/23/2022 12:00:00 AM
Last Editorial Review: 8/23/2022 12:00:00 AM

Title: Get Moving! Any Sports Can Lower Seniors' Odds of Early Death
Category: Health News
Created: 8/25/2022 12:00:00 AM
Last Editorial Review: 8/26/2022 12:00:00 AM

Title: Hepatitis C Infection Can Kill, But Less Than a Third of Patients Get Treatment
Category: Health News
Created: 8/10/2022 12:00:00 AM
Last Editorial Review: 8/10/2022 12:00:00 AM

Title: When Removing a Big Kidney Stone, Get the Little Ones, Too
Category: Health News
Created: 8/11/2022 12:00:00 AM
Last Editorial Review: 8/11/2022 12:00:00 AM

Title: GERD (Acid Reflux) in Infants and Children
Category: Diseases and Conditions
Created: 1/31/2005 12:00:00 AM
Last Editorial Review: 8/18/2022 12:00:00 AM

Title: Kidneys' Resilience May Depend on Your Gender, Study Finds
Category: Health News
Created: 8/22/2022 12:00:00 AM
Last Editorial Review: 8/22/2022 12:00:00 AM

Title: Digestive Enzymes Oral
Category: Medications
Created: 3/2/2005 12:00:00 AM
Last Editorial Review: 8/24/2022 12:00:00 AM

Title: How to Get Rid of Mucus in My Chest Fast
Category: Diseases and Conditions
Created: 6/22/2022 12:00:00 AM
Last Editorial Review: 6/22/2022 12:00:00 AM

Title: CDC Panel Urges Seniors to Get New, More Potent Flu Shot This Fall
Category: Health News
Created: 6/23/2022 12:00:00 AM
Last Editorial Review: 6/23/2022 12:00:00 AM

Title: How Do I Get Rid of Winter Depression?
Category: Diseases and Conditions
Created: 4/27/2022 12:00:00 AM
Last Editorial Review: 4/27/2022 12:00:00 AM

Extract

Living with a respiratory illness requires patients to manage a wide range of symptoms, many of which will worsen as a disease progresses. Breathlessness is a hallmark feature of respiratory conditions, occurring in almost all individuals with COPD and interstitial lung disease (ILD) [1, 2]. Cough is present in 78% of people with ILD and is frequently distressing, with physical, social and emotional impacts [1, 3].

Influenza A virus (IAV) is one of the leading causes of respiratory infections. The lack of efficient anti-influenza therapeutics requires a better understanding of how IAV interacts with host cells. Alveolar macrophages are tissue-specific macrophages that play a critical role in lung innate immunity and homeostasis, yet their role during influenza infection remains unclear. First, our review highlights an active IAV replication within alveolar macrophages, despite an abortive viral cycle. Such infection leads to persistent alveolar macrophage inflammation and diminished phagocytic function, alongside direct mitochondrial damage and indirect metabolic shifts in the alveolar micro-environment. We also discuss the "macrophage disappearance reaction", which is a drastic reduction of the alveolar macrophage population observed after influenza infection in mice but debated in humans, with unclear underlying mechanisms. Furthermore, we explore the dual nature of alveolar macrophage responses to IAV infection, questioning whether they are deleterious or protective for the host. While IAV may exploit immuno-evasion strategies and induce alveolar macrophage alteration or depletion, this could potentially reduce excessive inflammation and allow for the replacement of more effective cells. Despite these insights, the pathophysiological role of alveolar macrophages during IAV infection in humans remains understudied, urging further exploration to unravel their precise contributions to disease progression and resolution.

Bronchiectasis is a chronic lung condition which is characterised by recurrent chest infections, chronic sputum production and cough, and limited exercise tolerance. While bronchiectasis may be caused by various aetiologies, these features are shared by most patients with bronchiectasis regardless of the cause. This review consolidates the existing evidence on patient-managed interventions for adults with bronchiectasis, while also outlining areas for future research. Airway clearance techniques and hyperosmolar agents are key components of the bronchiectasis management and consistently recommended for clinical implementation. Questions around their prescription, such as optimal sequence of delivery, are still to be answered. Pulmonary rehabilitation and exercise are also recommended for patients with bronchiectasis. Relatively strong evidence underpins this recommendation during a clinically stable stage of the disease, although the role of pulmonary rehabilitation following an exacerbation is still unclear. Additionally, self-management programmes feature prominently in bronchiectasis treatment, yet the lack of consensus regarding their definition and outcomes presents hurdles to establishing a cohesive evidence base. Moreover, cough, a cardinal symptom of bronchiectasis, warrants closer examination. Although managing cough in bronchiectasis may initially appear risky, further research is necessary to ascertain whether strategies employed in other respiratory conditions can be safely and effectively adapted to bronchiectasis, particularly through identifying patient responder populations and criteria where cough may not enhance airway clearance efficacy and its control is needed. Overall, there is a growing recognition of the importance of patient-managed interventions in the bronchiectasis management. Efforts to improve research methodologies and increase research funding are needed to further advance our understanding of these interventions, and their role in optimising patient care and outcomes.

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Retrotransposable elements (RTEs) are common mobile genetic elements comprising ~42% of the human genome. RTEs play critical roles in gene regulation and function, but how they are specifically involved in complex diseases is largely unknown. Here, we investigate the cellular heterogeneity of RTEs using 12 single-cell transcriptome profiles covering three neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease, and multiple sclerosis. We identify cell type marker RTEs in neurons, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells that are related to these diseases. The differential expression analysis reveals the landscape of dysregulated RTE expression, especially L1s, in excitatory neurons of multiple neurodegenerative diseases. Machine learning algorithms for predicting cell disease stage using a combination of RTE and gene expression features suggests dynamic regulation of RTEs in AD. Furthermore, we construct a single-cell atlas of retrotransposable elements in neurodegenerative disease (scARE) using these data sets and features. scARE has six feature analysis modules to explore RTE dynamics in a user-defined condition. To our knowledge, scARE represents the first systematic investigation of RTE dynamics at the single-cell level within the context of neurodegenerative diseases.

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.

Sequence variation observed in populations of pathogens can be used for important public health and evolutionary genomic analyses, especially outbreak analysis and transmission reconstruction. Identifying this variation is typically achieved by aligning sequence reads to a reference genome, but this approach is susceptible to reference biases and requires careful filtering of called genotypes. There is a need for tools that can process this growing volume of bacterial genome data, providing rapid results, but that remain simple so they can be used without highly trained bioinformaticians, expensive data analysis, and long-term storage and processing of large files. Here we describe split k-mer analysis (SKA2), a method that supports both reference-free and reference-based mapping to quickly and accurately genotype populations of bacteria using sequencing reads or genome assemblies. SKA2 is highly accurate for closely related samples, and in outbreak simulations, we show superior variant recall compared with reference-based methods, with no false positives. SKA2 can also accurately map variants to a reference and be used with recombination detection methods to rapidly reconstruct vertical evolutionary history. SKA2 is many times faster than comparable methods and can be used to add new genomes to an existing call set, allowing sequential use without the need to reanalyze entire collections. With an inherent absence of reference bias, high accuracy, and a robust implementation, SKA2 has the potential to become the tool of choice for genotyping bacteria. SKA2 is implemented in Rust and is freely available as open-source software.

The COVID-19 pandemic has highlighted the critical role of genomic surveillance for guiding policy and control. Timeliness is key, but sequence alignment and phylogeny slow most surveillance techniques. Millions of SARS-CoV-2 genomes have been assembled. Phylogenetic methods are ill equipped to handle this sheer scale. We introduce a pangenomic measure that examines the information diversity of a k-mer library drawn from a country's complete set of clinical, pooled, or wastewater sequence. Quantifying diversity is central to ecology. Hill numbers, or the effective number of species in a sample, provide a simple metric for comparing species diversity across environments. The more diverse the sample, the higher the Hill number. We adopt this ecological approach and consider each k-mer an individual and each genome a transect in the pangenome of the species. Structured in this way, Hill numbers summarize the temporal trajectory of pandemic variants, collapsing each day's assemblies into genome equivalents. For pooled or wastewater sequence, we instead compare days using survey sequence divorced from individual infections. Across data from the UK, USA, and South Africa, we trace the ascendance of new variants of concern as they emerge in local populations well before these variants are named and added to phylogenetic databases. Using data from San Diego wastewater, we monitor these same population changes from raw, unassembled sequence. This history of emerging variants senses all available data as it is sequenced, intimating variant sweeps to dominance or declines to extinction at the leading edge of the COVID-19 pandemic.

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.

Somatic mutations arise and accumulate during tissue culture and vegetative propagation, potentially affecting various traits in horticultural crops, but their characteristics are still unclear. Here, somatic mutations in regenerated woodland strawberry derived from tissue culture of shoot tips under different conditions and 12 cultivated strawberry individuals are analyzed by whole genome sequencing. The mutation frequency of single nucleotide variants is significantly increased with increased hormone levels or prolonged culture time in the range of 3.3 x 10^–8–3.0 x 10^–6 mutations per site. CG methylation shows a stable reduction (0.71%–8.03%) in regenerated plants, and hypoCG-DMRs are more heritable after sexual reproduction. A high-quality haplotype-resolved genome is assembled for the strawberry cultivar "Beni hoppe." The 12 "Beni hoppe" individuals randomly selected from different locations show 4731–6005 mutations relative to the reference genome, and the mutation frequency varies among the subgenomes. Our study has systematically characterized the genetic and epigenetic variants in regenerated woodland strawberry plants and different individuals of the same strawberry cultivar, providing an accurate assessment of somatic mutations at the genomic scale and nucleotide resolution in plants.

Understanding the evolution of chromatin conformation among species is fundamental to elucidate the architecture and plasticity of genomes. Nonrandom interactions of linearly distant loci regulate gene function in species-specific patterns, affecting genome function, evolution, and, ultimately, speciation. Yet, data from nonmodel organisms are scarce. To capture the macroevolutionary diversity of vertebrate chromatin conformation, here we generate de novo genome assemblies for two cryptodiran (hidden-neck) turtles via Illumina sequencing, chromosome conformation capture, and RNA-seq: Apalone spinifera (ZZ/ZW, 2n = 66) and Staurotypus triporcatus (XX/XY, 2n = 54). We detected differences in the three-dimensional (3D) chromatin structure in turtles compared to other amniotes beyond the fusion/fission events detected in the linear genomes. Namely, whole-genome comparisons revealed distinct trends of chromosome rearrangements in turtles: (1) a low rate of genome reshuffling in Apalone (Trionychidae) whose karyotype is highly conserved when compared to chicken (likely ancestral for turtles), and (2) a moderate rate of fusions/fissions in Staurotypus (Kinosternidae) and Trachemys scripta (Emydidae). Furthermore, we identified a chromosome folding pattern that enables "centromere–telomere interactions" previously undetected in turtles. The combined turtle pattern of "centromere–telomere interactions" (discovered here) plus "centromere clustering" (previously reported in sauropsids) is novel for amniotes and it counters previous hypotheses about amniote 3D chromatin structure. We hypothesize that the divergent pattern found in turtles originated from an amniote ancestral state defined by a nuclear configuration with extensive associations among microchromosomes that were preserved upon the reshuffling of the linear genome.

As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer–promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1, FOXA1, GATA3, GATA6, TP63, and VEGFA, as well as potentially novel oncogenes such as GRHL2, IRF2BP2, and CREB3L1. In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention.

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.

Background:

The COVID-19 pandemic social distancing requirements encouraged patients to avoid public spaces including in-office health care visits. Ambulatory-care-sensitive conditions (ACSCs) represent conditions that can be managed with quality primary care and when access is limited, these conditions can lead to avoidable emergency department (ED) visits.

Family physicians are fielding questions about cannabis --particularly for the use of cannabis for treatment of pain. Like about every substance ingested to treat medical conditions, cannabis has risks and benefits. But regarding evidence-based practice and practice-based recommendations for patients about cannabis use, the cart is in front of the horse. Cannabis use is still illegal at a federal level and a Schedule 1 drug, but most states have challenged federal law by decriminalizing or legalizing cannabis for a variety of uses. Research is difficult due to this federal status as a Schedule 1 drug since federal funding is not readily available to support research. As a result, physicians have little to no guidance about the clinical usefulness of the product. This article explores what we know and what we are learning about cannabis, and the authors provide clinical guidance for patient care based on this evidence.

Single maintenance and reliever therapy (SMART) is an asthma treatment approach that utilizes combined inhaled corticosteroids and long-acting β-agonists for maintenance and quick relief therapy. Despite the evidence for its benefits in asthma treatment and its adoption into American and international asthma guidelines and recommendations, SMART remains a practice of some debate. This article reviews the available evidence for SMART and offers guidance for its integration into comprehensive asthma management. Overall, short-acting β-agonist-only asthma therapy regimens should be avoided, regardless of condition severity (SOR A Recommendation). Family medicine clinicians should start SMART for patients requiring either GINA Step 3 or 4 therapy, especially if they have signs of poor adherence (SOR B Recommendation). Finally, use budesonide-formoterol over other inhaled corticosteroid/long-acting β-agonist combinations when implementing SMART (SOR B Recommendation).

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.

Introduction:

High-quality primary care can reduce avoidable emergency department visits and emergency hospitalizations. The availability of electronic medical record (EMR) data and capacities for data storage and processing have created opportunities for predictive analytics. This systematic review examines studies which predict emergency department visits, hospitalizations, and mortality using EMR data from primary care.

Objective:

In this study, we sought to comprehensively evaluate GPT-4 (Generative Pre-trained Transformer)’s performance on the 2022 American Board of Family Medicine’s (ABFM) In-Training Examination (ITE), compared with its predecessor, GPT-3.5, and the national family residents’ performance on the same examination.

Artificial Intelligence (AI) is poised to revolutionize family medicine, offering a transformative approach to achieving the Quintuple Aim. This article examines the imperative for family medicine to adapt to the rapidly evolving field of AI, with an emphasis on its integration in clinical practice. AI's recent advancements have the potential to significantly transform health care. We argue for the proactive engagement of family medicine in directing AI technologies toward enhancing the "Quintuple Aim."

The article highlights potential benefits of AI, such as improved patient outcomes through enhanced diagnostic tools, clinician well-being through reduced administrative burdens, and the promotion of health equity by analyzing diverse data sets. However, we also acknowledge the risks associated with AI, including the potential for automation to diverge from patient-centered care and exacerbate health care disparities. Our recommendations stress the need for family medicine education to incorporate AI literacy, the development of a collaborative for AI integration, and the establishment of guidelines and standards through interdisciplinary cooperation. We conclude that although AI poses challenges, its responsible and ethical implementation can revolutionize family medicine, optimizing patient care and enhancing the role of clinicians in a technology-driven future.

Artificial intelligence (AI) is certainly going to have a large, potentially huge, impact on the practice of family medicine. The specialty is fortunate to have leading experts in the field to guide us along the way. One such team of forward thinkers provides insights into where AI can take the specialty. Another article reports on how well AI performed on the American Board of Family Medicine In-Training Examination. In addition to AI, we have 3 articles that investigate the intersection of social needs and the practice of medicine. Four clinical review articles cover nonalcoholic fatty liver disease, headache treatments, single maintenance and reliever therapy for asthma, and the use of cannabis in the setting of chronic pain. The clinical research articles cover point-of-care hemoglobin A1c testing, continuous glucose monitoring, and screening for HIV. Another group of articles examines the profession of family medicine, covering topics ranging from how women family physicians negotiate their first jobs to the words we use to define primary care.

COPD and asthma are two of the most common chronic lung diseases, affecting over 545 million people globally and 34 million in the United States. Annual health care costs related to chronic lung disease are estimated at €380 billion in the European Union, and $24–$50 billion in the United States averaging to $4,000 in out-of-pocket costs per person in the U.S. A full-text literature search was conducted for English publications between January 1, 2005–March 18, 2024. It returned over 5,000 publications that were further narrowed using key search words, resulting in 172 peer-reviewed articles. Using their experience and subject expertise, the authors further narrowed the peer-reviewed articles to 55 that were in their opinion relevant. Also, 38 recently published industry reports and news articles specific to downstream effects of inhaler market changes and the future impact were included. The literature suggests that individuals with chronic lung disease face increased challenges with access to inhaled medication due to rising medication costs, discontinuation of branded medications, introduction of generic medications not covered by insurance, exclusionary preferred drug list tactics that force health care providers into non-medical switching of medication or devices, and ongoing medication shortages. Providers experience ongoing hurdles in prescribing appropriate inhaled medications for individuals with chronic lung disease, including increased time and costs spent on administrative tasks due to inhaler denials, a loss of patient trust, and limits on their ability to prescribe appropriate inhaled medication for individuals with chronic lung disease.

BACKGROUND:PEEP is a cornerstone treatment for children with pediatric ARDS. Unfortunately, its titration is often performed solely by evaluating oxygen saturation, which can lead to inadequate PEEP level settings and consequent adverse effects. This study aimed to assess the impact of increasing PEEP on hemodynamics, respiratory system mechanics, and oxygenation in children with ARDS.METHODS:Children receiving mechanical ventilation and on pressure-controlled volume-guaranteed mode were prospectively assessed for inclusion. PEEP was sequentially changed to 5, 12, 10, 8 cm H2O, and again to 5 cm H2O. After 10 min at each PEEP level, hemodynamic, ventilatory, and oxygenation variables were collected.RESULTS:A total of 31 subjects were included, with median age and weight of 6 months and 6.3 kg, respectively. The main reasons for pediatric ICU admission were respiratory failure caused by acute viral bronchiolitis (45%) and community-acquired pneumonia (32%). Most subjects had mild or moderate ARDS (45% and 42%, respectively), with a median (interquartile range) oxygenation index of 8.4 (5.8–12.7). Oxygen saturation improved significantly when PEEP was increased. However, although no significant changes in blood pressure were observed, the median cardiac index at PEEP of 12 cm H2O was significantly lower than that observed at any other PEEP level (P = .001). Fourteen participants (45%) experienced a reduction in cardiac index of > 10% when PEEP was increased to 12 cm H2O. Also, the estimated oxygen delivery was significantly lower, at 12 cm H2O PEEP. Finally, respiratory system compliance significantly reduced when PEEP was increased. At a PEEP of 12 cm H2O, static compliance had a median reduction of 25% in relation to the initial assessment (PEEP of 5 cm H2O).CONCLUSIONS:Although it may improve arterial oxygen saturation, inappropriately high PEEP levels may reduce cardiac output, oxygen delivery, and respiratory system compliance in pediatric subjects with ARDS with low potential for lung recruitability.

The pursuit of harnessing data for knowledge creation has been an enduring quest, with the advent of machine learning (ML) and artificial intelligence (AI) marking significant milestones in this journey. ML, a subset of AI, emerged as the practice of employing mathematical models to enable computers to learn and improve autonomously based on their experiences. In the pharmaceutical and biopharmaceutical sectors, a significant portion of manufacturing data remains untapped or insufficient for practical use. Recognizing the potential advantages of leveraging the available data for process design and optimization, manufacturers face the daunting challenge of data utilization. Diverse proprietary data formats and parallel data generation systems compound the complexity. The transition to Pharma 4.0 necessitates a paradigm shift in data capture, storage, and accessibility for manufacturing and process operations. This paper highlights the pivotal role of AI in converting process data into actionable knowledge to support critical functions throughout the whole product life cycle. Furthermore, it underscores the importance of maintaining compliance with data integrity guidelines, as mandated by regulatory bodies globally. Embracing AI-driven transformations is a crucial step toward shaping the future of the pharmaceutical industry, ensuring its competitiveness and resilience in an evolving landscape.

A prefilled syringe (PFS) should be able to be adequately and consistently extruded during injection for optimal safe drug delivery and accurate dosing. To facilitate appropriate break-loose and gliding forces (BLGFs) required during injection, certain primary packaging materials (PPMs) such as the syringe barrel and plunger are usually coated with silicone oil, which acts as a lubricant. Due to its direct contact with drug, silicone oil can increase the number of particles in the syringe, which could lead to adverse interactions. Compliance with regulatory-defined silicone oil quantities in certain drug products, such as ophthalmics, presents a trade-off with the necessity for desirable low and consistent BLGF. In addition to its siliconization, the dimensional accuracy of the PPM has an important role in controlling the BLGF. The dimensions of the PPM are individualized depending on the product and its design and have certain tolerances that must be met during manufacturing. Most studies on ophthalmics focused on the adverse interactions between silicone oil and the drug. To the authors' knowledge, there have been no public studies so far that have investigated the impact of the dimensional variability of the PPM on the BLGF in ophthalmic PFSs. In this study, we applied advanced optical shaft and tactile measuring technologies to investigate this impact. The syringes investigated were first sampled during aseptic production and tested for the BLGF. Subsequently, defined dimensions of the PPM were measured individually. The results showed that the dimensional variability of the PPM can have a negative impact on the BLGF, despite their conformity to specifications, which indicates that the currently available market quality of PPMs is improvable for critical drug products such as ophthalmics. This study could serve as an approach to define product-specific requirements for primary packaging combinations and thus appropriate specifications based on data during the development stage of drug products.

For clean-room technologies such as isolators and restricted access barrier systems (RABS), decontamination using hydrogen peroxide (H₂O₂) is increasingly attractive to fulfill regulatory requirements. Several approaches are currently used, ranging from manual wipe disinfection to vapor phase hydrogen peroxide (VPHP) or automated nebulization sanitization. Although the residual airborne H₂O₂ concentration can be easily monitored, detection of trace H₂O₂ residues in filled products is rather challenging. To simulate the filling process in a specific clean room, technical runs with water for injection (WfI) are popular. Thus, the ability to detect traces of H₂O₂ in water is an important prerequisite to ensure a safe and reliable use of H₂O₂ for isolator or clean room decontamination. The objective of this study was to provide a validated quantitative, fluorometric Amplex UltraRed assay, which satisfies the analytical target profile of quantifying H₂O₂ in WfI at low nanomolar to low micromolar concentrations (ppb range) with high accuracy and high precision. The Amplex UltraRed technology provides a solid basis for this purpose; however, no commercial assay kit that fulfills these requirements is available. Therefore, a customized Amplex UltraRed assay was developed, optimized, and validated. This approach resulted in an assay that is capable of quantifying H₂O₂ in WfI selectively, sensitively, accurately, precisely, and robustly. This assay is used in process development and qualification approaches using WfI in H₂O₂-decontaminated clean rooms and isolators.

Obidoxime chloride is an antidote for nerve gas intoxication. As an emergency medicine, it is being stored by the Israel Defense Forces (IDF) scattered throughout Israel in depots without a controlled environment (field conditions), thus being exposed to high and fluctuating temperatures. These conditions do not meet the manufacturer’s requirements. In addition, due to possible supply shortages, the utilization of expired batches was suggested. The current work investigated these matters. Long-term (15 years) storage under different conditions was initiated. Chemical stability and toxicity in rats were assessed. No difference was found between field conditions vs the controlled environment. The obidoxime assay remained >95% for 5 years and >90% for 7 years. The pH remained above the lower specification limit for 7–8 years. The major degradation product, 4-pyridinealdoxime, surpassed the allowed limit at 5 years. The content of total unknown impurities reached its maximum allowed by the IDF limit at 4–5 years. Threefold higher than clinically utilized doses of valid-to-date Toxogonin batches administered to rats did not cause any abnormality. However, expired batches produced significant toxic effects. Although no difference was found between storage of obidoxime ampoules when adhering to manufacturer’s recommendations vs field conditions, accumulation of degradants over the limit allowed by the IDF at 4–5 years of storage and the toxicity of the expired batches observed in rats led the IDF to a decision to shorten the shelf-life of this product from 5 to 4 years when stored in an uncontrolled environment of the Mediterranean climate.

Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m⁶A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone acetylation at DSBs. Our data suggest a direct role for NEAT1 in DDR.

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.

Cellular plasticity in adult multicellular organisms is a protective mechanism that allows certain tissues to regenerate in response to injury. Considering that aging involves exposure to repeated injuries over a lifetime, it is conceivable that cell identity itself is more malleable—and potentially erroneous—with age. In this review, we summarize and critically discuss the available evidence that cells undergo age-related shifts in identity, with an emphasis on those that contribute to age-associated pathologies, including neurodegeneration and cancer. Specifically, we focus on reported instances of programs associated with dedifferentiation, biased differentiation, acquisition of features from alternative lineages, and entry into a preneoplastic state. As some of the most promising approaches to rejuvenate cells reportedly also elicit transient changes to cell identity, we further discuss whether cell state change and rejuvenation can be uncoupled to yield more tractable therapeutic strategies.

Extract

As of 15 May 2024, >775 million confirmed cases of COVID-19 and >7 million deaths have been reported to the World Health Organization [1]. Although most patients with COVID-19 survive, survivors are at risk of long COVID, the sequelae of the viral infection affecting multiple organ systems [2]. Long COVID poses a substantial burden to individuals and society, even with a conservative estimate of 10% prevalence among COVID-19 survivors [3–5]. However, as the symptoms of long COVID vary substantially, ranging from respiratory symptoms, such as dyspnoea and cough, to fatigue and cognitive impairment [6], developing a standard set of investigations and management protocols for patients with long COVID is challenging.

Background

Long COVID is a heterogeneous clinical syndrome characterised by a variety of reported symptoms and signs. Its clinical management is expected to differ significantly worldwide.

Extract

It is of utmost importance that medicines are available at all times for our patients. Historically, medication unavailability has typically, if not exclusively, affected low- and middle-income countries [1]. More recently however, drug shortages have also been reported in high-income European countries [2]. Drug shortages have negative health consequences for patients [3], and a profound economic impact, with the need to resort to more expensive alternatives and demands on healthcare professionals’ time to find, prescribe and dispense alternatives [4].

Extract

In cystic fibrosis (CF), Pseudomonas aeruginosa acquisition represents a turning point in disease progression. The presence of chronic P. aeruginosa infection is associated with worsening lung function and increased risk of earlier death, whereas treatment substantially improves lung function and survival [1, 2]. Efforts to diagnose and eradicate early P. aeruginosa provide lasting benefits for children with CF [3, 4]. However, the timing of infection varies considerably between individuals with CF, treatment centres [5, 6], and different birth cohorts of people with the disease [7, 8].