Title: People Underestimate Impact of Random Acts of Kindness
Category: Health News
Created: 8/24/2022 12:00:00 AM
Last Editorial Review: 8/25/2022 12:00:00 AM

Title: More Evidence Fitness Trackers Can Boost Your Health
Category: Health News
Created: 7/26/2022 12:00:00 AM
Last Editorial Review: 7/27/2022 12:00:00 AM

Title: Torn ACL (Anterior Cruciate Ligament Tear)
Category: Diseases and Conditions
Created: 11/4/2010 12:00:00 AM
Last Editorial Review: 8/15/2022 12:00:00 AM

Title: Will Inflation Cut Back on Your Health Care?
Category: Health News
Created: 8/8/2022 12:00:00 AM
Last Editorial Review: 8/8/2022 12:00:00 AM

Title: Here's How the Inflation Reduction Act Will Lower the Cost of Health Care
Category: Health News
Created: 8/17/2022 12:00:00 AM
Last Editorial Review: 8/17/2022 12:00:00 AM

Title: Helmets Protect Young Lacrosse Players, Study Finds
Category: Health News
Created: 8/25/2022 12:00:00 AM
Last Editorial Review: 8/25/2022 12:00:00 AM

Title: Too Few U.S. Cities Have Good Hurricane Evacuation Plans
Category: Health News
Created: 8/26/2022 12:00:00 AM
Last Editorial Review: 8/26/2022 12:00:00 AM

Title: Cystic Acne
Category: Diseases and Conditions
Created: 3/4/2016 12:00:00 AM
Last Editorial Review: 8/5/2022 12:00:00 AM

Title: New Approach Cuts Odds for Anal Cancer in People With HIV
Category: Health News
Created: 6/16/2022 12:00:00 AM
Last Editorial Review: 6/16/2022 12:00:00 AM

Title: Many Older Women Have Active Sex Lives, But Menopause Can Interfere
Category: Health News
Created: 5/18/2022 12:00:00 AM
Last Editorial Review: 5/19/2022 12:00:00 AM

Title: ACE Inhibitors
Category: Medications
Created: 4/19/2001 12:00:00 AM
Last Editorial Review: 7/22/2022 12:00:00 AM

Title: Vegetarian Women at Higher Odds for Hip Fracture
Category: Health News
Created: 8/11/2022 12:00:00 AM
Last Editorial Review: 8/12/2022 12:00:00 AM

Title: U.S. HPV Vaccination Rates Rising, Even Among Boys
Category: Health News
Created: 6/22/2022 12:00:00 AM
Last Editorial Review: 6/23/2022 12:00:00 AM

Title: FDA Mulling Over-the-Counter Sale of Contraceptive Pill
Category: Health News
Created: 7/11/2022 12:00:00 AM
Last Editorial Review: 7/11/2022 12:00:00 AM

Title: Vaccines Have Slashed Rates of HPV Infection in Young American Women
Category: Health News
Created: 8/22/2022 12:00:00 AM
Last Editorial Review: 8/23/2022 12:00:00 AM

Title: Steps to Long Life: Short Walk Each Day Helps Folks Over 85
Category: Health News
Created: 8/25/2022 12:00:00 AM
Last Editorial Review: 8/25/2022 12:00:00 AM

Title: Picture of Nickel Contact Dermatitis
Category: Images
Created: 2/22/2010 3:07:00 PM
Last Editorial Review: 6/23/2022 12:00:00 AM

Title: Picture of Nickel Contact Dermatitis from Necklace
Category: Images
Created: 2/22/2010 3:21:00 PM
Last Editorial Review: 6/28/2022 12:00:00 AM

Title: Prehistoric People Drank Animal Milk, Despite Lactose Intolerance
Category: Health News
Created: 7/27/2022 12:00:00 AM
Last Editorial Review: 7/28/2022 12:00:00 AM

Title: SIBO (Small Intestinal Bacterial Overgrowth)
Category: Diseases and Conditions
Created: 10/28/2005 12:00:00 AM
Last Editorial Review: 8/8/2022 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

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.

Background

Immature lung development and respiratory morbidity place preterm-born children at high risk of long-term pulmonary sequelae. This systematic review and meta-analysis aims to quantify lung function in preterm-born children and identify risk factors for a compromised lung function.

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.

Most studies of genome organization have focused on intrachromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans-contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands," and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans-acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA-binding proteins interact with one another in trans, especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. We observe that these trans-interacting loci are close to nuclear speckles. These findings support the existence of trans-interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.

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.

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.

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.

Without compromising accuracy, point of care testing (POCT) provides immediate results at the time of in person patient consultation. The purpose of this study was to evaluate time until therapeutic intervention with POCT HbA1c versus venipuncture, where venipuncture was considered standard of care.

The primary outcome was time (hours) to implementation of a therapeutic intervention based on POCT HbA1c result, as compared with most recent venipuncture HbA1c before the study and its associated therapeutic intervention. A total of 94 POCT HbA1c tests were included in the primary analysis.

For the POCT HbA1c, the mean time to therapeutic intervention was 1.6 ± 3.14 hours. For the previous venipuncture HbA1c, the mean time to therapeutic intervention was 1376.66 ± 3356.6 hours (P < .001). Overall, this trial showed that POCT HbA1c results in a significantly faster time to therapeutic intervention than venipuncture in a primary care clinic that serves a rural population.

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.

The rising obesity epidemic is a phenomenon that has gained increasing attention from health providers and health policy makers. This led to recognition of nonalcoholic fatty liver disease (MASLD). The standard for its assessment has been histologic, which is neither practical nor acceptable by patients. Subsequently, a number of noninvasive assessment methods have been developed. However, despite ease of implementation, their confounding variables do hinder their accuracy. Nonetheless, the development of the liver stiffness measurement (LSM) and incorporation of other biological parameters has minimized but not eliminated the need for liver biopsy. Imaging methods are useful in evaluation, estimation, and following the progression of steatosis and fibrosis with particular attention to controlled attenuation parameter (CAP) and MRI–Proton Density Fat Fraction (MRI-PDFF). The choices for the family physician are broad and rely on tests’ availability, cost, and patient acceptance. Great efforts have been undertaken to produce more robust and novel noninvasive markers that indicate fibrinogenesis directly in an implementable and cost-effective way.

Family medicine physicians often see headache as the chief complaint when meeting patients within their practice. The goal is to try different treatment modalities without having to send the patient to a specialist. Headaches affect different individuals during their lifetime. Before any treatment begins, it is best that one rules out possible causes of the headache, for example, drug interactions or structural cerebrum conditions. Nonpharmacological treatment is recommended first before attempting a stepwise approach to cost-effective pharmacological treatment options. Pharmacological treatment options should include preventive and on-demand options. A family physician has all the resources to assist patients with different types of headaches.

Background:

Certain health-related risk factors require legal interventions. Medical-legal partnerships (MLPs) are collaborations between clinics and lawyers that address these health-harming legal needs (HHLNs) and have been shown to improve health and reduce utilization.

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: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:Practice on fasting prior to extubation in critically ill patients is variable. Efficacy of fasting in reducing gastric volume has not been well established. The primary objective of this study was to assess the effect of 4 h of fasting on prevalence of empty stomach using gastric ultrasonography in critically ill subjects who are fasted for extubation. The secondary objectives were to evaluate the change in gastric volumes during 4 h of fasting and to determine factors associated with empty stomach after fasting.METHODS:This was a single-center, prospective, observational study on adult ICU subjects who were enterally fed for at least 6 h continuously and mechanically ventilated. Gastric ultrasound was performed immediately prior to commencement of fasting, after 4 h of fasting, and after nasogastric (NG) aspiration after 4 h of fasting. An empty stomach was defined as a gastric volume ≤ 1.5 mL/kg.RESULTS:Forty subjects were recruited, and 38 (95%) had images suitable for analysis. The prevalence of empty stomach increased after 4 h of fasting (25 [65.8%] vs 31 [81.6%], P = .041) and after 4 h of fasting with NG aspiration (25 [65.8%] vs 34 [89.5%], P = .008). There was a significant difference in median (interquartile range) gastric volume per body weight between before fasting and 4 h after fasting (1.0 [0.5–1.8] mL/kg vs 0.4 [0.2–1.0] mL/kg, P < .001). No patient factors were associated with higher prevalence of empty stomach after 4 h of fasting.CONCLUSIONS:Most mechanically ventilated subjects had empty stomachs prior to fasting for extubation. Fasting for 4 h further increased the prevalence of empty stomach at extubation to > 80%.

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.

BACKGROUND:This study sought to estimate the overall cumulative incidence and odds of Hospital-acquired venous thromboembolism (VTE) among critically ill children with and without exposure to invasive ventilation. In doing so, we also aimed to describe the temporal relationship between invasive ventilation and hospital-acquired VTE development.METHODS:We performed a retrospective cohort study using Virtual Pediatric Systems (VPS) data from 142 North American pediatric ICUs among children < 18 y of age from January 1, 2016–December 31, 2022. After exclusion criteria were applied, cohorts were identified by presence of invasive ventilation exposure. The primary outcome was cumulative incidence of hospital-acquired VTE, defined as limb/neck deep venous thrombosis or pulmonary embolism. Multivariate logistic regression was used to determine whether invasive ventilation was an independent risk factor for hospital-acquired VTE development.RESULTS:Of 691,118 children studied, 86,922 (12.4%) underwent invasive ventilation. The cumulative incidence of hospital-acquired VTE for those who received invasive ventilation was 1.9% and 0.12% for those who did not (P < .001). The median time to hospital-acquired VTE after endotracheal intubation was 6 (interquartile range 3–14) d. In multivariate models, invasive ventilation exposure and duration were each independently associated with development of hospital-acquired VTE (adjusted odds ratio 1.64 [95% CI 1.42–1.86], P < .001; and adjusted odds ratio 1.03 [95% CI 1.02–1.03], P < .001, respectively).CONCLUSIONS:In this multi-center retrospective review from the VPS registry, invasive ventilation exposure and duration were independent risk factors for hospital-acquired VTE among critically ill children. Children undergoing invasive ventilation represent an important target population for risk-stratified thromboprophylaxis trials.

BACKGROUND:Pulmonary function tests (PFTs) have historically used race-specific prediction equations. The recent American Thoracic Society guidelines recommend the use of a race-neutral approach in prediction equations. There are limited studies centering the opinions of practicing pulmonologists on the use of race in spirometry. Provider opinion will impact adoption of the new guideline. The aim of this study was to ascertain the beliefs of academic pulmonary and critical care providers regarding the use of race as a variable in spirometry prediction equations.METHODS:We report data from 151 open-ended responses from a voluntary, nationwide survey (distributed by the Association of Pulmonary Critical Care Medicine Program Directors) of academic pulmonary and critical care providers regarding the use of race in PFT prediction equations. Responses were coded using inductive and deductive methods, and a thematic content analysis was conducted.RESULTS:There was a balanced distribution of opinions among respondents supporting, opposing, or being unsure about the incorporation of race in spirometry prediction equations. Responses demonstrated a wide array of understanding related to the concept and definition of race and its relationship to physiology.CONCLUSIONS:There was no consensus among providers regarding the use of race in spirometry prediction equations. Concepts of race having biologic implications persist among pulmonary providers and will likely affect the uptake of the Global Lung Function Initiative per the American Thoracic Society guidelines.

The Coalition for Epidemic Preparedness Innovations (CEPI) has developed a robust CMC (Chemistry, Manufacturing, and Controls) Framework to enhance the likelihood of successful vaccine development. This Framework serves as a comprehensive guide, aiding developers in building effective strategies to overcome the challenges posed by the different phases of vaccine development, including the ones often referred to as the "valleys of death". The Framework lists stage-appropriate deliverables, categorized and refined, spanning five key areas: manufacturing process, formulation and stability, analytics, supply chain, and compliance. By emphasizing the critical aspects of CMC development, CEPI's objective is to expedite the progression of vaccine candidates from research to deployment, reducing delays, mitigating risks, and optimizing the overall development process, all while upholding uncompromising quality standards, ultimately increasing the probability of success.

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.

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.

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.

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.

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.