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Purpose: The purpose of this integrative literature review was to determine factors that increase the risk of immune checkpoint inhibitor (ICI)-related myocarditis in the cancer patient population. Methods: A literature review was conducted using the following databases: PubMed, Scopus, and Cochrane Review. Dates searched were from inception through March 1, 2022. Inclusion criteria included English language, cancer patients receiving ICI treatment, and risk factors for myocarditis. Articles were excluded if they were a non-human study, duplicate, had an irrelevant title or content, or were a review or commentary. Results: Patients with cancer who receive ICIs have an associated increased risk of myocarditis if they are older than 64 years, have a body mass index (BMI) greater than 28, and have a history of cardiovascular medication use. Conclusions: Myocarditis remains a rare cardiovascular adverse effect of ICIs. However, the mortality risk among this subset of patients remains high. Additional prospective randomized-controlled trials would be beneficial to further determine a causal relationship between risk factors for ICI-related myocarditis. Risk stratification tools may allow oncology medical providers to identify patients at a higher risk of ICI-related myocarditis to increase earlier surveillance.
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Introduction: Critically ill patients show large variability in drug disposition due to e.g., age, size, disease and treatment modalities. Physiologically-based pharmacokinetic (PBPK) models can be used to design individualized dosing regimens taking this into account. Dexamethasone, prescribed for the prevention post-extubation stridor (PES), is metabolized by the drug metabolizing enzyme CYP3A. As CYP3A4 undergoes major changes during childhood, we aimed to develop age-appropriate dosing recommendations for children of dexamethasone for PES, as proof of concept for PBPK modeling to individualize dosing for critically ill patients. Methods: All simulations were conducted in Simcyp™ v21 (a population-based PBPK modeling platform), using an available dexamethasone compound model and pediatric population model in which CYP3A4 ontogeny is incorporated. Published pharmacokinetic (PK) data was used for model verification. Evidence for the dose to prevent post-extubation stridor was strongest for 2-6 year old children, hence simulated drug concentrations resulting from this dose from this age group were targeted when simulating age-appropriate doses for the whole pediatric age range. Results: Dexamethasone plasma concentrations upon single and multiple intravenous administration were predicted adequately across the pediatric age range. Exposure-matched predictions of dexamethasone PK indicated that doses (in mg/kg) for the 2-6 years olds can be applied in 3 month-2 year old children, whereas lower doses are needed in children of other age groups (60% lower for 0-2 weeks, 40% lower for 2-4 weeks, 20% lower for 1-3 months, 20% lower for 6-12 year olds, 40% lower for 12-18 years olds). Discussion: We show that PBPK modeling is a valuable tool that can be used to develop model-informed recommendations using dexamethasone to prevent PES in children. Based on exposure matching, the dose of dexamethasone should be reduced compared to commonly used doses, in infants <3 months and children ≥6 years, reflecting age-related variation in drug disposition. PBPK modeling is an promising tool to optimize dosing of critically ill patients.
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Chytrids, often overshadowed by their other fungal counterparts, take center stage as we unravel the mysteries surrounding new species within Rhizophydiales and explore their unique characteristics. In the broader spectrum of chytrids, their significance lies not only in their roles as decomposers but also as key players in nutrient cycling within aquatic ecosystems as parasites and saprobes. Baited soil and aquatic samples collected from various provinces of Thailand, yielded new species of the Rhizophydiales (Chytridiomycota), some of which expanded previously single species genera. Our investigation incorporated a combination of morphological and phylogenetic approaches, enabling us to identify these isolates as distinct taxa. The novel isolates possess distinguishing features, such as variations in size and shape of the sporangium and zoospores, that somewhat differentiate them from described taxa. To confirm the novelty of the species, we employed robust phylogenetic analyses using maximum likelihood and bayesian methods. The results provided strong support for the presence of eight distinct lineages within the Rhizophydiales, representing our newly discovered species. Furthermore, we employed Poisson Tree Processes to infer putative species boundaries and supplement evidence for the establishment of our new Rhizophydiales species. By meticulously exploring their morphological characteristics and genetic makeup, we expand the known catalogue of fungal diversity by describing Alphamyces thailandicus, Angulomyces ubonensis, Gorgonomyces aquaticus, G. chiangraiensis, G. limnicus, Pateramyces pingflumenensis, Terramyces aquatica, and T. flumenensis and also provide valuable insights into the intricacies of this order. This newfound knowledge not only enriches our understanding of Rhizophydiales but also contributes significantly to the broader field of mycology, addressing a critical gap in the documentation of fungal species. The identification and characterization of these eight novel species mark a noteworthy stride towards a more comprehensive comprehension of fungal ecosystems and their vital role.
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BACKGROUND: Antenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome (RDS). The current treatment regimens, effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures. Data from nonhuman primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels. OBJECTIVE: We aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures. STUDY DESIGN: A pregnancy physiologically based pharmacokinetic (PBPK) model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal pharmacokinetic data. The verified pregnancy PBPK models were then used to simulate alternative dosing regimens to establish a model-informed dose. RESULTS: Ex vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7±1.7% and for dexamethasone 14.4±1.5%, the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy PBPK models that include these ex vivo-derived placental transfer rates accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular, a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from 4 times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours. CONCLUSION: A combined placenta perfusion and pregnancy PBPK modeling approach adequately predicted both maternal and fetal drug exposures of 2 antenatal corticosteroids (ACSs). Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated ACS scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.
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BACKGROUND: Team-based care is critical to achieving health care value while maximizing patient outcomes. Few descriptions exist of graduate-level team training interventions and practice models. Experience from the multisite, decade-long Veterans Affairs (VA) Centers of Excellence in Primary Care Education provides lessons for developing internal medicine training experiences in interprofessional clinical learning environments. METHODS: A review of multisite demonstration project transforming traditional silo-model training to interprofessional team-based primary care. Using iterative quality improvement approaches, sites evaluated curricula with learner, faculty and staff feedback. Learner- and patient-level outcomes and organizational culture change were examined using mixed methods, within and across sites. Participants included more than 1600 internal medicine, nurse practitioner, nursing, pharmacy, psychology, social work and physical therapy trainees. This took place in seven academic university-affiliated VA primary care clinics with patient centered medical home design RESULTS: Each site developed innovative design and curricula using common competencies of shared decision making, sustained relationships, performance improvement and interprofessional collaboration. Educational strategies included integrated didactics, workplace collaboration and reflection. Sites shared implementation best practices and outcomes. Cross-site evaluations of the impacts of these educational strategies indicated improvements in trainee clinical knowledge, team-based approaches to care and interest in primary care careers. Improved patient outcomes were seen in the quality of chronic disease management, reduction in polypharmacy, and reduced emergency department and hospitalizations. Evaluations of the culture of training environments demonstrated incorporation and persistence of interprofessional learning and collaboration. CONCLUSIONS: Aligning education and practice goals with cross-site collaboration created a robust interprofessional learning environment. Improved trainee/staff satisfaction and better patient care metrics supports use of this model to transform ambulatory care training. TRIAL REGISTRATION: This evaluation was categorized as an operation improvement activity by the Office of Academic Affairs based on Veterans Health Administration Handbook 1058.05, in which information generated is used for business operations and quality improvement (Title 38 Code of Federal Regulations Part 16 (38 CFR 16.102(l)). The overall project was subject to administrative oversight rather Human Subjects Institutional Review Board, as such informed consent was waived as part of the project implementation and evaluation.
Subject(s)
Curriculum , Organizational Culture , Primary Health Care , United States Department of Veterans Affairs , Humans , Primary Health Care/standards , United States , Patient Care Team , Quality Improvement , Organizational Innovation , Patient-Centered Care/standards , Hospitals, Veterans/standards , Internal Medicine/educationABSTRACT
BACKGROUND: Uterine fibroids are non-cancerous neoplasms that arise from the uterus affecting over 75% of women. However, there is a disparity with Black women having an increased prevalence of nearly 80%. Black women also experience increased symptom burden, including younger age at the time of diagnosis and increased number and volume of fibroids. Less is known about other ethnoracially diverse women such as Latinas and the potential cultural impacts on fibroid burden and treatment. METHODS: Community engagement studios were conducted to facilitate discussions with stakeholders on their uterine fibroid and menstruation experience. We recruited Black women (n = 6) diagnosed with uterine fibroids and Latinas (n = 7) without uterine fibroids. We held two virtual community engagement studios split by uterine fibroid diagnosis. The studios were not audio recorded and notes were taken by four notetakers. The notes were thematically analyzed in Atlas.ti using content analysis. RESULTS: Participants felt there was a lack of discussion around menstruation overall, whether in the home or school settings. This lack of menstruation education was pronounced when participants had their first menstruation experience, with many unaware of what to expect. This silence around menstruation led to a normalization of painful menstruation symptoms. When it came to different treatment options for uterine fibroids, some women wanted to explore alternative treatments but were dismissed by their healthcare providers. Many participants advocated for having discussions with their healthcare provider about life goals to discuss different treatment options for their uterine fibroids. CONCLUSION: Despite uterine fibroid diagnosis, there is silence around menstruation. Menstruation is a normal biological occurrence and needs to be discussed to help prevent delayed diagnosis of uterine fibroids and possibly other gynecological disorders. Along with increased discussions around menstruation, further discussion is needed between healthcare providers and uterine fibroid patients to explore appropriate treatment options.
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Leiomyoma , Menstruation , Female , Humans , Black People , Dysmenorrhea , Hispanic or Latino , Leiomyoma/complications , Black or African AmericanABSTRACT
PURPOSE: The variations in the diameter of the optic nerve (ON) are important clinically in the diagnosis of conditions associated with the ON such as raised intracranial pressure, meningioma, optic neuritis, and Grave's orbitopathy. This study determined the normal diameters of the ON in adult Nigerians seen in a Hospital in Delta State. METHODS: Axial T1-weighted brain magnetic resonance imaging images of 150 patients (75 males and 75 females) aged ≥20 years were retrieved from the hospital's radiological database and retrospectively used to evaluate the diameter of the ON on axial and coronal sections. The data were analyzed and summarized using descriptive statistics. The mean diameters were compared based on gender, side, and age groups and correlated with age using inferential statistics. The significance level was considered at 5%. RESULTS: The diameter of the ON measured 0.45 ± 0.07 cm on the coronal section, besides 0.50 ± 0.07 cm, and 0.46 ± 0.06 cm at 0.3 cm and 0.8 cm from the posterior pole of the globe, respectively, on the axial slices. The diameters were significantly larger in males than in females (P < 0.05) and were symmetrical. However, they lacked significant association with age (P > 0.05). The three diameters measured had a significant positive correlation with each other (P < 0.05). CONCLUSION: The study provides a normal range of ON diameter in the study center to aid in the diagnosis of raised intracranial pressure and pathologies involving the nerve and its sheath.
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Exertional dyspnea has been documented in US military personnel after deployment to Iraq and Afghanistan. We studied whether continued exertional dyspnea in this patient population is associated with pulmonary vascular disease (PVD). We performed detailed histomorphometry of pulmonary vasculature in 52 Veterans with biopsy-proven post-deployment respiratory syndrome (PDRS) and then recruited five of these same Veterans with continued exertional dyspnea to undergo a follow-up clinical evaluation, including symptom questionnaire, pulmonary function testing, surface echocardiography, and right heart catheterization (RHC). Morphometric evaluation of pulmonary arteries showed significantly increased intima and media thicknesses, along with collagen deposition (fibrosis), in Veterans with PDRS compared to non-diseased (ND) controls. In addition, pulmonary veins in PDRS showed increased intima and adventitia thicknesses with prominent collagen deposition compared to controls. Of the five Veterans involved in our clinical follow-up study, three had borderline or overt right ventricle (RV) enlargement by echocardiography and evidence of pulmonary hypertension (PH) on RHC. Together, our studies suggest that PVD with predominant venular fibrosis is common in PDRS and development of PH may explain exertional dyspnea and exercise limitation in some Veterans with PDRS.
Subject(s)
Afghan Campaign 2001- , Hypertension, Pulmonary , Pulmonary Artery , Humans , Male , Pulmonary Artery/pathology , Pulmonary Artery/physiopathology , Pulmonary Artery/diagnostic imaging , Adult , Hypertension, Pulmonary/pathology , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/etiology , Middle Aged , Female , Iraq War, 2003-2011 , Pulmonary Veins/pathology , Pulmonary Veins/physiopathology , Pulmonary Veins/diagnostic imaging , Dyspnea/etiology , Dyspnea/physiopathology , Veterans , Case-Control Studies , Veterans Health , Biopsy , FibrosisABSTRACT
BACKGROUND AND OBJECTIVES: Neonatal endotracheal tube (ETT) size recommendations are based on limited evidence. We sought to determine data-driven weight-based ETT sizes for infants undergoing tracheal intubation and to compare these with Neonatal Resuscitation Program (NRP) recommendations. METHODS: Retrospective multicenter cohort study from an international airway registry. We evaluated ETT size changes (downsizing to a smaller ETT during the procedure or upsizing to a larger ETT within 7 days) and risk of procedural adverse outcomes associated with first-attempt ETT size selection when stratifying the cohort into 200 g subgroups. RESULTS: Of 7293 intubations assessed, the initial ETT was downsized in 5.0% of encounters and upsized within 7 days in 1.5%. ETT downsizing was most common when NRP-recommended sizes were attempted in the following weight subgroups: 1000 to 1199 g with a 3.0 mm (12.6%) and 2000 to 2199 g with a 3.5 mm (17.1%). For infants in these 2 weight subgroups, selection of ETTs 0.5 mm smaller than NRP recommendations was independently associated with lower odds of adverse outcomes compared with NRP-recommended sizes. Among infants weighing 1000 to 1199 g: any tracheal intubation associated event, 20.8% with 2.5 mm versus 21.9% with 3.0 mm (adjusted OR [aOR] 0.62, 95% confidence interval [CI] 0.41-0.94); severe oxygen desaturation, 35.2% with 2.5 mm vs 52.9% with 3.0 mm (aOR 0.53, 95% CI 0.38-0.75). Among infants weighing 2000 to 2199 g: severe oxygen desaturation, 41% with 3.0 mm versus 56% with 3.5mm (aOR 0.55, 95% CI 0.34-0.89). CONCLUSIONS: For infants weighing 1000 to 1199 g and 2000 to 2199 g, the recommended ETT size was frequently downsized during the procedure, whereas 0.5 mm smaller ETT sizes were associated with fewer adverse events and were rarely upsized.
Subject(s)
Intubation, Intratracheal , Resuscitation , Humans , Infant, Newborn , Cohort Studies , Intubation, Intratracheal/methods , OxygenABSTRACT
Bovine milk contains bioactive proteins, carbohydrates, and phospholipids with immunomodulatory properties impacting human immunity, potentially contributing to resistance to infections and allergies through diverse mechanisms. One such mechanism is the enhancing of the innate immune response to secondary pathogen-related stimuli, termed innate immune training. Although in vitro studies demonstrate that milk immunoglobulin G (IgG) can train human monocytes, evidence for in vivo immune training is limited. To explore the potential of bovine IgG for inducing innate immune training in vivo, this human study utilized an IgG-rich whey protein concentrate (WPC). Healthy male volunteers were assigned to a high dose WPC, low dose WPC, or placebo group. Blood was collected pre- and post-two weeks of WPC consumption. Peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with TLR ligands, evaluating IL-6 and TNF-α production by monocytes, myeloid DCs, and plasmacytoid DCs. Additionally, RNA was isolated for differential gene expression (DGE) analysis. Results indicated that the two-week WPC intervention did not influence the ex vivo response of studied cells to TLR agonists. Furthermore, PBMC gene expression patterns showed no significant differences between the placebo and high dose WPC groups. The data suggests that oral WPC ingestion did not enhance immune responses in young, healthy male participants.
Subject(s)
Leukocytes, Mononuclear , Toll-Like Receptors , Humans , Male , Whey Proteins/pharmacology , Healthy Volunteers , Immunoglobulin G , Gene ExpressionABSTRACT
Salmonella serovars Typhi and Paratyphi cause a prolonged illness known as enteric fever, whereas other serovars cause acute gastroenteritis. Mechanisms responsible for the divergent clinical manifestations of nontyphoidal and enteric fever Salmonella infections have remained elusive. Here, we show that S. Typhi and S. Paratyphi A can persist within human macrophages, whereas S. Typhimurium rapidly induces apoptotic macrophage cell death that is dependent on Salmonella pathogenicity island 2 (SPI2). S. Typhi and S. Paratyphi A lack 12 specific SPI2 effectors with pro-apoptotic functions, including nine that target nuclear factor κB (NF-κB). Pharmacologic inhibition of NF-κB or heterologous expression of the SPI2 effectors GogA or GtgA restores apoptosis of S. Typhi-infected macrophages. In addition, the absence of the SPI2 effector SarA results in deficient signal transducer and activator of transcription 1 (STAT1) activation and interleukin 12 production, leading to impaired TH1 responses in macrophages and humanized mice. The absence of specific nontyphoidal SPI2 effectors may allow S. Typhi and S. Paratyphi A to cause chronic infections. IMPORTANCE: Salmonella enterica is a common cause of gastrointestinal infections worldwide. The serovars Salmonella Typhi and Salmonella Paratyphi A cause a distinctive systemic illness called enteric fever, whose pathogenesis is incompletely understood. Here, we show that enteric fever Salmonella serovars lack 12 specific virulence factors possessed by nontyphoidal Salmonella serovars, which allow the enteric fever serovars to persist within human macrophages. We propose that this fundamental difference in the interaction of Salmonella with human macrophages is responsible for the chronicity of typhoid and paratyphoid fever, suggesting that targeting the nuclear factor κB (NF-κB) complex responsible for macrophage survival could facilitate the clearance of persistent bacterial infections.
Subject(s)
Salmonella typhi , Salmonella , Typhoid Fever , Humans , Animals , Mice , Salmonella typhi/genetics , Typhoid Fever/microbiology , NF-kappa B , Macrophages/microbiologyABSTRACT
OBJECTIVE: This study aims to determine the added value of a geometrically accurate diffusion-weighted (DW-) MRI sequence on the accuracy of gross tumor volume (GTV) delineations, using pathological tumor delineations as a ground truth. METHODS: Sixteen patients with laryngeal or hypopharyngeal carcinoma were included. After total laryngectomy, the specimen was cut into slices. Photographs of these slices were stacked to create a 3D digital specimen reconstruction, which was registered to the in vivo imaging. The pathological tumor (tumorHE) was delineated on the specimen reconstruction. Six observers delineated all tumors twice: once with only anatomical MR imaging, and once (a few weeks later) when DW sequences were also provided. The majority voting delineation of session one (GTVMRI) and session two (GTVDW-MRI), as well as the clinical target volumes (CTVs), were compared to the tumorHE. RESULTS: The mean tumorHE volume was 11.1 cm3, compared to a mean GTVMRI volume of 18.5 cm3 and a mean GTVDW-MRI volume of 15.7 cm3. The median sensitivity (tumor coverage) was comparable between sessions: 0.93 (range: 0.61-0.99) for the GTVMRI and 0.91 (range: 0.53-1.00) for the GTVDW-MRI. The CTV volume also decreased when DWI was available, with a mean CTVMR of 47.1 cm3 and a mean CTVDW-MRI of 41.4 cm3. Complete tumor coverage was achieved in 15 and 14 tumors, respectively. CONCLUSION: GTV delineations based on anatomical MR imaging tend to overestimate the tumor volume. The availability of the geometrically accurate DW sequence reduces the GTV overestimation and thereby CTV volumes, while maintaining acceptable tumor coverage.
Subject(s)
Diffusion Magnetic Resonance Imaging , Hypopharyngeal Neoplasms , Laryngeal Neoplasms , Humans , Hypopharyngeal Neoplasms/diagnostic imaging , Hypopharyngeal Neoplasms/pathology , Laryngeal Neoplasms/diagnostic imaging , Laryngeal Neoplasms/pathology , Diffusion Magnetic Resonance Imaging/methods , Male , Aged , Middle Aged , Female , Tumor Burden , LaryngectomyABSTRACT
PURPOSE OF REVIEW: Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders characterized by increased susceptibility to infection and/or aberrant regulation of immunological pathways. This review summarizes and highlights the new IEI disorders in the International Union of Immunological Societies (IUIS) 2022 report and current trends among new PIDs. RECENT FINDINGS: Since the 2019 IUIS report and the 2021 IUIS interim update, the IUIS IEI classification now includes 485 validated IEIs. Increasing utilization of genetic testing and advances in the strategic evaluation of genetic variants has continued to drive the identification of, not only novel IEI disorders, but additional genetic etiologies for known IEI disorders and phenotypes. SUMMARY: The recognition of new IEIs continues to advance at a rapid pace, which is due in part to increased performance and application of genetic modalities as well as expansion of the underlying science that is applied to convincingly establish causality. These disorders, as a whole, continue to emphasize the specificity of immunity, complexity of immune mechanisms, and the fine balance that defines immune homeostasis.
Subject(s)
Genetic Testing , Humans , Homeostasis , PhenotypeABSTRACT
Adolescent and young adult cancer survivors (AYAs) are uniquely challenged with navigating health care systems during an important developmental phase of life. During the Coronavirus disease 2019 (COVID-19) pandemic, many people experienced social isolation, mental health symptoms, and schooling and employment changes, which may have affected vulnerable AYA cancer survivors. The purpose of this integrative review is to explore the psychosocial impact of the COVID-19 pandemic on AYA cancer survivors in the United States. A literature search was conducted in November 2022 using PubMed, Web of Science, and SCOPUS databases with the following search terms: distress*, depress*, lonel*, anx*, insomnia*, cancer*, neoplasm, COVID-19, coronavirus, young adult, AYA, teen*, and adolescen*. The initial search yielded 468 articles. Inclusion criteria required that studies were conducted in the United States, published in English, with a sample of patients diagnosed with cancer between ages 15 and 39. After review and appraisal of each relevant article, eight were included. Through comparative analysis of eight articles, including qualitative and quantitative studies, three themes emerged: mental health impact, health care impact, and financial impact. Mental health impact included increased anxiety, worsening depression and social isolation, and sleep disturbances. Changes in health care included delays in care, medical cost-coping and benefits of virtual care. Financial difficulties included employment changes and benefits of remote work. The COVID-19 pandemic had an immense impact on the psychosocial health of AYA cancer survivors. It is essential that oncology providers and health care teams consider specific interventions to best serve the psychosocial needs of their AYA patients.