Management Strategies for Acute Pulmonary Embolism in the Intensive Care Unit.

TOPIC IMPORTANCE: Acute pulmonary embolism (PE) is a common disease encountered by pulmonologists, cardiologists, and critical care physicians throughout the world. For patients with high risk (defined by systemic hypotension) and intermediate high-risk (defined by the absence of systemic hypotension but the presence of numerous other concerning clinical and imaging features) acute PE, intensive care is often necessary. Initial management strategies should focus on optimization of right ventricular (RV) function while decisions about advanced interventions are being considered. REVIEW FINDINGS: Here we review the existing literature of various vasoactive agents, intravenous fluids and diuretics, and pulmonary vasodilators in both animal models and human trials of acute PE. We also review the potential complications of endotracheal intubation and positive pressure ventilation in acute PE. Finally, we review the data of veno-arterial extracorporeal membrane oxygen use in acute PE. The above interventions are discussed in the context of the underlying pathophysiology of acute RV failure in acute PE with corresponding illustrations. SUMMARY: Norepinephrine is a reasonable first choice for hemodynamic support with vasopressin as an adjunct. Intravenous loop diuretics may be useful if there is evidence of RV dysfunction or volume overload. Fluids should only be given if there is concern for hypovolemia and absence of RV dilatation. Supplemental oxygen administration should be considered even without hypoxemia. Positive pressure ventilation should be avoided if possible. VA-ECMO cannulation should be implemented early if ongoing deterioration occurs despite these interventions.

A rare case of Balo's disease in a young adult: A clinical presentation and management.

Key Clinical Message: Accurate diagnosis of rare neurological conditions like Balo's concentric sclerosis (BCS) is challenging but crucial for tailored treatment. Interdisciplinary collaboration and further research are essential to advance our understanding. Abstract: This case report presents a 32-year-old female patient with a puzzling neurological condition characterized by feverish feelings, joint pain, unclear speech, and an unsteady gait. Initial management did not lead to improvement, and further examination revealed neurological involvement and joint tenderness without signs of inflammatory arthritis. Laboratory investigations ruled out infectious and autoimmune causes. Magnetic resonance imaging (MRI) showed well-defined lesions with concentric rings, leading to a diagnosis of Balo' concentric sclerosis. Treatment with intravenous methylprednisolone resulted in limited improvement. This case highlights the importance of thorough evaluation and collaboration in diagnosing rare neurological conditions. Further research is needed to enhance the understanding and treatment of rare neurological disorders.

Circulating MicroRNAs associated with Bronchodilator Response in Childhood Asthma.

Rationale: Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology. Objective: The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation. Methods: We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into high and low bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N= 277) vs low (N= 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed. Results: We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR=2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways. Conclusion: MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients. Trial registration: LOCCS cohort [ClinicalTrials.gov number: NCT00156819], GACRS cohort [ClinicalTrials.gov number: NCT00021840].

Implementing Holistic Review Practices in a Pulmonary and Critical Care Fellowship.

Background: Medical schools have used holistic review in admissions to increase mission-aligned enrollment of students from backgrounds underrepresented in medicine. Graduate medical education programs have increasingly followed suit. However, there is a paucity of literature regarding holistic review at the fellowship level. Objective: Here, we share our experience implementing the Association of American Medical Colleges core principles of holistic review during the 2021 recruitment cycle. Methods: We used a partially asynchronous and online learning strategy to train division members on the principles of holistic review. Following the match, we conducted a survey of faculty members and fellows to understand their opinions on our holistic review training and implementation. Results: Although few of our colleagues clearly understood holistic review before the training, they were able to identify broad-based criteria that aligned with our division's mission and balanced applicants' experiences, attributes, competencies, and metrics. These were viewed as better selection criteria than traditional measures and were incorporated into the individualized consideration of applicants. Our survey had a 41.5% response rate, with 10 of 22 fellows and 24 of 60 faculty members responding. Most faculty members and fellows agreed that holistic review decreases socioeconomic disparities in fellowship recruitment (79.2% and 80.0%, respectively) and promotes inclusion and diversity (83.3% and 90.0%, respectively). Faculty members appeared more confident than fellows that our training efforts had influenced recruitment. All respondents agreed that it would be critical for such training to be repeated yearly. Conclusion: Although this was a single-institution experience, implementing holistic review was feasible and well received by faculty and fellows.

A Case of Allergic Bronchopulmonary Aspergillosis With Bronchial Asthma.

Allergic bronchopulmonary aspergillosis (ABPA) is a fungal hypersensitivity reaction in chronic lung diseases like bronchial asthma and cystic fibrosis. It is caused by an allergic reaction to aspergillus antigen in the lung mucus resulting in airway inflammation and damage. This condition usually presents in a patient with asthma as a poorly controlled disease with recurrent infection symptoms that do not respond to standard antibiotic therapy. Diagnosis is made by chest X-ray, computed tomography, eosinophilia, and raised serum IgE on serology and immunological tests for aspergillus antigen. Lack of diagnosis and treatment of the condition can lead to respiratory failure from bronchiectasis and pulmonary fibrosis.

Adolescent Pride Festival Attendees-Assessing Their Interactions With Primary Care Physicians.

PURPOSE: Pride festivals celebrate the lesbian, gay, bisexual, transgender (LGBT) community. This study aimed to describe adolescent Pride festival attendees, determine rates of accessing health care via their primary care physician (PCP), and assess if providers are discussing sex and offering screening for sexually transmitted infections (STIs) to these adolescents. METHODS: Adolescents, aged 13-17 years, attending the 2017 Minnesota Pride Festival were invited to complete an 18-question survey regarding gender identity, sexual orientation, access to a physician the preceding year, and whether sexual activity was discussed and/or STI screening provided at these encounters. RESULTS: A total of 490 surveys were evaluated. Sixty-nine percent of respondents identified as having nonheterosexual orientation. Rural participants were significantly more likely to identify as LGBT than urban or suburban participants. The majority (90%) of adolescents had been seen in the past year by a physician. Of these, 68% had been asked a sexual history, and 29% were offered STI testing. Older adolescents were more likely to be asked about sex and offered STI testing by a physician. Identifying as LGBT was not associated with rate of sexual history taken or STI screening offered but was associated with perceived need for STI testing. CONCLUSIONS: LGBT youth attending Minnesota Pride are accessing a PCP with the same regularity as cisgender, heterosexual peers but are infrequently offered STI testing, despite knowledge of increased STI rates in this population. Taking a sexual history and screening for STIs is something all physicians can do and represents an important first step in any STI reduction initiative.

Creating Online Training for Procedures in Global Health with PEARLS (Procedural Education for Adaptation to Resource-Limited Settings).

The authors describe a multiinstitutional collaborative project to address a gap in global health training by creating a free online platform to share a curriculum for performing procedures in resource-limited settings. This curriculum called PEARLS (Procedural Education for Adaptation to Resource-Limited Settings) consists of peer-reviewed instructional and demonstration videos describing modifications for performing common pediatric procedures in resource-limited settings. Adaptations range from the creation of a low-cost spacer for inhaled medications to a suction chamber for continued evacuation of a chest tube. By describing the collaborative process, we provide a model for educators in other fields to collate and disseminate procedural modifications adapted for their own specialty and location, ideally expanding this crowd-sourced curriculum to reach a wide audience of trainees and providers in global health.

A molecular evolution approach to study the roles of tropomyosin in fission yeast.

Tropomyosin, a coiled-coil protein that binds along the length of the actin filament, is a universal regulator of the actin cytoskeleton. We have taken a bioinformatics/proteomic approach to studying structure-function relationships in this protein. The presence of a single, essential tropomyosin gene, cdc8, in fission yeast, Schizosaccharomyces pombe, enables a systems-based approach to define the residues that are important for cellular functions. Using molecular evolution methodologies we identified the most conserved residues and related them to the coiled coil structure. Mutants in which one or more of 21 of the most conserved surface residues was mutated to Ala were tested for the ability to rescue growth of a temperature-sensitive cdc8 mutant when overexpressed at the restrictive temperature. Based on altered morphology of the septum and actin cytoskeleton, we selected three sets of mutations for construction of mutant cdc8 strains using marker reconstitution mutagenesis and analysis of recombinant protein in vitro: D16A.K30A, V114S.E117A.H118A and R121A.D131A.E138A. The mutations have sequence-specific effects on cellular morphology including cell length, organization of cytoskeletal structures (actin patches, actin cables and contractile rings), and in vitro actin affinity, lending credence to the proteomic approach introduced here. We propose that bioinformatics is a valid analysis tool for defining structure-function relationships in conserved proteins in this model organism.

Mutations changing tropomodulin affinity for tropomyosin alter neurite formation and extension.

Assembly of the actin cytoskeleton is an important part of formation of neurites in developing neurons. Tropomodulin, a tropomyosin-dependent capping protein for the pointed end of the actin filament, is one of the key players in this process. Tropomodulin binds tropomyosin in two binding sites. Tmod1 and Tmod2, tropomodulin isoforms found in neurons, were overexpressed in PC12 cells, a model system for neuronal differentiation. Tmod1 did not affect neuronal differentiation; while cells expressing Tmod2 showed a significant reduction in the number and the length of neurites. Both tropomodulins bind short α-, γ- and δ-tropomyosin isoforms. Mutations in one of the tropomyosin-binding sites of Tmod1, which increased its affinity to short γ- and δ-tropomyosin isoforms, caused a decrease in binding short α-tropomyosin isoforms along with a 2-fold decrease in the length of neurites. Our data demonstrate that Tmod1 is involved in neuronal differentiation for proper neurite formation and outgrowth, and that Tmod2 inhibits these processes. The mutations in the tropomyosin-binding site of Tmod1 impair neurite outgrowth, suggesting that the integrity of this binding site is critical for the proper function of Tmod1 during neuronal differentiation.

Identification of residues within tropomodulin-1 responsible for its localization at the pointed ends of the actin filaments in cardiac myocytes.

Tropomodulin is a tropomyosin-dependent actin filament capping protein involved in the structural formation of thin filaments and in the regulation of their lengths through its localization at the pointed ends of actin filaments. The disordered N-terminal domain of tropomodulin contains three functional sites: two tropomyosin-binding and one tropomyosin-dependent actin-capping sites. The C-terminal half of tropomodulin consists of one compact domain containing a tropomyosin-independent actin-capping site. Here we determined the structural properties of tropomodulin-1 that affect its roles in cardiomyocytes. To explore the significance of individual tropomyosin-binding sites, GFP-tropomodulin-1 with single mutations that destroy each tropomyosin-binding site was expressed in cardiomyocytes. We demonstrated that both sites are necessary for the optimal localization of tropomodulin-1 at thin filament pointed ends, with site 2 acting as the major determinant. To investigate the functional properties of the tropomodulin C-terminal domain, truncated versions of GFP-tropomodulin-1 were expressed in cardiomyocytes. We discovered that the leucine-rich repeat (LRR) fold and the C-terminal helix are required for its proper targeting to the pointed ends. To investigate the structural significance of the LRR fold, we generated three mutations within the C-terminal domain (V232D, F263D, and L313D). Our results show that these mutations affect both tropomyosin-independent actin-capping activity and pointed end localization, most likely by changing local conformations of either loops or side chains of the surfaces involved in the interactions of the LRR domain. Studying the influence of these mutations individually, we concluded that, in addition to the tropomyosin-independent actin-capping site, there appears to be another regulatory site within the tropomodulin C-terminal domain.

Evidence of angiogenic vessels in Alzheimer's disease.

Alterations in the blood brain barrier and brain vasculature may be involved in neurodegeneration and neuroinflammation. We sought to determine if vascular remodeling characterized by angiogenic vessels or increased vascular density, occurred in pathologically confirmed Alzheimer's disease (AD) postmortem human brain tissues. We examined brains of deceased, older catholic clergy from the Religious Order Study, a longitudinal clinical-pathological study of aging and AD. The hippocampus, midfrontal cortex, substantia nigra, globus pallidus and locus ceruleus were examined for integrin alphavbeta3 immunoreactivity, a marker of angiogenesis, and vascular densities. Activated microglia cell counts were also performed. All areas except the globus pallidus exhibited elevated alphavbeta3 immunoreactivity in AD cases compared with controls. Only in the hippocampus did the ongoing angiogenesis result in increased vascular density compared with controls. Vascular density was correlated with Abeta load in the hippocampus and alphavbeta3 reactivity was correlated with neurofibrillary tangles in the midfrontal cortex and in the substantia nigra. These data indicate that ongoing angiogenesis is present in brain regions affected by AD pathology and may be related to tissue injury.

Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy.

The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.