Dyspnea and Dyspnea-Associated Anxiety in the ICU Patient Population: A Narrative Review for CL Psychiatrists.

BACKGROUND: Consultation-liaison psychiatrists frequently address dyspnea in intensive care unit (ICU) patients. Dyspnea is common in this patient population, but is frequently misunderstood and underappreciated in noncommunicative ICU patients. OBJECTIVE: This paper provides an updated review on dyspnea specifically in the ICU population, including its pathophysiology and management, pharmacological and nonpharmacological, aimed at consultation-liaison psychiatrists consulting in ICU. METHODS: A literature review was conducted with PubMed, querying published articles for topics associated with dyspnea and dyspnea-associated anxiety in ICU patient populations. When literature in ICU populations was limited, information was deduced from dyspnea and anxiety management from non-ICU populations. Articles discussing the definition of dyspnea, mechanistic pathways, screening tools, and pharmacologic and nonpharmacologic management were included. RESULTS: A reference guide was created to help consultation-liaison psychiatrists and intensivists in the screening and treatment of dyspnea and dyspnea-associated anxiety in critically ill patients. CONCLUSIONS: Dyspnea is frequently associated with anxiety, prolonged days on mechanical ventilation, and worse quality of life after discharge. It can also increase the risk of posttraumatic stress disorder post-ICU discharge. However, it is not routinely screened for, identified, or addressed in the ICU. This manuscript provides an updated review on dyspnea and dyspnea-associated anxietyin the ICU population, including its pathophysiology and management, and offers a useful reference for consultation-liaison psychiatrists to provide treatment recommendations.

Arrest Outcome Consortium Registry Analysis [AOCRA 2022]: Outcome Statistics of Cardiac Arrest in Tertiary Care Hospitals in India, Analysis of Five Year Data of Indian Online Cardiac Arrest Registry, www.aocregistry.com.

Aim and background: To publish data with outcome statistics from our online cardiac arrest (CA) outcome consortium (AOC) online registry. Materials and methods: Data on cardiac arrest (CA) from tertiary care hospitals were collected on the AOC registry online portal from January 2017 to May 2022. Survival endpoints from cardiac arrest events like ROSC, and survival at hospital discharge with neurological status at discharge were analyzed and presented. Studies of demographics, the association of outcome with age, gender, bystander CPR, low and no flow times, and admission lactate were also done along with suitable statistical analysis. Results: Out of 2,235 CA, 2,121 received CPR (1,998 IHCA, 123 Out of hospital Cardiac Arrest (OHCA)) as 114 were DNR. The males-female ratio was 70:30. Average age at arrest was 58.7 years. 26% OHCA received bystander CPR but survival advantage was not significant. (with 16%, without 14% p = 0.78). Asystole (67.7%), Pulseless Electrical Activity (PEA) (25.6%), and VF/pVT (6.7%) as first rhythm significantly influence survival (4.9, 8.6 and 39.4%: p < 0.001) ROSC was achieved in 355 (16.7%), with 173 (8.2%) alive and 141 (6.6%) having good (CPC ≤ 2) neurological state at discharge. At discharge, survival as well as CPC ≤ 2 outcomes were significantly better in females. On multivariate regression analysis, first rhythm and low flow time influence survival at discharge. Admission lactate (available only in 102 OHCA) was lower in survivors than non-survivors 10.3 vs 11.5 mmol/L but the difference was not statistically significant (p = 0.397]. Conclusion: Data from our AOC registry shows poor overall survival from CA. The Female gender had a higher survival rate. Ventricular Fibrillation/Pulseless Ventricular Tachycardia (VF/pVT) as first rhythm and low flow time influence the survival to discharge (CTRI/2022/11/047140). How to cite this article: Clerk AM, Patel K, Shah BA, Prajapati D, Shah RJ, Rachhadia J, et al. Arrest Outcome Consortium Registry Analysis [AOCRA 2022]: Outcome Statistics of Cardiac Arrest in Tertiary Care Hospitals in India, Analysis of Five Year Data of Indian Online Cardiac Arrest Registry, www.aocregistry.com. Indian J Crit Care Med 2023;27(5):322-329.

Expanding the role of pneumatic dilation for nonachalasia patients: a comparative study.

BACKGROUND AND AIMS: Treatment options for nonachalasia obstructive disorders of the esophagogastric junction (EGJ) are limited. The aim of this study was to assess the treatment efficacy of pneumatic dilation (PD) for the disorders of EGJ outflow obstruction (EGJOO) and postfundoplication EGJ obstruction (PF-EGJO) and to assess attitudes regarding training in PD. METHODS: This was a 2-part study. The main study was a prospective, single-center study comparing treatment outcomes after PD in patients with EGJOO and PF-EGJO, defined using manometry criteria, versus achalasia. Treatment success was defined as a post-PD Eckardt score (ES) of ≤2 at the longest duration of follow-up available. In a substudy, a 2-question survey was sent to 78 advanced endoscopy fellowship sites in the United States regarding training in PD. RESULTS: Of the 58% of respondents to the advanced endoscopy program director survey, two-thirds reported no training in PD at their program. The primary rationale cited was lack of a clinical need for PD. Sixty-one patients (15 achalasia, 32 EGJOO, and 14 PF-EGJO) were included in the main study with outcomes available at a mean follow-up of 8.8 months. Overall, mean ES decreased from 6.30 to 2.89 (P < .0001), and a mean percentage of improvement in symptoms reported by patients was 55.3%. ES ≤2 was achieved by 33 of 61 patients (54.1%). CONCLUSIONS: PD is an effective treatment for the nonachalasia obstructive disorders of the EGJ. There may be a current gap in training and technical expertise in PD.

Gastric submucosal mass lesions.

PURPOSE OF REVIEW: Gastric submucosal mass lesions are a collection of tumours that arise in the stomach and are deep to the mucosal layer. Distinct from gastric epithelial carcinomas, these tumours are generally more indolent. They are often found incidentally on upper endoscopy. Most often they present as smooth protuberant masses covered by normal intact gastric mucosa. The majority are asymptomatic. Endoscopic ultrasound (EUS) is frequently employed to further characterize the lesions. EUS can be diagnostic of some lesions, such as lipomas, and can be used to guide fine needle aspiration to diagnose others. Adding to the traditional management approaches of observation and surgical resection, numerous new and emerging endoscopic therapies are now being used to resect these gastric tumours. RECENT FINDINGS: This review focuses on evolving strategies in the diagnosis and management of submucosal mass lesions. Although surgical intervention was once the lone option for intervention, there are an increasing number of endoscopic therapies. There have also been advancements in neoadjuvant therapies and in distinguishing the malignant potential of submucosal mass lesions. SUMMARY: Gastric submucosal lesions are common. EUS is frequently indicated in the evaluation and diagnosis. For tumours for which observation is not recommended, novel endoscopic therapies may offer less invasive management options.

The druggable genome: Twenty years later.

The concept of the druggable genome has been with us for 20 years. During this time, researchers have developed several methods and resources to help assess a target's druggability. In parallel, evidence for target-disease associations has been collated at scale by Open Targets. More recently, the Protein Data Bank in Europe (PDBe) have built a knowledge base matching per-residue annotations with available protein structure. While each resource is useful in isolation, we believe there is enormous potential in bringing all relevant data into a single knowledge graph, from gene-level to protein residue. Automation is vital for the processing and assessment of all available structures. We have developed scalable, automated workflows that provide hotspot-based druggability assessments for all available structures across large numbers of targets. Ultimately, we will run our method at a proteome scale, an ambition made more realistic by the arrival of AlphaFold 2. Bringing together annotations from the residue up to the gene level and building connections within the graph to represent pathways or protein-protein interactions will create complexity that mirrors the biological systems they represent. Such complexity is difficult for the human mind to utilise effectively, particularly at scale. We believe that graph-based AI methods will be able to expertly navigate such a knowledge graph, selecting the targets of the future.

Smoking and pregnancy: The era of electronic nicotine delivery systems.

Electronic nicotine delivery systems have been commercially available in the United States since 2007. Despite a decrease in combustible cigarette use, electronic nicotine delivery systems use has dramatically increased among both adults and adolescents. These devices have been marketed as smoking cessation aids, although data on their efficacy are scarce. Pregnant women are an especially vulnerable population susceptible to claims of safety and efficacy, and the medical community remains inadequately informed on how to counsel these women. The purpose of this article is to review known literature regarding the use of electronic nicotine delivery systems in pregnancy, to understand the differences between cigarettes and electronic nicotine delivery systems use in pregnancy, and to further guide clinicians on how to advise the pregnant woman on their use.

An automated, high-throughput methodology optimized for quantitative cell-free mitochondrial and nuclear DNA isolation from plasma.

Progress in the study of circulating, cell-free nuclear DNA (ccf-nDNA) in cancer detection has led to the development of noninvasive clinical diagnostic tests and has accelerated the evaluation of ccf-nDNA abundance as a disease biomarker. Likewise, circulating, cell-free mitochondrial DNA (ccf-mtDNA) is under similar investigation. However, optimal ccf-mtDNA isolation parameters have not been established, and inconsistent protocols for ccf-nDNA collection, storage, and analysis have hindered its clinical utility. Until now, no studies have established a method for high-throughput isolation that considers both ccf-nDNA and ccf-mtDNA. We initially optimized human plasma digestion and extraction conditions for maximal recovery of these DNAs using a magnetic bead-based isolation method. However, when we incorporated this method onto a high-throughput platform, initial experiments found that DNA isolated from identical human plasma samples displayed plate edge effects resulting in low ccf-mtDNA reproducibility, whereas ccf-nDNA was less affected. Therefore, we developed a detailed protocol optimized for both ccf-mtDNA and ccf-nDNA recovery that uses a magnetic bead-based isolation process on an automated 96-well platform. Overall, we calculate an improved efficiency of recovery of ∼95-fold for ccf-mtDNA and 20-fold for ccf-nDNA when compared with the initial procedure. Digestion conditions, liquid-handling characteristics, and magnetic particle processor programming all contributed to increased recovery without detectable positional effects. To our knowledge, this is the first high-throughput approach optimized for ccf-mtDNA and ccf-nDNA recovery and serves as an important starting point for clinical studies.

The landscape of viral associations in human cancers.

Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.

Should We Screen Oncotype DX Eligible Patients With Breast MRI?

PURPOSE: Oncotype DX is a genomic test used to predict chemotherapy benefit and recurrence risk in early stage breast cancer patients. A previous study has shown that in patients with multiple tumors sent for Oncotype DX analysis, differing results between the tumors were yielded that ultimately changed chemotherapy management in 27% of cases. The purpose of this study is to determine the utility of preoperative MRI in Oncotype DX eligible patients. METHODS: A retrospective, Institutional review board approved study identified 888 consecutive new breast cancer patients from 2012 to 2016 at a single institution and identified 541 patients who potentially would be eligible for Oncotype DX. Frequency of additional disease in this population group was recorded. The method of imaging used, either conventional imaging (mammography and ultrasound) or additional MRI, was evaluated. RESULTS: Of 541 patients, 360 patients had conventional imaging performed only and 181 patients had an additional breast MRI. Of 541 patients, 73 patients (13.5%) had additional biopsy proven multifocal, multicentric, or contralateral tumors identified. The total number of additional disease within the conventional imaging group was 39 of 360 patients (10.8%), vs 34 of 181 patients (18.8%) in the MRI group, which was statistically significant (P = 0.02). Total 34 of 73 patients (46.6%) had additional disease only detected by MRI. CONCLUSIONS: In patients who may be eligible for Oncotype DX evaluation, 13.5% of patients were found to have additional disease. Nearly half of the patients had additional disease only detected by MRI, indicating the potentially utility of preoperative MRI in this patient population.

Morphological processing in Chinese engages left temporal regions.

Morphological awareness, the ability to manipulate the smallest units of meaning, is critical for Chinese literacy. This is because Chinese characters typically reflect the morphemic, or morpho-syllabic units of language. Yet, the neurocognitive mechanisms underlying Chinese speakers' morphological processing remain understudied. Proficient readers (N = 14) completed morphological and phonological judgment tasks in Chinese, in both auditory and visual modalities, during fMRI imaging. Key to our inquiry were patterns of activation in left temporal regions, especially the superior temporal gyrus, which is critical for phonological processing and reading success. The findings revealed that morphological tasks elicited robust activation in superior and middle temporal regions commonly associated with automated phonological and lexico-semantic analyses. In contrast, the rhyme judgment task elicited greater activation in left frontal lobe regions, reflecting the analytical complexity of sound-to-print mapping in Chinese. The findings suggest that left temporal regions are sensitive to salient morpho-syllabic characteristics of a given language.

The Role of Motivational Interviewing in Children and Adolescents in Pediatric Care.

Motivational interviewing (MI) addresses patient ambivalence about a desired goal in a directed, patient-centered manner. MI intervention is established as a therapeutic tool within the pediatric population with positive outcomes for obesity, asthma, medication adherence, and HIV management. MI is especially promising within the adolescent population where increasing independence tends to contribute to poorer health outcomes. Multidisciplinary adaptation of the MI format works well to address traditionally difficult pediatric care issues such as obesity. In the future, MI training of physicians may incorporate an online medium for wider distribution. More research is required to determine the most efficacious style and to support the generalizability and reproducibility of MI interventions for widespread application. [Pediatr Ann. 2019;48(9):e376-e379.].

Petite Integration Factor 1 (PIF1) helicase deficiency increases weight gain in Western diet-fed female mice without increased inflammatory markers or decreased glucose clearance.

Petite Integration Factor 1 (PIF1) is a multifunctional helicase present in nuclei and mitochondria. PIF1 knock out (KO) mice exhibit accelerated weight gain and decreased wheel running on a normal chow diet. In the current study, we investigated whether Pif1 ablation alters whole body metabolism in response to weight gain. PIF1 KO and wild type (WT) C57BL/6J mice were fed a Western diet (WD) rich in fat and carbohydrates before evaluation of their metabolic phenotype. Compared with weight gain-resistant WT female mice, WD-fed PIF1 KO females, but not males, showed accelerated adipose deposition, decreased locomotor activity, and reduced whole-body energy expenditure without increased dietary intake. Surprisingly, PIF1 KO females did not show obesity-induced alterations in fasting blood glucose and glucose clearance. WD-fed PIF1 KO females developed mild hepatic steatosis and associated changes in liver gene expression that were absent in weight-matched, WD-fed female controls, linking hepatic steatosis to Pif1 ablation rather than increased body weight. WD-fed PIF1 KO females also showed decreased expression of inflammation-associated genes in adipose tissue. Collectively, these data separated weight gain from inflammation and impaired glucose homeostasis. They also support a role for Pif1 in weight gain resistance and liver metabolic dysregulation during nutrient stress.

Nonallergic Triggers and Comorbidities in Asthma Exacerbations and Disease Severity.

Asthma triggers are exogenous or endogenous factors that could worsen asthma acutely to cause an exacerbation, or perpetuate chronic symptoms and airflow limitation. Because it is well known that recent asthma exacerbations and poor symptom control are strong predictors of future disease activity, it is not surprising that the number of (allergic or nonallergic) asthma triggers in the environment correlates with the disease-related quality of life. There is a need to identify and avoid specific triggers as the centerpiece of disease management, especially in those with heightened sensitivity to certain factors.

Predictors of Short Intensive Care Unit Stay for Patients with Diabetic Ketoacidosis Using a Novel Emergency Department-Based Resuscitation and Critical Care Unit.

BACKGROUND: The resuscitation and critical care unit is a novel emergency department-intensive care unit designed to provide early critical care to emergency department patients for ≤24 h. OBJECTIVES: This study sought to identify clinical variables associated with short intensive care unit (ICU) stays in patients with diabetic ketoacidosis (DKA), who commonly require ICU-level care. METHODS: We conducted a retrospective, single-center, cross-sectional study of DKA patients ≥18 years of age who presented to an academic, urban hospital emergency department over 16 months. Patient demographics and clinical variables extracted from medical records were compared between prolonged ICU stay patients of ≥24 h versus short ICU stay patients (SSPs) of <24 h. ICU care was defined as treatment in the resuscitation and critical care unit or inpatient ICU. RESULTS: One hundred sixty-eight emergency department visits with a primary diagnosis of DKA were analyzed. There were 53 prolonged ICU stay patients, 58 SSPs, and 57 patients required no ICU time. SSPs had significantly higher initial serum bicarbonate (13.0 vs. 9.0 mEq/L, p = 0.01) and shorter anion gap closure time (9.8 vs. 14.4 hours, p = 0.003). Medication nonadherence was a significantly more frequent precipitant in SSPs (67.2% vs. 47.2%, p = 0.03). Initial anion gap, glucose, beta-hydroxybutyrate, and severity of illness scores were not significantly different between groups. After multivariate logistic regression adjusting for variables significant from univariate analysis, higher initial bicarbonate (p = 0.04) and medication nonadherence (p = 0.03) remained significantly associated with SSPs. CONCLUSIONS: Patients with DKA with short ICU stays have higher initial bicarbonate levels and are more likely to have medication nonadherence than patients requiring prolonged critical care. These variables may identify patients with DKA who are best treated in an emergency department-intensive care unit to potentially reduce inpatient ICU use.

Successful Thoracic Duct Ligation for Plastic Bronchitis in an Adult.

Plastic bronchitis is a rare and potentially life-threatening disease characterized by the development of obstructive fibrinous tracheobronchial casts and hypoxic respiratory failure. With its poorly understood cause and rare occurrence in the adult population, few treatment strategies have been described in adults with this condition. In this report, we present a case of successful treatment of an adult with plastic bronchitis, using thoracic duct ligation and resulting in full resolution of airway cast development.

Synthetic lethal interaction between the tumour suppressor STAG2 and its paralog STAG1.

Cohesin is a multi-protein complex that tethers sister chromatids during mitosis and mediates DNA repair, genome compartmentalisation and regulation of gene expression. Cohesin subunits frequently acquire cancer loss-of-function alterations and act as tumour suppressors in several tumour types. This has led to increased interest in cohesin as potential target in anti-cancer therapy. Here we show that the loss-of-function of STAG2, a core component of cohesin and an emerging tumour suppressor, leads to synthetic dependency of mutated cancer cells on its paralog STAG1. STAG1 and STAG2 share high sequence identity, encode mutually exclusive cohesin subunits and retain partially overlapping functions. We inhibited STAG1 and STAG2 in several cancer cell lines where the two genes have variable mutation and copy number status. In all cases, we observed that the simultaneous blocking of STAG1 and STAG2 significantly reduces cell proliferation. We further confirmed the synthetic lethal interaction developing a vector-free CRISPR system to induce STAG1/STAG2 double gene knockout. We provide strong evidence that STAG1 is a promising therapeutic target in cancers with inactivating alterations of STAG2.

A Drosophila-centric view of protein tyrosine phosphatases.

Most of our knowledge on protein tyrosine phosphatases (PTPs) is derived from human pathologies and mouse knockout models. These models largely correlate well with human disease phenotypes, but can be ambiguous due to compensatory mechanisms introduced by paralogous genes. Here we present the analysis of the PTP complement of the fruit fly and the complementary view that PTP studies in Drosophila will accelerate our understanding of PTPs in physiological and pathological conditions. With only 44 PTP genes, Drosophila represents a streamlined version of the human complement. Our integrated analysis places the Drosophila PTPs into evolutionary and functional contexts, thereby providing a platform for the exploitation of the fly for PTP research and the transfer of knowledge onto other model systems.