The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes.

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, anti-pathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodeling, and airway hyperresponsiveness; and summarize the impact on lung diseases, including COPD, respiratory infection, lung cancer, and asthma. We highlight how the inclusion of nicotine or flavoring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette - the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarize the research needed in this under-investigated area.

Private Equity-Acquired Physician Practices And Market Penetration Increased Substantially, 2012-21.

Private equity (PE) firms have been acquiring physician practices at an increasing rate, raising concerns about such firms' penetration at the physician level into local markets and the impact on health care quality and prices. However, limited knowledge exists about the extent of PE firms' control in local markets. By linking data on PE acquisitions to physician data and using full-time-equivalent physicians as the base of assessment, we estimated the local market share of each PE firm within ten physician specialties at the Metropolitan Statistical Area (MSA) level. PE-acquired physician practice sites increased from 816 across 119 MSAs in 2012 to 5,779 across 307 MSAs in 2021. Single PE firms had significant market share, exceeding 30 percent in 108 MSA specialty markets and exceeding 50 percent in 50 of those markets. The findings raise concerns about competition and call for closer scrutiny by the Federal Trade Commission, state regulators, and policy makers.

Through the Looking Glass: Revisiting Smoking and Health.

January 11, 2024, marked the 60th anniversary of the initial U.S. Surgeon General report "Smoking and Health," which definitively linked cigarette smoking and lung cancer.1 Similar to the old Virginia Slims slogan "you've come a long way, baby," smoking rates have diminished greatly since the release of that report.2 However, smoking still represents the leading cause of preventable deaths.3 Numerous countries have enacted policies aimed at decreasing conventional cigarette use, such as including warning labels on tobacco products, limiting advertising, and imposing bans on particular products. Such measures have contributed to significant reductions in cigarette use.

High parasite virulence necessary for the maintenance of host outcrossing via parasite-mediated selection.

Biparental sex is widespread in nature, yet costly relative to uniparental reproduction. It is generally unclear why self-fertilizing or asexual lineages do not readily invade outcrossing populations. The Red Queen hypothesis predicts that coevolving parasites can prevent self-fertilizing or asexual lineages from invading outcrossing host populations. However, only highly virulent parasites are predicted to maintain outcrossing, which may limit the general applicability of the Red Queen hypothesis. Here, we tested whether the ability of coevolving parasites to prevent invasion of self-fertilization within outcrossing host populations was dependent on parasite virulence. We introduced wild-type Caenorhabditis elegans hermaphrodites, capable of both self-fertilization and outcrossing, into C. elegans populations fixed for a mutant allele conferring obligate outcrossing. Replicate C. elegans populations were exposed for 24 host generations to one of four strains of Serratia marcescens parasites that varied in virulence, under three treatments: a heat-killed (control, noninfectious) parasite treatment, a fixed-genotype (nonevolving) parasite treatment, and a copassaged (potentially coevolving) parasite treatment. As predicted, self-fertilization invaded C. elegans host populations in the control and fixed-parasite treatments, regardless of parasite virulence. In the copassaged treatment, selfing invaded host populations coevolving with low- to mid-virulence strains, but remained rare in hosts coevolving with highly virulent bacterial strains. Therefore, we found that only highly virulent coevolving parasites can impede the invasion of selfing.

Duration of intermittent hypoxia impacts metabolic outcomes and severity of murine NAFLD.

Rationale: Obstructive sleep apnea (OSA) is associated with metabolic dysfunction, including progression of nonalcoholic fatty liver disease (NAFLD). Chronic intermittent hypoxia (IH) as a model of OSA worsens hepatic steatosis and fibrosis in rodents with diet induced obesity. However, IH also causes weight loss, thus complicating attempts to co-model OSA and NAFLD. We sought to determine the effect of various durations of IH exposure on metabolic and liver-related outcomes in a murine NAFLD model. We hypothesized that longer IH duration would worsen the NAFLD phenotype. Methods: Male C57BL/6J mice (n = 32) were fed a high trans-fat diet for 24 weeks, to induce NAFLD with severe steatohepatitis. Mice were exposed to an IH profile modeling severe OSA, for variable durations (0, 6, 12, or 18 weeks). Intraperitoneal glucose tolerance test was measured at baseline and at six-week intervals. Liver triglycerides, collagen and other markers of NAFLD were measured at sacrifice. Results: Mice exposed to IH for 12 weeks gained less weight (p = 0.023), and had lower liver weight (p = 0.008) relative to room air controls. These effects were not observed in the other IH groups. IH of longer duration transiently worsened glucose tolerance, but this effect was not seen in the groups exposed to shorter durations of IH. IH exposure for 12 or 18 weeks exacerbated liver fibrosis, with the largest increase in hepatic collagen observed in mice exposed to IH for 12 weeks. Discussion: Duration of IH significantly impacts clinically relevant outcomes in a NAFLD model, including body weight, fasting glucose, glucose tolerance, and liver fibrosis.

The DNA glycosylase NEIL2 is protective during SARS-CoV-2 infection.

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant NEIL2 in A549-ACE2 cells shows decreased expression of proinflammatory genes and viral E-gene, as well as lowers the yield of viral progeny compared to mock-treated cells. Mechanistically, NEIL2 cooperatively binds to the 5'-UTR of SARS-CoV-2 genomic RNA to block viral protein synthesis. Collectively, these data strongly suggest that the maintenance of basal NEIL2 levels is critical for the protective response of hosts to viral infection and disease.

Rationale and protocol for a safety, tolerability and feasibility randomized, parallel group, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms.

Background: Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults. Objectives: The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. Methods: Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. Conclusion: This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty.

Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY): protocol of a prospective, multicentre, observational study.

INTRODUCTION: Recurrence rate following radical therapy for lung cancer remains high, potentially reflecting occult metastatic disease, and better staging tools are required. Minimal pleural effusion (mini-PE) is associated with particularly high recurrence risk and is defined as an ipsilateral pleural collection (<1/3 hemithorax on chest radiograph), which is either too small to safely aspirate fluid for cytology using a needle, or from which fluid cytology is negative. Thoracoscopy (local anaesthetic thoracoscopy (LAT) or video-assisted thoracoscopic surgery (VATS)) is the gold-standard diagnostic test for pleural malignancy in patients with larger symptomatic effusions. Staging by Thoracoscopy in potentially radically treatable Lung Cancer associated with Minimal Pleural Effusion (STRATIFY) will prospectively evaluate thoracoscopic staging in lung cancer associated-mini-PE for the first time. METHODS AND ANALYSIS: STRATIFY is a prospective multicentre observational study. Recruitment opened in January 2020. The primary objective is to determine the prevalence of detectable occult pleural metastases (OPM). Secondary objectives include assessment of technical feasibility and safety, and the impact of thoracoscopy results on treatment plans, overall survival and recurrence free survival. Inclusion criteria are (1) suspected/confirmed stages I-III lung cancer, (2) mini-PE, (3) Performance Status 0-2 (4), radical treatment feasible if OPM excluded, (5) ≥16 years old and (6) informed consent. Exclusion criteria are any metastatic disease or contraindication to the chosen thoracoscopy method (LAT/VATS). All patients have LAT or VATS within 7 (±5) days of registration, with results returned to lung cancer teams for treatment planning. Following an interim analysis, the sample size was reduced from 96 to 50, based on a lower-than-expected OPM rate. An MRI substudy was removed in November 2022 due to pandemic-related site setup/recruitment delays. These also necessitated a no-cost recruitment extension until October 2023. ETHICS AND DISSEMINATION: Protocol approved by the West of Scotland Research Ethics Committee (Ref: 19/WS/0093). Results will be published in peer-reviewed journals and presented at international meetings. TRIAL REGISTRATION NUMBER: ISRCTN13584097.

Transcriptomic responses in the blood and sputum of cigarette smokers compared to e-cigarette vapers.

RATIONALE: Electronic (e)-cigarettes are popular among youth and cigarette smokers attempting to quit. Studies to date have focused on the utility of e-cigarettes as a smoking cessation tool, but the biological effects are largely unknown. OBJECTIVES: To identify transcriptomic differences in the blood and sputum of e-cigarette users compared to conventional cigarettes smokers and healthy controls and describe biological pathways affected by these tobacco products. METHODS: Cross-sectional analysis of whole blood and sputum RNA-sequencing data from 8 smokers, 9 e-cigarette users (e-cigs) and 4 controls. Weighted gene co-network analysis (WGCNA) identified gene module associations. Ingenuity Pathway Analysis (IPA) identified canonical pathways associated with tobacco products. MAIN RESULTS: In blood, a three-group comparison showed 16 differentially expressed genes (DEGs); pair-wise comparison showed 7 DEGs between e-cigs and controls, 35 DEGs between smokers and controls, and 13 DEGs between smokers and e-cigs. In sputum, 438 DEGs were in the three-group comparison. In pair-wise comparisons, there were 2 DEGs between e-cigs and controls, 270 DEGs between smokers and controls, and 468 DEGs between smokers and e-cigs. Only 2 genes in the smokers vs. control comparison overlapped between blood and sputum. Most gene modules identified through WGCNA associated with tobacco product exposures also were associated with cotinine and exhaled CO levels. IPA showed more canonical pathways altered by conventional cigarette smoking than by e-cigarette use. CONCLUSION: Cigarette smoking and e-cigarette use led to transcriptomic changes in both blood and sputum. However, conventional cigarettes induced much stronger transcriptomic responses in both compartments.

Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome.

STUDY OBJECTIVES: The coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in a single individual, also known as overlap syndrome (OVS), is associated with higher cardiovascular risk and mortality than either OSA or COPD alone. However, the underlying mechanisms remain unclear. We hypothesized that patients with OVS have elevated systemic inflammatory biomarkers relative to patients with either disease alone, which could explain greater cardiovascular risk observed in OVS. METHODS: We included 255 participants in the study, 55 with COPD alone, 100 with OSA alone, 50 with OVS, and 50 healthy controls. All participants underwent a home sleep study, spirometry, and a blood draw for high-sensitivity C-reactive protein and total blood count analysis. In a randomly selected subset of 186 participants, inflammatory protein profiling was performed using Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assays. Biomarker level differences across groups were identified using a mixed linear model. RESULTS: Levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and granulocyte colony stimulating factor (G-CSF) were higher in participants with OVS and COPD compared with healthy controls and participants with OSA. Furthermore, participants with OVS had higher circulating levels of leukocytes and neutrophils than those with COPD, OSA, and controls. CONCLUSIONS: COPD and OVS are associated with higher systemic inflammation relative to OSA and healthy controls. This work proposes the potential utilization of interleukin 6, granulocyte colony stimulating factor, and high-sensitivity C-reactive protein as screening biomarkers for COPD in patients with OSA. Inflammatory pathways may not fully explain the higher cardiovascular risk observed in OVS, indicating the need for further investigation. CITATION: Sanchez-Azofra A, Gu W, Masso-Silva JA, et al. Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome. J Clin Sleep Med. 2023;19(8):1447-1456.

Isolation of RNA from the Murine Colonic Tissue and qRT-PCR for Inflammatory Cytokines.

E-cigarette (E-cig) inhalation affects health status by modulating inflammation profiles in several organs, including the brain, lung, heart, and colon. The effect of flavored fourth-generation pod-based E-cigs (JUUL) on murine gut inflammation is modulated by both flavor and exposure period. Exposure of mice to JUUL mango and JUUL mint for one month upregulated inflammatory cytokines, particularly TNF-α, IL-6, and Cxcl-1 (IL-8). JUUL Mango effects were more prominent than those incurred by JUUL Mint after one month of exposure. However, JUUL Mango reduced the expression of colonic inflammatory cytokines after three months of exposure. In this protocol, we detail the process of RNA isolation from the mouse colon and the use of extracted RNA in profiling the inflammatory milieu. Efficient RNA extraction from the murine colon is the most important step in the evaluation of inflammatory transcripts in the colon.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.

A Digital Health Intervention for Concussion: Development and Clinical Feasibility Study.

BACKGROUND: Concussion is a common condition that can lead to a constellation of symptoms that affect quality of life, social integration, and return to work. There are several evidence-based behavioral and psychological interventions that have been found to improve postconcussion symptom burden. However, these are not routinely delivered, and individuals receive limited support during their concussion recovery. OBJECTIVE: This study aimed to develop and test the feasibility of a digital health intervention using a systematic evidence-, theory-, and person-based approach. METHODS: This was a mixed methodology study involving a scoping review (n=21), behavioral analysis, and logic model to inform the intervention design and content. During development, the intervention was optimized with feedback from individuals who had experienced concussions (n=12) and health care professionals (n=11). The intervention was then offered to patients presenting to the emergency department with a concussion (n=50). Participants used the intervention freely and input symptom data as part of the program. A number of outcome measures were obtained, including participant engagement with the intervention, postconcussion symptom burden, and attitudes toward the intervention. A selection of participants (n=15) took part in in-depth qualitative interviews to understand their attitudes toward the intervention and how to improve it. RESULTS: Engagement with the intervention functionality was 90% (45/50) for the symptom diary, 62% (31/50) for sleep time setting, 56% (28/50) for the alcohol tracker, 48% (24/50) for exercise day setting, 34% (17/50) for the thought diary, and 32% (16/50) for the goal setter. Metrics indicated high levels of early engagement that trailed off throughout the course of the intervention, with an average daily completion rate of the symptom diary of 28.23% (494/1750). A quarter of the study participants (13/50, 26%) were classified as high engagers who interacted with all the functionalities within the intervention. Quantitative and qualitative feedback indicated a high level of usability and positive perception of the intervention. Daily symptom diaries (n=494) demonstrated a wide variation in individual participant symptom burden but a decline in average burden over time. For participants with Rivermead scores on completion of HeadOn, there was a strong positive correlation (r=0.86; P<.001) between their average daily HeadOn symptom diary score and their end-of-program Rivermead score. Insights from the interviews were then fed back into development to optimize the intervention and facilitate engagement. CONCLUSIONS: Using this systematic approach, we developed a digital health intervention for individuals who have experienced a concussion that is designed to facilitate positive behavior change. Symptom data input as part of the intervention provided insights into postconcussion symptom burden and recovery trajectories. TRIAL REGISTRATION: ClinicalTrials.gov NCT05069948; https://clinicaltrials.gov/ct2/show/NCT05069948.

Assessing Barriers to Implementation of Machine Learning and Artificial Intelligence-Based Tools in Critical Care: Web-Based Survey Study.

BACKGROUND: Although there is considerable interest in machine learning (ML) and artificial intelligence (AI) in critical care, the implementation of effective algorithms into practice has been limited. OBJECTIVE: We sought to understand physician perspectives of a novel intubation prediction tool. Further, we sought to understand health care provider and nonprovider perspectives on the use of ML in health care. We aim to use the data gathered to elucidate implementation barriers and determinants of this intubation prediction tool, as well as ML/AI-based algorithms in critical care and health care in general. METHODS: We developed 2 anonymous surveys in Qualtrics, 1 single-center survey distributed to 99 critical care physicians via email, and 1 social media survey distributed via Facebook and Twitter with branching logic to tailor questions for providers and nonproviders. The surveys included a mixture of categorical, Likert scale, and free-text items. Likert scale means with SD were reported from 1 to 5. We used student t tests to examine the differences between groups. In addition, Likert scale responses were converted into 3 categories, and percentage values were reported in order to demonstrate the distribution of responses. Qualitative free-text responses were reviewed by a member of the study team to determine validity, and content analysis was performed to determine common themes in responses. RESULTS: Out of 99 critical care physicians, 47 (48%) completed the single-center survey. Perceived knowledge of ML was low with a mean Likert score of 2.4 out of 5 (SD 0.96), with 7.5% of respondents rating their knowledge as a 4 or 5. The willingness to use the ML-based algorithm was 3.32 out of 5 (SD 0.95), with 75% of respondents answering 3 out of 5. The social media survey had 770 total responses with 605 (79%) providers and 165 (21%) nonproviders. We found no difference in providers' perceived knowledge based on level of experience in either survey. We found that nonproviders had significantly less perceived knowledge of ML (mean 3.04 out of 5, SD 1.53 vs mean 3.43, SD 0.941; P<.001) and comfort with ML (mean 3.28 out of 5, SD 1.02 vs mean 3.53, SD 0.935; P=.004) than providers. Free-text responses revealed multiple shared concerns, including accuracy/reliability, data bias, patient safety, and privacy/security risks. CONCLUSIONS: These data suggest that providers and nonproviders have positive perceptions of ML-based tools, and that a tool to predict the need for intubation would be of interest to critical care providers. There were many shared concerns about ML/AI in health care elucidated by the surveys. These results provide a baseline evaluation of implementation barriers and determinants of ML/AI-based tools that will be important in their optimal implementation and adoption in the critical care setting and health care in general.

Phase II proof-of-concept study of atorvastatin in castration-resistant prostate cancer.

OBJECTIVES: To test for evidence of statin-mediated effects in patients with castration-resistant prostate cancer (CRPC) as post-diagnosis use of statins in patients with prostate cancer is associated with favourable survival outcome. PATIENTS AND METHODS: The SPECTRE trial was a 6-weeks-long proof-of-concept single-arm Phase II treatment trial, combining atorvastatin and androgen deprivation therapy in patients with CRPC (regardless of metastatic status), designed to test for evidence of statin-mediated effects in patients with CRPC. The primary study endpoint was the proportion of patients achieving a ≥50% drop from baseline in prostate-specific antigen (PSA) levels at any time over the 6-week period of atorvastatin medication (PSA response). Exploratory endpoints include PSA velocity and serum metabolites identified by mass spectrometry . RESULTS: At the scheduled interim analysis, one of 12 patients experienced a ≥50% drop in PSA levels (primary endpoint), with ≥2 patients satisfying the primary endpoint required for further recruitment. All 12 patients experienced substantial falls in serum cholesterol levels following statin treatment. While all patients had comparable pre-study PSA velocities, six of 12 patients showed decreased PSA velocities after statin treatment, suggestive of disease stabilization. Unbiased metabolomics analysis on serial weekly blood samples identified tryptophan to be the dominant metabolite associated with patient response to statin. CONCLUSIONS: Data from the SPECTRE study provide the first evidence of statin-mediated effects on CRPC and early sign of disease stabilization. Our data also highlight the possibility of altered tryptophan metabolism being associated with tumour response.

Modes of therapeutic delivery in synthetic microbiology.

For decades, bacteria have been exploited as vectors for vaccines and therapeutics. However, the bacterial arsenal used has historically been limited to a few strains. Advancements in immunology, combined with the development of genetic tools, have expanded our strategies and capabilities to engineer bacteria using various delivery strategies. Depending on the application, each delivery strategy requires specific considerations, optimization, and safety concerns. Here, we review various modes of therapeutic delivery used to target or vaccinate against a variety of ailments in preclinical models and in clinical trials. We highlight modes of bacteria-derived delivery best suited for different applications. Finally, we discuss current obstacles in bacteria-derived therapies and explore potential improvements of the various modes of therapeutic delivery.

Very Low Driving-Pressure Ventilation in Patients With COVID-19 Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation: A Physiologic Study.

OBJECTIVES: To determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE). DESIGN: A single-center prospective physiologic study. SETTING: At a single university medical center. PARTICIPANTS: Adult patients with severe COVID-19 ARDS on VV ECMO. INTERVENTIONS: Participants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV. MAIN MEASUREMENTS AND RESULTS: Twenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers. CONCLUSIONS: Biomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

The E-cigarette or Vaping Product Use-Associated Lung Injury Epidemic: Pathogenesis, Management, and Future Directions: An Official American Thoracic Society Workshop Report.

E-cigarette or vaping product use-associated lung injury (EVALI) is a severe pulmonary illness associated with the use of e-cigarettes or vaping products that was officially identified and named in 2019. This American Thoracic Society workshop was convened in 2021 to identify and prioritize research and regulatory needs to adequately respond to the EVALI outbreak and to prevent similar instances of disease associated with e-cigarette or vaping product use. An interdisciplinary group of 26 experts in adult and pediatric clinical care, public health, regulatory oversight, and toxicology were convened for the workshop. Four major topics were examined: 1) the public health and regulatory response to EVALI; 2) EVALI clinical care; 3) mechanisms contributing to EVALI; and 4) needed actions to address the health effects of EVALI. Oral presentations and group discussion were the primary modes used to identify top priorities for addressing EVALI. Initiatives including a national EVALI case registry and biorepository, integrated electronic medical record coding system, U.S. Food and Drug Administration regulation and enforcement of nicotine e-cigarette standards, regulatory authority over nontobacco-derived e-cigarettes, training in evaluating exogenous exposures, prospective clinical studies, standardized clinical follow-up assessments, ability to more readily study effects of cannabinoid e-cigarettes, and research to identify biomarkers of exposure and disease were identified as critical needs. These initiatives will require substantial federal investment as well as changes to regulatory policy. Overall, the workshop identified the need to address the root causes of EVALI to prevent future outbreaks. An integrated approach from multiple perspectives is required, including public health; clinical, basic, and translational research; regulators; and users of e-cigarettes. Improving the public health response to reduce the risk of another substantial disease-inducing event depends on coordinated actions to better understand the inhalational toxicity of these products, informing the public of the risks, and developing and enforcing regulatory standards for all e-cigarettes.

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.