Biomarkers in Sepsis: A Current Review of New Technologies.

Sepsis syndromes have been recognized since antiquity yet still pose significant challenges to modern medicine. One of the biggest challenges lies in the heterogeneity of triggers and its protean clinical manifestations, as well as its rapidly progressive and lethal nature. Thus, there is a critical need for biomarkers that can quickly and accurately detect sepsis onset and predict treatment response. In this review, we will briefly describe the current consensus definitions of sepsis and the ideal features of a biomarker. We will then delve into currently available and in-development markers of pathogens, hosts, and their interactions that together comprise the sepsis syndrome.

Adsorption of an antiseptic in a functionalized fixed-bed: Analysis of breakthrough scenarios and validation of simplistic models defending a novel proposition.

BACKGROUND: Chlorhexidine gluconate (CHG) and cetrimide, which are widely used in various pharmaceutical compositions, are considered potentially hazardous compounds. This combination was largely used during and after Covid 19 pandemic for sanitization. Removal of these two compounds from pharmaceutical waste-water with commercial and functionalized activated carbon in a packed bed column is reported. METHODS: Effects of changes in bed height, flow rate, and initial concentration on the performance of the packed bed are analyzed using Yoon-Nelson, BDST and Thomas models for commercial scale-up operation. The effects of primary design parameters like bed depth and operating parameters like inflow rate and inlet concentration of influent wastewater are studied on the extent of removal of cetrimide and chlorhexidine gluconate. Granular activated carbon (GAC) is functionalized using HF and NH4OH. The extent of enhanced adsorption using the functionalized GAC is demonstrated using breakthrough curves. SIGNIFICANT FINDINGS: K. H. Chu's iconic proposition is validated. Breakthrough time (BT) increases with bed heights and it is less in the case of cetrimide as compared to chlorhexidine gluconate. This shows that cetrimide wins in the competition and occupies the pores much faster than CHG. Mostly, BT-CHG (GAC) < BT-CHG (FAC-HF) < BT-CHG (FAC-NH3) and BT-cetrimide (GAC) < BT-cetrimide (FAC-NH3) < BT-cetrimide (FAC-HF) for a particular bed height. BT-CHG(FAC-HF)BT-cetrimide(FAC-HF)

The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock (RIFTS): A Randomized Pilot Study.

OBJECTIVES: It is unclear if a low- or high-volume IV fluid resuscitation strategy is better for patients with severe sepsis and septic shock. DESIGN: Prospective randomized controlled trial. SETTING: Two adult acute care hospitals within a single academic system. PATIENTS: Patients with severe sepsis and septic shock admitted from the emergency department to the ICU from November 2016 to February 2018. INTERVENTIONS: Patients were randomly assigned to a restrictive IV fluid resuscitation strategy (≤ 60 mL/kg of IV fluid) or usual care for the first 72 hours of care. MEASUREMENTS AND MAIN RESULTS: We enrolled 109 patients, of whom 55 were assigned to the restrictive resuscitation group and 54 to the usual care group. The restrictive group received significantly less resuscitative IV fluid than the usual care group (47.1 vs 61.1 mL/kg; p = 0.01) over 72 hours. By 30 days, there were 12 deaths (21.8%) in the restrictive group and 12 deaths (22.2%) in the usual care group (odds ratio, 1.02; 95% CI, 0.41-2.53). There were no differences between groups in the rate of new organ failure, hospital or ICU length of stay, or serious adverse events. CONCLUSIONS: This pilot study demonstrates that a restrictive resuscitation strategy can successfully reduce the amount of IV fluid administered to patients with severe sepsis and septic shock compared with usual care. Although limited by the sample size, we observed no increase in mortality, organ failure, or adverse events. These findings further support that a restrictive IV fluid strategy should be explored in a larger multicenter trial.

Changes in the process of alternative RNA splicing results in soluble B and T lymphocyte attenuator with biological and clinical implications in critical illness.

BACKGROUND: Critically ill patients with sepsis and acute respiratory distress syndrome have severely altered physiology and immune system modifications. RNA splicing is a basic molecular mechanism influenced by physiologic alterations. Immune checkpoint inhibitors, such as B and T Lymphocyte Attenuator (BTLA) have previously been shown to influence outcomes in critical illness. We hypothesize altered physiology in critical illness results in alternative RNA splicing of the immune checkpoint protein, BTLA, resulting in a soluble form with biologic and clinical significance. METHODS: Samples were collected from critically ill humans and mice. Levels soluble BTLA (sBTLA) were measured. Ex vivo experiments assessing for cellular proliferation and cytokine production were done using splenocytes from critically ill mice cultured with sBTLA. Deep RNA sequencing was done to look for alternative splicing of BTLA. sBTLA levels were fitted to models to predict sepsis diagnosis. RESULTS: sBTLA is increased in the blood of critically ill humans and mice and can predict a sepsis diagnosis on hospital day 0 in humans. Alternative RNA splicing results in a premature stop codon that results in the soluble form. sBTLA has a clinically relevant impact as splenocytes from mice with critical illness cultured with soluble BTLA have increased cellular proliferation. CONCLUSION: sBTLA is produced as a result of alternative RNA splicing. This isoform of BTLA has biological significance through changes in cellular proliferation and can predict the diagnosis of sepsis.

Age, exercise, and the outcome of sepsis.

We report on the increasingly important need to diagnose and care for the elderly with sepsis as a distinct patient population. We share an overview of age-related changes in sepsis physiology and the potential role of exercise.See related research by Tyml et al., https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1783-1.

Pulmonary Hypertension in Pregnancy.

Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy associated with abnormal cardiopulmonary hemodynamics and a limited life expectancy due to right heart failure. Young women are preferentially affected. Women with PAH are at increased risk of complications and death during pregnancy for both the mother and the fetus. While it is not well characterized how changes in sex steroids and other hormones during pregnancy affect pulmonary hypertension, many expected systemic and heart­lung physiologic adaptations during gestation are poorly tolerated in women with PAH. Despite the approval of numerous therapies for PAH in recent years, pregnancy avoidance or early termination is still recommended in women with PAH because of poor outcomes. In this review, we will discuss physiologic and hormonal changes in pregnancy as they relate to pulmonary vascular disease and right heart function. We will review current consensus recommendations and outline the management of pregnancy in PAH when it does occur.

Theater for Healthcare Equity; A Model for Inclusion and Anti-Bias Training in Academic Medicine.

There are no standardized methods for training medical personnel in antiracist action, such as how to be an upstander or how to use micro-resistance. Roleplay and drama-based pedagogy can empower and educate healthcare professionals by providing experiential training and a safe space for antiracist practice and discussion. The Theater for Healthcare Equity (THE) is an innovative methodology that explores upstander techniques in real time with facilitated instruction. We implemented eight THE sessions at our institution and assessed participant responses via a voluntary survey. Forty-one participants completed a REDCap survey, and 32 participants completed the Continuing Medical Education survey. Participants appreciated the creation of safe spaces, the practice format, and the learning experience, which provided an honest and open environment for the sharing of experiences, addressing race-based bias, and practicing responses to real-life scenarios. Constructive feedback included changes to session duration, participant discomfort with improvisation, and lack of printed tools.

Perspectives on Using Race in Pulmonary Function Testing: A National Survey Fellows and Program Directors.

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

Integrating Primary Care into the Management of Cystic Fibrosis.

Over the last 50 years, cystic fibrosis has radically transformed from a fatal disease of infancy to a chronic disease of adulthood. By 2025 it is estimated that 70% of individuals with cystic fibrosis (iwCF) will be cared for in adult clinics. We believe the role of a dedicated primary care provider (PCP) for preventative care will be crucial for the longevity of iwCF. There are various models for incorporating primary care medicine into CF management, but no universally accepted standard exists. Ideally, the PCP and pulmonologist practice in a patientcentered medical home, given the growing evidence that these care models are associated with improved quality-of-life measures, mental health, and disease-specific outcomes. To improve engagement with primary care in CF, there needs to be a shift in education at the undergraduate medical education and provider training levels. Increasing the knowledge of CF-related illness is vital in fostering a close relationship between the PCP and their patient. To meet this need, primary care doctors will need tools and practical experiences in managing this rare condition. This can start being addressed by providing ample opportunities for the inclusion of PCPs into subspecialty clinics and through engagement with community providers through readily available didactics, seminars, and open lines of communication. As PCPs and CF clinicians, we feel that shifting the domain of preventative care to the expertise of a primary care physician will allow for a more CF-specific focus in subspecialty clinics and help prevent these vital health maintenance tasks from being overlooked, altogether advancing the health and well-being of iwCF.

Perceptions and Use of E-cigarettes among Young Adults with Cystic Fibrosis: An Observational Study.

While smoking prevalence has decreased among the general population, the use of electronic cigarettes (E- cigarettes) has risen significantly and can cause significant lung injury. We sought to determine if persons with cystic fibrosis (PwCF) have similar rates of E-cigarette use as compared with age-matched peers, and to understand perceptions of E-cigarette safety through a survey-based study. A total of 29 PwCF and 26 age-matched control patients participated in this study. There was no significant difference between PwCF and control patients regarding perceptions of the negative impact of E-cigarette use on one's health. Overall, both PwCF and control patients reported a good quality of life. PwCF were equally likely to identify E-cigarettes as harmful to one's lung health as healthy controls but were significantly more likely to have heard of EVALI. While small, our study has demonstrated the need for further education of both PwCF and healthy young adults.

Sexual Health-related Quality of Life in Women with Pulmonary Arterial Hypertension: Compensating for Loss.

Rationale: Health-related quality of life in patients with pulmonary arterial hypertension (PAH) has become increasingly important in disease management as numerous treatment options have improved prognosis and time to clinical worsening. Sexual health-related quality of life (SHRQoL) is poorly understood in patients with PAH, but previous work has shown that patients may face unrecognized challenges, especially related to parenteral prostanoid analogue therapies. Objectives: Using qualitative methods, to describe challenges and perspectives related to SHRQoL among women with PAH. Methods: We conducted 13 semistructured in-depth interviews at the Pulmonary Hypertension Association's International Pulmonary Hypertension Conference and Scientific Sessions among female attendees with World Symposium on Pulmonary Hypertension group 1 PAH. A coding structure using both deductive and inductive coding was developed to organize and analyze data using applied thematic analysis. Salient themes were identified and are presented here using summary and illustrative quotations. Results: Ninety-two percent (12 of 13) of participants reported declines in the frequency of sex after diagnosis of PAH. A significant portion (62% [8 of 13]) experienced fear of having sexual intercourse because of cardiopulmonary symptoms. All participants (100% [13 of 13]) reported compensatory behaviors/strategies during and around sexual intercourse; some participants on subcutaneous prostanoids also reported timing intercourse to coincide with infusion site changes and, as a result, interrupted treatment during this time. Participants reported changing positions during sex to reduce breathlessness, and some reported removing oxygen to avoid interrupting intimacy. Most participants endorsed negative body image related to their medications, external oxygen supplementation, and/or body weight fluctuations (54% [7 of 13]). Many participants revealed that they had never discussed sexual practices with healthcare professionals and desired increased communication and discussion with their providers. Conclusions: Women with PAH face significant burdens and challenges regarding SHRQoL. PAH therapies directly affect SHRQoL. Further targeted qualitative and quantitative studies are needed to better characterize and improve SHRQoL in patients with PAH.

Intervention of an Upgraded Ventilation System and Effects of the COVID-19 Lockdown on Air Quality at Birmingham New Street Railway Station.

High NO2 concentrations (long term average of 383 µg/m3 in 2016/2017) recorded at Birmingham New Street railway station have resulted in the upgrade of the bi-directional fan system to aid wind dispersion within the enclosed platform environment. This paper attempts to examine how successful this intervention has been in improving air quality for both passengers and workers within the station. New air pollution data in 2020 has enabled comparisons to the 2016/2017 monitoring campaign revealing a 23-42% decrease in measured NO2 concentrations. The new levels of NO2 are below the Occupational Health standards but still well above the EU Public Health Standards. This reduction, together with a substantial decrease (up to 81%) in measured Particulate Matter (PM) concentrations, can most likely be attributed to the new fan system effectiveness. Carbon Monoxide levels were well below Occupational and Public Health Standards at all times. The COVID-19 pandemic "initial lockdown" period has also allowed an insight into the resultant air quality at lower rail-traffic intensities, which produced a further reduction in air pollutants, to roughly half the pre-lockdown concentrations. This study shows the scope of improvement that can be achieved through an engineering solution implemented to improve the ventilation system of an enclosed railway station. Further reduction in air pollution would require additional approaches, such as the removal of diesel engine exhaust emissions via the adoption of electric or diesel-electric hybrid powered services.

Management of the Patient with Chronic Critical Illness - Part 2.

Patients with chronic critical illness (CCI) represent a growing segment of the hospitalized population. Key aspects of care in CCI patients including tracheostomy, prolonged mechanical ventilation, nutritional support, wound care, and others require a comprehensive, goal-directed approach. Infectious complications of CCI including pneumonia, tracheobronchitis and urinary tract infection may be caused by nosocomial organisms requiring awareness and adjustment of treatment regimen. Finally, psychiatric, palliative, rehabilitative components of care impact heavily upon outcomes in CCI patients. As care that is typically associated with the intensive care unit is extended to the hospital ward, we aim to increase awareness among providers and outline a systematic approach to deliver high quality, patient centered care to CCI patients.

Management of the Patient with Chronic Critical Illness - Part 1: This is part one of a two part series. Part two will be published in September.

Patients with chronic critical illness (CCI) represent a growing segment of the hospitalized population. Key aspects of care in CCI patients including tracheostomy, prolonged mechanical ventilation, nutritional support, wound care, and others require a comprehensive, goal-directed approach. Infectious complications of CCI including pneumonia, tracheobronchitis and urinary tract infection may be caused by nosocomial organisms requiring awareness and adjustment of treatment regimen. Finally, psychiatric, palliative, rehabilitative components of care impact heavily upon outcomes in CCI patients. As care that is typically associated with the intensive care unit is extended to the hospital ward, we aim to increase awareness among providers and outline a systematic approach to deliver high quality, patient centered care to CCI patients.

The association between household and neighborhood characteristics and COVID-19 related ICU admissions.

Introduction: Approaches to COVID-19 mitigation can be more efficiently delivered with a more detailed understanding of where the severe cases occur. Our objective was to assess which demographic, housing and neighborhood characteristics were independently and collectively associated with differing rates of severe COVID-19. Methods: A cohort of patients with SARS-CoV-2 in a single health system from March 1, 2020 to February 15, 2021 was reviewed to determine whether demographic, housing, or neighborhood characteristics are associated with higher rates of severe COVID-19 infections and to create a novel scoring index. Characteristics included proportion of multifamily homes, essential workers, and ages of the homes within neighborhoods. Results: There were 735 COVID-19 ICU admissions in the study interval which accounted for 61 percent of the state's ICU admissions for COVID-19. Compared to the general population of the state those admitted to the ICU with COVID-19 were disproportionately older, male sex, and were more often Black, Indigenous, People of Color. Patients disproportionately resided in neighborhoods with three plus unit multifamily homes, homes built before 1940, homes with more than one person to a room, homes of lower average value, and in neighborhoods with a greater proportion of essential workers. From this our COVID-19 Neighborhood Index value was comparatively higher for the ICU patients (61.1) relative to the population of Rhode Island (49.4). Conclusion: COVID-19-related ICU admissions are highly related to demographic, housing and neighborhood-level factors. This may guide more nuanced and targeted vaccine distribution plans and public health measures for future pandemics.

Feasibility of an Antiracism Curriculum in an Academic Pulmonary, Critical Care, and Sleep Medicine Division.

Background: Structural health inequities and racism adversely affect patient health and the culture of academic medicine. Formal training to educate fellows and faculty on antiracism is lacking. Objective: Our objective was to design, implement, and assess the feasibility and preliminary efficacy of a year-long antiracism curriculum within a pulmonary, critical care, and sleep medicine division. Methods: This was a pre- and postintervention observational study conducted between July 2020 and June 2021. The curriculum was offered during an allotted educational meeting time slot at a single-center pulmonary, critical care, and sleep medicine division at a large academic institution to fellows and faculty. The curriculum consisted of 13 1-hour virtual interactive workshops delivered by local experts in diversity, equity, and inclusion topics. Surveys assessed knowledge on racism in medicine; opinions, understanding, and comfort surrounding race and racism in medicine; as well as additional questions to solicit feedback on the curriculum itself via visual analog scale and write-in comments. Results: Before initiating the curriculum, 74% (n = 28) of respondents reported interest in an antiracism curriculum, and the majority (95%, n = 36) believed that discrimination affects medical staff and patients. Respondents reported only moderate comfort in talking about race (median, 58; interquartile range 41-70 on visual analog scale 0-100, where 100 is strongly agree with "I feel comfortable talking about race"). The postintervention survey demonstrated stability of the belief of the presence of racial discrimination and a 15% increase in self-directed learning about related topics. Although knowledge related to the use of race in medical algorithms improved, 14% fewer participants reported interest in continuing to engage in a division-wide structured antiracism curriculum. Conclusion: Implementation of a curriculum on justice, equity, diversity, and inclusion within a fellowship program is feasible and addresses an unmet need within graduate medical education.

Chitinase 3 like 1 contributes to the development of pulmonary vascular remodeling in pulmonary hypertension.

Chitinase 3 like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggest CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including group 1 PAH and group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1-null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a target for the treatment of PAH and PH associated with fibrotic lung disease.

Metabolomics and the Microbiome as Biomarkers in Sepsis.

Metabolomics is an emerging field of research interest in sepsis. Metabolomics provides new ways of exploring the diagnosis, mechanism, and prognosis of sepsis. Advancements in technologies have enabled significant improvements in identifying novel biomarkers associated with the disease progress of sepsis. The use of metabolomics in the critically ill may provide new approaches to enable precision medicine. Furthermore, the dynamic interactions of the host and its microbiome can lead to further progression of sepsis. Understanding these interactions and the changes in the host's genomics and the microbiome can provide novel preventive and therapeutic strategies against sepsis.