Five-Year Outcomes Among U.S. Bronchiectasis and Nontuberculous Mycobacterial Registry Patients.

RATIONALE: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described. OBJECTIVE: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis. METHODS: Patients in the United States Bronchiectasis and Nontuberculous Mycobacteria Research Registry with ≥5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test. MEASUREMENTS AND MAIN RESULTS: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline forced expiratory volume in 1 second % predicted, age, hospitalization within 2 years before baseline, body mass index, and gender (all p<0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar irrespective of NTM status, except that annual exacerbations were lower in patients with NTM (p<0.05). CONCLUSIONS: Outcomes including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate were similar across 5 years in patients with bronchiectasis with or without NTM.

The effect of plasma exchange on serum levels of lacosamide: A case report.

PURPOSE: We describe the case of a 22-year-old male who developed thyroid storm necessitating therapeutic plasma exchange (TPE). The patient's past medical history was complicated by epilepsy, for which he took lacosamide. Little evidence was available to guide lacosamide dosing during TPE. Because of an exacerbation of the patient's underlying epilepsy in the context of the thyroid storm, we conducted therapeutic medication monitoring of lacosamide concentrations to guide management. SUMMARY: We arranged for measurement of the lacosamide concentration immediately before TPE (5.1 µg/mL) and 2.5 hours after the initial measurement (3.4 µg/mL) to determine the amount of lacosamide removed by TPE. Utilizing population pharmacokinetic parameters, we calculated the expected concentration and compared this to the measured concentration. The difference between these values was used to determine the percentage removed via TPE compared to the expected post-TPE concentration. We found that one TPE session removed an additional 20% of serum lacosamide. CONCLUSION: TPE appeared to remove an additional 20% of lacosamide when compared to the expected post-TPE concentration.

A pediatric cystic fibrosis arthropathy case who responded to Elexacaftor/Tezacaftor/Ivacaftor therapy.

Cystic fibrosis arthropathy (CFA) is a transient, intermittent form of arthritis that cannot be associated with any other disease other than CF thus making CFA a diagnosis of exclusion. NSAIDs, short-term intermittent splinting, glucocorticoids, and disease-modifying anti-rheumatic drugs are treatment options for CFA. Currently, there is no consensus on how to best treat CFA. Diagnosis and treatment of CFA remain a challenge for physicians and people with CF. The newest CFTR modulator therapy, elexacaftor/tezacaftor/ivacaftor (ETI), was approved by the FDA recently for children over the age of 6 with at least one Phe508del allele in the CFTR gene. Multiple clinical benefits of ETI in pulmonary functions and overall disease burden have been reported since its approval, however, the data on the musculoskeletal therapeutic benefits of ETI has been limited. In this report, we present a 7-year-old female with CF whose CFA symptoms resolved after starting ETI therapy.

Suicide attempts in adolescents with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor therapy.

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.

Anticoagulation Prescribing Patterns in Intensive Care Unit Patients Admitted with Prehospital Direct Oral Anticoagulant Therapy: A Single Academic Center Experience.

OBJECTIVE: To describe the current prescribing practices of direct oral anticoagulants (DOACs) in intensive care unit (ICU) patients and the associated clinical outcomes, including the incidence of major bleeding episodes and the need for intervention (endoscopic, surgical, or interventional radiology guided). DESIGN: Observational, retrospective chart review. SETTING AND PARTICIPANTS: Single large academic center study. Participants included patients with critical illness who were admitted to the intensive care units (ICU) at Mayo Clinic from January 1st, 2012, until May 4th, 2018. Adult ICU patients with a DOAC (apixaban, rivaroxaban, dabigatran, or edoxaban) listed as one of the active medications at the time of hospital admission were included. RESULTS: 37 249 patients in medical and surgical intensive care units were screened for the study period. After excluding patients who did not qualify, 558 unique encounters were included. The median age was 69 (IQR 59-78) years; most patients were male, white Caucasians, and had a median SOFA score of 4. After excluding the patients who had major bleeding episodes in the first 24 hours, 188 (39%) were continued on the same DOAC therapy, 204 (42%) were discontinued without transitioning to another agent, and 95 (20%) were transitioned to another agent. Finally, 410 (84%) were dismissed on DOAC therapy at the end of hospitalization. The difference in the continuation rate of the same DOAC agent beyond 24 hours, discontinuation without transition to an alternate agent, or discontinuation of DOAC with a transition to an alternate anticoagulation agent was not statistically significant (P = .60). A total of 52 major bleeding events were identified. Gastrointestinal bleeding was the most common bleeding complication [n (%): 34 (65)], followed by intra-abdominal and peri-procedural bleeding [7 (13.5) and 7 (13.5)]. Thirty-three (65%) patients had a major bleeding complication requiring intervention. CONCLUSIONS: Our single-center retrospective study describes the current prescribing practices and preliminary outcomes in ICU patients with prehospital use of DOACs. Up to 20% of the patients were transitioned to a different agent within 24 hours of ICU admission, whereas a significant proportion of patients (42%) had anticoagulation discontinued altogether. Most patients who suffered a major bleeding episode required either endoscopic or surgical intervention to control bleeding.

Admission serum sodium and osmolarity are not associated with the occurrence or outcomes of acute respiratory distress syndrome in critically ill.

BACKGROUND: Previous studies suggested that hypernatremia or hyperosmolarity may have protective effects in lung injury. We hypothesized that hypernatremia and/or hyperosmolarity would prevent ARDS. DESIGN: Retrospective cohort study of all admissions at medical, surgical, and multidisciplinary intensive care units in Mayo Clinic, Rochester from the year of 2009 to 2019. The occurrence of ARDS was identified using a validated computerized search strategy. The association between serum sodium/osmolarity and the occurrence of ARDS was analyzed using a multivariable logistic regression model. The relationship between serum sodium/osmolarity and outcomes of ARDS was analyzed using linear and logistic regression models. RESULTS: Among 50,498 patients, the serum sodium level on admission did not have a significant association with the occurrence of ARDS, with an adjusted odds ratio of 0.95 [95% CI (0.86, 1.05)]. There was no significant association between calculated serum osmolarity and the occurrence of ARDS, with an adjusted odds ratio of 1.03 [95% CI (1.00, 1.07)]. 1560 patients developed ARDS during the ICU stay. Their serum sodium level and osmolarity level did not have a significant association with their outcomes. CONCLUSIONS: Admission serum sodium or serum osmolarity were not associated with the occurrence or outcomes of ARDS in ICU.

Early, biomarker-guided steroid dosing in COVID-19 Pneumonia: a pilot randomized controlled trial.

ClinicalTrials.gov identifier (NCT number): NCT03852537 , Registered February 25, 2019.

New therapies for nontuberculous mycobacterial lung infection.

PURPOSE OF REVIEW: Although nontuberculous mycobacterial pulmonary disease is increasing in incidence, outcomes remain less than optimal highlighting the unmet need for developing novel therapies. RECENT FINDINGS: Several new antibiotic formulations, novel antibiotics, and novel nonantibiotic treatments have recently demonstrated positive results in treating nontuberculous mycobacterial pulmonary disease. SUMMARY: Promising novel therapies are currently under investigation fueling much needed interest and enthusiasm in the nontuberculous mycobacterial pulmonary disease space and will hopefully lead to improved understanding and outcomes in this complex disease.

Timing of ARDS Resolution (TARU): A Pragmatic Clinical Assessment of ARDS Resolution in the ICU.

PURPOSE: Lack of a pragmatic outcome measures for acute respiratory distress syndrome (ARDS) resolution is a barrier to meaningful interventional trials of novel treatments. We evaluated a pragmatic, electronic health record (EHR)-based approach toward the clinical assessment of a novel outcome measure: ICU ARDS resolution. METHODS: We conducted a retrospective observational cohort study evaluating adult patients with moderate-severe ARDS admitted to the medical intensive care unit (ICU) at Mayo Clinic in Rochester, MN, from January 2001 through December 2010. We compared the association of ICU ARDS resolution vs non-resolution with mortality. ICU ARDS resolution was defined as improvement in P/F > 200 for at least 48 h or (if arterial blood gas unavailable) SpO2:FiO2 (S/F) > 235, or discharge prior to 48 h from first P/F > 200 without subsequent decline in P/F, as documented in EHR. RESULTS: Of the 254 patients included, ICU ARDS resolution was achieved in 179 (70%). Hospital mortality was lower in patients who met ICU ARDS resolution criteria as compared to those who did not (23% vs. 41%, p < 0.01). After adjusting for age, gender, and illness severity, the patients who met ICU ARDS resolution criteria had lower odds of hospital mortality [odds ratio 0.47, 95% CI 0.25-0.86; p = 0.015]. CONCLUSION: The electronic health record-based pragmatic measure of ICU ARDS resolution is associated with patient outcomes and may serve as an intermediate outcome assessing novel mechanistic treatments.

FIO2 Trajectory as a Pragmatic Intermediate Marker in Acute Hypoxic Respiratory Failure.

BACKGROUND: Several markers of oxygenation are used as prognostic markers in acute hypoxemic respiratory failure. Real-world use is limited by the need for invasive measurements and unreliable availability in the electronic health record. A pragmatic, reliable, and accurate marker of acute hypoxemic respiratory failure is needed to facilitate epidemiologic studies, clinical trials, and shared decision-making with patients. [Formula: see text] is easily obtained at the bedside and from the electronic health record. The [Formula: see text] trajectory may be a valuable marker of recovery in patients with acute hypoxemic respiratory failure. METHODS: This was a historical cohort study of adult subjects admitted to an ICU with acute hypoxemic respiratory failure secondary to community-acquired pneumonia and/or ARDS. RESULTS: Our study included 2,670 subjects. [Formula: see text] and [Formula: see text] were consistently more available than was [Formula: see text] in the electronic health record: ([Formula: see text] vs [Formula: see text] vs [Formula: see text] : 100 vs 100 vs 72.8% on day 1, and 100 vs 99 vs 21% on day 5). A worsening [Formula: see text] trajectory was associated with reduced ventilator-free days. From days 2 to 5, every increase in [Formula: see text] by 10% from the previous day was associated with fewer ventilator-free days (on day 2: adjusted mean -1.25 [95% CI -1.45 to -1.05] d, P < .001). The [Formula: see text] trajectory also provided prognostic information. On days 3 - 5, an increase in [Formula: see text] from the previous day was associated with increased ventilator-free days (on day 3: adjusted mean 2.09 (95% CI 1.44-2.74) d; P < .001). [Formula: see text] models did not add predictive information compared with models with [Formula: see text] alone (on day 2: adjusted [Formula: see text] vs [Formula: see text] R2 0.122 vs 0.119; and on day 3: 0.153 vs 0.163). CONCLUSIONS: [Formula: see text] and [Formula: see text] are pragmatic and readily available intermediate prognostic markers in acute hypoxic respiratory failure. The [Formula: see text] trajectory in the first 5 d of ICU admission provided important prognostic information (ventilator-free days). Although the [Formula: see text] trajectory was also associated with ventilator-free days, it did not provide more information than the [Formula: see text] trajectory alone.

Rule-Based Cohort Definitions for Acute Respiratory Distress Syndrome: A Computable Phenotyping Strategy Based on the Berlin Definition.

Accurate identification of acute respiratory distress syndrome is essential for understanding its epidemiology, patterns of care, and outcomes. We aimed to design a computable phenotyping strategy to detect acute respiratory distress syndrome in electronic health records of critically ill patients. DESIGN: This is a retrospective cohort study. Using a near real-time copy of the electronic health record, we developed a computable phenotyping strategy to detect acute respiratory distress syndrome based on the Berlin definition. SETTING: Twenty multidisciplinary ICUs in Mayo Clinic Health System. SUBJECTS: The phenotyping strategy was applied to 196,487 consecutive admissions from year 2009 to 2019. INTERVENTIONS: The acute respiratory distress syndrome cohort generated by this novel strategy was compared with the acute respiratory distress syndrome cohort documented by clinicians during the same period. The sensitivity and specificity of the phenotyping strategy were calculated in randomly selected patient cohort (50 patients) using the results from manual medical record review as gold standard. MEASUREMENTS AND MAIN RESULTS: Among the patients who did not have acute respiratory distress syndrome documented, the computable phenotyping strategy identified 3,169 adult patients who met the Berlin definition, 676 patients (21.3%) were classified to have severe acute respiratory distress syndrome (Pao2/Fio2 ratio ≤ 100), 1,535 patients (48.4%) had moderate acute respiratory distress syndrome (100 < Pao2/Fio2 ratio ≤ 200), and 958 patients (30.2%) had mild acute respiratory distress syndrome (200 < Pao2/Fio2 ratio ≤ 300). The phenotyping strategy achieved a sensitivity of 94.4%, specificity of 96.9%, positive predictive value of 94.4%, and negative predictive value of 96.9% in a randomly selected patient cohort. The clinicians documented acute respiratory distress syndrome in 1,257 adult patients during the study period. The clinician documentation rate of acute respiratory distress syndrome was 28.4%. Compared with the clinicians' documentation, the phenotyping strategy identified a cohort that had higher acuity and complexity of illness suggested by higher Sequential Organ Failure Assessment score (9 vs 7; p < 0.0001), higher Acute Physiology and Chronic Health Evaluation score (76 vs 63; p < 0.0001), higher rate of requiring invasive mechanical ventilation (99.1% vs 71.8%; p < 0.0001), higher ICU mortality (20.6% vs 16.8%; p < 0.0001), and longer ICU length of stay (5.1 vs 4.2 d; p < 0.0001). CONCLUSIONS: Our rule-based computable phenotyping strategy can accurately detect acute respiratory distress syndrome in critically ill patients in the setting of high clinical complexity. This strategy can be applied to enhance early recognition of acute respiratory distress syndrome and to facilitate best-care delivery and clinical research in acute respiratory distress syndrome.

Biomarker-Concordant Steroid Use in Critically Ill Patients with Pneumonia.

OBJECTIVES: To evaluate the frequency and consequences of prescribing corticosteroids for pneumonia in a biomarker-concordant manner. PATIENTS AND METHODS: This was a single-center retrospective cohort study of adults with pneumonia admitted to the medical intensive care unit (ICU) at Mayo Clinic in Rochester, Minnesota, between January 1, 2009, and June 30, 2014. Steroid use was "biomarker concordant" if given when C-reactive protein (CRP) was ≥150 mg/L or withheld when CRP was <150 mg/L, and vice versa for biomarker discordant. RESULTS: Of 3481 ICU admissions with community-acquired pneumonia, 169 (4.9%) had CRPs measured within 48 hours of admission to the ICU. Steroid use in the ICU was biomarker concordant in 88 (52%) patients and biomarker discordant in 81 (48%) patients. Biomarker-concordant steroid use was associated with faster resolution of lung injury: median fraction of inspired oxygen on day 3 (0.4 [0.3, 0.5] vs 0.3 [0.21, 0.4], P=.005), day 4 (0.35 [0.3, 0.5] vs 0.28 [0.21, 0.38], P=<.001), and day 5 (0.30 [0.24, 0.45] vs 0.28 [0.21, 0.40], P=.03), and increased ICU (3.5; 95% CI, 0.5 to 6.4, P=.02), and hospital-free days (3.6; 95% CI, 0.4 to 6.8, P=.03) on multivariate analysis. CONCLUSIONS: In critically ill patients with community-acquired pneumonia, steroid use is rarely biomarker informed and often discordant with inflammatory biomarker levels. Biomarker-concordant steroid use was associated with a faster recovery of hypoxemia and increased ICU- and hospital-free days. Future well-designed prospective studies are justified to test the potential value of biomarker-concordant steroid therapy.

Development and Verification of a Digital Twin Patient Model to Predict Specific Treatment Response During the First 24 Hours of Sepsis.

To develop and verify a digital twin model of critically ill patient using the causal artificial intelligence approach to predict the response to specific treatment during the first 24 hours of sepsis. DESIGN: Directed acyclic graphs were used to define explicitly the causal relationship among organ systems and specific treatments used. A hybrid approach of agent-based modeling, discrete-event simulation, and Bayesian network was used to simulate treatment effect across multiple stages and interactions of major organ systems (cardiovascular, neurologic, renal, respiratory, gastrointestinal, inflammatory, and hematology). Organ systems were visualized using relevant clinical markers. The application was iteratively revised and debugged by clinical experts and engineers. Agreement statistics was used to test the performance of the model by comparing the observed patient response versus the expected response (primary and secondary) predicted by digital twin. SETTING: Medical ICU of a large quaternary- care academic medical center in the United States. PATIENTS OR SUBJECTS: Adult (> 18 year yr old), medical ICU patients were included in the study. INTERVENTIONS: No additional interventions were made beyond the standard of care for this study. MEASUREMENTS AND MAIN RESULTS: During the verification phase, model performance was prospectively tested on 145 observations in a convenience sample of 29 patients. Median age was 60 years (54-66 d) with a median Sequential Organ Failure Assessment score of 9.5 (interquartile range, 5.0-14.0). The most common source of sepsis was pneumonia, followed by hepatobiliary. The observations were made during the first 24 hours of the ICU admission with one-step interventions, comparing the output in the digital twin with the real patient response. The agreement between the observed versus and the expected response ranged from fair (kappa coefficient of 0.41) for primary response to good (kappa coefficient of 0.65) for secondary response to the intervention. The most common error detected was coding error in 50 observations (35%), followed by expert rule error in 29 observations (20%) and timing error in seven observations (5%). CONCLUSIONS: We confirmed the feasibility of development and prospective testing of causal artificial intelligence model to predict the response to treatment in early stages of critical illness. The availability of qualitative and quantitative data and a relatively short turnaround time makes the ICU an ideal environment for development and testing of digital twin patient models. An accurate digital twin model will allow the effect of an intervention to be tested in a virtual environment prior to use on real patients.

COVID-19: General practice education in the 'new normal'.

COVID-19 has provided learning opportunities for medical students, supervisors and the public.

Mate-pair sequencing identifies a cryptic BMPR2 mutation in hereditary pulmonary arterial hypertension.

Current guidelines suggest screening all patients with idiopathic pulmonary arterial hypertension for genetic aberrations, particularly mutations in Bone Morphogenic Protein Receptor Type II (BMPR2), the gene most commonly implicated in the pathogenesis of PAH. Herein, we present a novel technique used to identify a pathogenic germline BMPR2 alteration in a 36-year-old female and family members with hereditary pulmonary arterial hypertension who each screened negative by standard cytogenetics and molecular genetics testing.

Methicillin-Resistant Staphylococcus aureus Infection and Treatment Options.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of infection worldwide, including a wide array of both hospital- and community-acquired infections-most commonly bacteremia, upper and lower respiratory tract infection, skin and soft-tissue infection, osteomyelitis, and septic arthritis. This chapter describes the epidemiology of MRSA infection, its ability to confer antibiotic resistance and produce a wide array of virulence factors, and its pivotal role in human infection, especially cystic fibrosis. It also provides an introduction to the strategies for treatment of both chronic and acute MRSA infections.

VpALI-Vaping-related Acute Lung Injury: A New Killer Around the Block.

The use of electronic cigarettes, known as vaping, has become increasingly popular over the past decade, particularly in the adolescent and young adult population, often exposing users to harmful chemicals. Vaping has been associated with a heterogeneous group of pulmonary disease. Recently, a multistate epidemic has emerged surrounding vaping-related acute lung injury, prompting the Centers for Disease Control and Prevention to list an official health advisory. In this review, we describe the current literature on the epidemiology, clinical significance, as well as recommended evaluation and treatment of vaping-related lung injury.

Diagnosis and treatment of acute pulmonary inflammation in critically ill patients: The role of inflammatory biomarkers.

Pneumonia and acute respiratory distress syndrome are common and important causes of respiratory failure in the intensive care unit with a significant impact on morbidity, mortality and health care utilization despite early antimicrobial therapy and lung protective mechanical ventilation. Both clinical entities are characterized by acute pulmonary inflammation in response to direct or indirect lung injury. Adjunct anti-inflammatory treatment with corticosteroids is increasingly used, although the evidence for benefit is limited. The treatment decisions are based on radiographic, clinical and physiological variables without regards to inflammatory state. Current evidence suggests a role of biomarkers for the assessment of severity, and distinguishing sub-phenotypes (hyper-inflammatory versus hypo-inflammatory) with important prognostic and therapeutic implications. Although many inflammatory biomarkers have been studied the most common and of interest are C-reactive protein, procalcitonin, and pro-inflammatory cytokines including interleukin 6. While extensively studied as prognostic tools (prognostic enrichment), limited data are available for the role of biomarkers in determining appropriate initiation, timing and dosing of adjunct anti-inflammatory treatment (predictive enrichment).

Longitudinal Effects of Embryonic Exposure to Cocaine on Morphology, Cardiovascular Physiology, and Behavior in Zebrafish.

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.