Diffusion-Limited Kinetics in Reactive Systems.

A proper representation of chemical kinetics is vital to understanding, modeling, and optimizing many important chemical processes. In liquid and surface phases, where diffusion is slow, the rate at which the reactants diffuse together limits the overall rate of many elementary reactions. Commonly, the textbook Smoluchowski theory is utilized to estimate effective rate coefficients in the liquid phase. On surfaces, modelers commonly resort to much more complex and expensive Kinetic Monte Carlo (KMC) simulations. Here, we extend the Smoluchowski model to allow the diffusing species to undergo chemical reactions and derive analytical formulas for the diffusion-limited rate coefficients for 3D, 2D, and 2D/3D interface cases. With these equations, we are able to demonstrate that when species react faster than they diffuse they can react orders of magnitude faster than predicted by Smoluchowski theory, through what we term "the reactive transport effect". We validate the derived steady-state equations against particle Monte Carlo (PMC) simulations, KMC simulations, and non-steady-state solutions. Furthermore, using PMC and KMC simulations, we propose corrections that agree with all limits and the computed data for the 2D and 2D/3D interface steady-state equations, accounting for unique limitations in the associated derived equations. Additionally, we derive equations to handle couplings between diffusion-limited rate coefficients in reaction networks. We believe these equations should make it possible to run much more accurate mean-field simulations of liquids, surfaces, and liquid-surface interfaces accounting for diffusion limitations and the reactive transport effect.

Lipidomic-Based Approach to 10 s Classification of Major Pediatric Brain Cancer Types with Picosecond Infrared Laser Mass Spectrometry.

Picosecond infrared laser mass spectrometry (PIRL-MS) is shown, through a retrospective patient tissue study, to differentiate medulloblastoma cancers from pilocytic astrocytoma and two molecular subtypes of ependymoma (PF-EPN-A, ST-EPN-RELA) using laser-extracted lipids profiled with PIRL-MS in 10 s of sampling and analysis time. The average sensitivity and specificity values for this classification, taking genomic profiling data as standard, were 96.41 and 99.54%, and this classification used many molecular features resolvable in 10 s PIRL-MS spectra. Data analysis and liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) further allowed us to reduce the molecular feature list to only 18 metabolic lipid markers most strongly involved in this classification. The identified 'metabolite array' was comprised of a variety of phosphatidic and fatty acids, ceramides, and phosphatidylcholine/ethanolamine and could mediate the above-mentioned classification with average sensitivity and specificity values of 94.39 and 98.78%, respectively, at a 95% confidence in prediction probability threshold. Therefore, a rapid and accurate pathology classification of select pediatric brain cancer types from 10 s PIRL-MS analysis using known metabolic biomarkers can now be available to the neurosurgeon. Based on retrospective mining of 'survival' versus 'extent-of-resection' data, we further identified pediatric cancer types that may benefit from actionable 10 s PIRL-MS pathology feedback. In such cases, aggressiveness of the surgical resection can be optimized in a manner that is expected to benefit the patient's overall or progression-free survival. PIRL-MS is a promising tool to drive such personalized decision-making in the operating theater.

Development and Implementation of an Acute Kidney Injury Remote Patient Monitoring Program: Research Letter.

Acute kidney injury (AKI) survivors have a dynamic posthospital course which warrants close monitoring. Remote patient monitoring (RPM) could be used to improve quality and efficiency of AKI survivor care. Objective: The objective of this report was to describe the development and preliminary feasibility of an AKI RPM program launched in October 2021. Setting: Academic medical center. Patients: Patients enrolled in the AKI RPM program were those who experienced AKI during a hospitalization and underwent nephrology consultation. Measurements/Methods: At enrollment, patients were provided with home monitoring technology and underwent weekly laboratory assessments. Nurses evaluated the data daily and adhered to prespecified protocols for management and escalation of care if needed. Results: Twenty patients were enrolled in AKI RPM in the first 5 months. Median duration of program participation was 36 (31, 40) days. Eight patients (40%) experienced an unplanned readmission, or an emergency department visit, half (N = 4) of which were attributed to AKI and related circumstances. Of the 9 postgraduation survey respondents, all were satisfied with the RPM program and 89% would recommend RPM to other patients with similar health conditions. Limitations: Acute kidney injury RPM was made possible by the existing infrastructure in our integrated health system and the robust resources available in the Mayo Clinic Center for Digital Health. Such infrastructure may not be universally available which could limit scale and generalizability of such a program. Conclusions: Remote patient monitoring can offer a unique opportunity to bridge the care transition from hospital to home and increase access to quality care for the AKI survivors.

Les survivants d'un épisode d'insuffisance rénale aiguë (IRA) ont un parcours post-hospitalier dynamique qui justifie une surveillance étroite. La télésurveillance des patients (TSP) pourrait être employée pour améliorer la qualité et l'efficacité des soins pour les survivants de l'IRA. Objectif: L'objectif de ce rapport était de décrire le développement et la faisabilité préliminaire d'un programme de TSP-IRA (télésurveillance des patients atteints d'IRA) en octobre 2021. Cadre: Centre médical universitaire. Sujets: Les patients inscrits au programme de TSP-IRA étaient des patients qui avaient vécu un épisode d'IRA lors d'une hospitalisation et obtenu une consultation en néphrologie. Mesures et méthodologie: Au moment de l'inclusion, les patients ont reçu un dispositif de surveillance à domicile et se sont soumis à des évaluations de laboratoire hebdomadaires. Les infirmières ont évalué les données quotidiennement et ont respecté des protocoles prédéfinis pour la gestion et l'escalade des soins si nécessaire. Résultats: Vingt patients ont été inclus dans le programme de TSP-IRA au cours des cinq premiers mois. La durée médiane de participation au programme était de 36 (31, 40) jours. Huit patients (40%) ont dû être réadmis de façon non planifiée ou ont dû faire une visite aux urgences; pour la moitié d'entre eux (N = 4) en raison de l'IRA et de circonstances connexes. Parmi les neuf répondants qui ont répondu au sondage à la complétion du programme, tous se sont dits satisfaits du programme de TSP et 89% le recommanderaient à d'autres patients ayant des problèmes de santé similaires. Limites: Le programme de TSP-IRA a été rendu possible grâce à l'infrastructure existante dans notre système de santé intégré et aux ressources robustes disponibles au Mayo Clinic Center for Digital Health. Une telle infrastructure n'est peut-être pas universellement disponible, ce qui pourrait limiter l'ampleur et la généralisabilité d'un tel programme. Conclusion: La TSP peut offrir une occasion unique de faciliter la transition des soins entre l'hôpital et le domicile et d'accroître l'accès à des soins de qualité pour les survivants d'un épisode d'IRA.

Implementation and evaluation of sepsis surveillance and decision support in medical ICU and emergency department.

OBJECTIVE: To improve the timely diagnosis and treatment of sepsis many institutions implemented automated sepsis alerts. Poor specificity, time delays, and a lack of actionable information lead to limited adoption by bedside clinicians and no change in practice or clinical outcomes. We aimed to compare sepsis care compliance before and after a multi-year implementation of a sepsis surveillance coupled with decision support in a tertiary care center. DESIGN: Single center before and after study. SETTING: Large academic Medical Intensive Care Unit (MICU) and Emergency Department (ED). POPULATION: Patients 18 years of age or older admitted to *** Hospital MICU and ED from 09/4/2011 to 05/01/2018 with severe sepsis or septic shock. INTERVENTIONS: Electronic medical record-based sepsis surveillance system augmented by clinical decision support and completion feedback. MEASUREMENTS AND MAIN RESULTS: There were 1950 patients admitted to the MICU with the diagnosis of severe sepsis or septic shock during the study period. The baseline characteristics were similar before (N = 854) and after (N = 1096) implementation of sepsis surveillance. The performance of the alert was modest with a sensitivity of 79.9%, specificity of 76.9%, positive predictive value (PPV) 27.9%, and negative predictive value (NPV) 97.2%. There were 3424 unique alerts and 1131 confirmed sepsis patients after the sniffer implementation. During the study period average care bundle compliance was higher; however after taking into account improvements in compliance leading up to the intervention, there was no association between intervention and improved care bundle compliance (Odds ratio: 1.16; 95% CI: 0.71 to 1.89; p-value 0.554). Similarly, the intervention was not associated with improvement in hospital mortality (Odds ratio: 1.55; 95% CI: 0.95 to 2.52; p-value: 0.078). CONCLUSIONS: A sepsis surveillance system incorporating decision support or completion feedback was not associated with improved sepsis care and patient outcomes.

The transcriptional landscape of Shh medulloblastoma.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

Mass Spectrometry Imaging Reveals a Gradient of Cancer-like Metabolic States in the Vicinity of Cancer Not Seen in Morphometric Margins from Microscopy.

Spatially resolved ambient mass spectrometry imaging methods have gained popularity to characterize cancer sites and their borders using molecular changes in the lipidome. This utility, however, is predicated on metabolic homogeneity at the border, which would create a sharp molecular transition at the morphometric borders. We subjected murine models of human medulloblastoma brain cancer to mass spectrometry imaging, a technique that provides a direct readout of tissue molecular content in a spatially resolved manner. We discovered a distance-dependent gradient of cancer-like lipid molecule profiles in the brain tissue within 1.2 mm of the cancer border, suggesting that a cancer-like state progresses beyond the histologic border, into the healthy tissue. The results were further corroborated using orthogonal liquid chromatography and mass spectrometry (LC-MS) analysis of selected tissue regions subjected to laser capture microdissection. LC-MS/MS analysis for robust identification of the affected molecules implied changes in a number of different lipid classes, some of which are metabolized from the essential docosahexaenoic fatty acid (DHA) present in the interstitial fluid. Metabolic molecular borders are thus not as sharp as morphometric borders, and mass spectrometry imaging can reveal molecular nuances not observed with microscopy. Caution must be exercised in interpreting multimodal imaging results stipulated on a coincidental relationship between metabolic and morphometric borders of cancer, at least within animal models used in preclinical research.

Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Near-simultaneous intensive care unit (ICU) admissions and all-cause mortality: a cohort study.

PURPOSE: Prior studies have reported the adverse effects of strain on patient outcomes. There is a paucity of literature about a type of strain that may be caused by near-simultaneous intensive care unit (ICU) admissions. We hypothesized that when multiple admissions arrive nearly at the same time, the ICU teams are excessively strained, and this leads to unfavorable patient outcomes. METHODS: This is a retrospective cohort study of consecutive adult patients admitted to an academic medical ICU of a tertiary referral center over five consecutive years. Primary outcomes were the all-cause hospital and ICU mortality. RESULTS: We enrolled 13,234 consecutive ICU admissions during the study period. One-fourth of the admissions had an elapsed time since the last admission (ETLA) of < 55 min. Near-simultaneous admissions (NSA) had on average, a higher unadjusted odds ratio (OR) of ICU death of 1.16 (95% CI 1-1.35, P = 0.05), adjusted 1.23 (95% CI 1.04-1.44, P = 0.01), unadjusted hospital death of 1.11 (95% CI 0.99-1.24, P = 0.06), adjusted 1.20 (95% 1.05-1.35, P = 0.004), and a lower adjusted OR of home discharge of 0.91 (95% CI 0.84-0.99, P = 0.04). NSA was associated with 0.16 (95% CI 0.04-0.29, P = 0.01) added days in the ICU. For each incremental unit increase of the logarithmic transformation of ETLA [log (ETLA in minutes)], the average adjusted hospital mortality OR incrementally decreased by an added average OR of 0.93 (95% CI 0.89‒0.97, P = 0.001). CONCLUSION: Our results suggest that near-simultaneous ICU admissions (NSA) are frequent and are associated with a dose-dependent effect on mortality, length of stay, and odds of home versus nursing facility discharge.

Incidence of metastatic disease and survival among patients with newly diagnosed primary CNS tumors in the United States from 2004-2013.

Background: Population-based estimates of the incidence and prognosis of metastatic disease at the initial diagnosis of primary central nervous system (CNS) tumors are currently lacking. Methods: A total of 43,455 patients diagnosed with a primary CNS tumor were enrolled to evaluate metastatic rates utilizing the data from the Surveillance, Epidemiology, and End Results (SEER) program. We used multivariate logistic regression to analyze the risk factors associated with the presence of metastasis at the first visit of patients with metastatic medulloblastoma (MB), atypical teratoid/rhabdoid tumor (ATRT), glioblastoma multiforme (GBM), or pilocytic astrocytoma (PA). Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific death (CSD) of patients with these four CNS tumors were analyzed using multivariate Cox regression. Results: In patients with primary CNS embryonal tumors, the metastatic rates of patients with MB and ATRT were 14.51% and 19.25%, respectively. The metastatic rate for MB patients aged 0 to 18 years was 16.69%. In the patients with glioma, the metastatic rates of patients with PA and GBM were 1.55% and 1.39%, respectively. On multivariate logistic regression among patients with glioma, GBM (vs PA; OR, 2.12; 95% CI, 1.37 to 3.30; P=0.001) was associated with greater odds of having metastatic disease at diagnosis. On multivariate logistic regression among patients with GBM, MB, or ATRT, MB (vs GBM; OR, 4.66; 95% CI, 2.81 to 7.72; P<0.001) and ATRT (vs GBM; OR, 5.65; 95% CI, 3.27 to 9.75; P<0.001) were associated with greater odds of having metastatic disease at diagnosis. In the multivariate Cox proportional hazards model for CSD among patients with metastatic GBM or MB at diagnosis, gross total resection/total lobectomy (vs partial resection/partial lobectomy) was not related to a decreased or an increased risk of CSD. In patients with metastatic ATRT, compared to no surgery, gross total resection/total lobectomy or partial resection/partial lobectomy was not associated with a decreased risk of CSD. Conclusions: The findings in this study provide a population-based estimate of the incidence and prognosis of metastatic disease at the initial diagnosis of primary CNS tumors. These survival outcomes are relevant because they will help to prioritize future research directions to improve the treatment strategies of these metastatic CNS tumors.

Childhood cerebellar tumours mirror conserved fetal transcriptional programs.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.

Reducing Iatrogenic Pneumothoraces: Using Real-Time Ultrasound Guidance for Pleural Procedures.

OBJECTIVES: Awareness of the impact of bedside ultrasound to reduce iatrogenic pneumothoraces while performing bedside pleural procedures has increased but with little understanding in how ultrasound is used for these procedures. DESIGN AND SETTING: We conducted a retrospective chart review at a tertiary referral center in the United States from January 1, 2014, to March 31, 2017. Our study assessed adverse effect rates between real-time ultrasound-guided and ultrasound-marked thoracenteses and thoracostomy tube placements. PATIENTS: Three-hundred ninety-four ICU patients were included in this study. MEASUREMENTS AND MAIN RESULTS: There was a significant difference in the rate of adverse effects between real-time ultrasound-guided (0.63% [95% CI, 0.11-3.4%]) and ultrasound-marked (6.89% [95% CI, 4.15-11.24%]; p ≤ 0.01) procedures. More specifically, the rate of pneumothoraces was different between the two procedures (0.63% [95% CI, 0.11-3.4%] vs 4.43% [95% CI, 2.35-8.21%]; p = 0.02). In patients mechanically ventilated, there was a significant difference in overall adverse effect rates between groups of ultrasound use (p = 0.01). CONCLUSIONS: The use of real-time ultrasound guidance was associated with a lower rate of iatrogenic pneumothoraces.

Effect of plasma exchange on antifactor Xa activity of enoxaparin and serum levetiracetam levels.

PURPOSE: The effect of therapeutic plasma exchange (TPE) on antifactor Xa activity in a patient treated with enoxaparin and levetiracetam is reported. SUMMARY: A 52-year-old woman was treated with levetiracetam and prophylactic enoxaparin while receiving TPE to manage respiratory failure due to anti-MDA5 antibody-associated interstitial lung disease (ILD) with dermatomyositis. Due to a scant amount of evidence regarding the management of these medications in TPE, therapeutic monitoring principles were used to assess the effect TPE had on these medications. A pre-TPE antifactor Xa activity level and levetiracetam serum assay, a post-TPE antifactor Xa activity level and levetiracetam serum assay, levetiracetam serum assays at 1 and 6 hours after the patient received her next dose, and a levetiracetam assay of the waste plasma from the TPE were collected for therapeutic drug monitoring and pharmacokinetic calculations. Utilizing standard population pharmacokinetic data, the expected antifactor Xa activity without TPE was 0.14 IU/mL. This concentration was significantly higher than the undetectable concentration (<0.1 IU/mL) that was drawn immediately after TPE, suggesting significant removal of antifactor Xa activity. The measured levetiracetam level did not significantly differ from the expected post-TPE levetiracetam level that was calculated using patient-specific pharmacokinetic data. CONCLUSION: In a patient receiving TPE to manage anti-MDA5 antibody ILD associated with dermatomyositis and a prior seizure, TPE significantly altered enoxaparin antifactor Xa activity as evidenced by the undetectable antifactor Xa activity level drawn after TPE. Alternatively, TPE had a minimal effect on the clearance of levetiracetam as evidenced by the post-TPE level and fraction elimination of only 5% of total body stores.

Severe Babesia microti infection presenting as multiorgan failure in an immunocompetent host.

A previously healthy 67-year-old farmer presented to an outside hospital after a 2-week history of non-specific respiratory symptoms. A certain diagnosis was not initially apparent, and the patient was discharged home on a regimen for presumed chronic obstructive pulmonary disease exacerbation. He re-presented to the emergency department with shock and hypoxaemic respiratory failure requiring prompt intubation and fluid resuscitation. He was then transferred to our institution due to multiorgan failure. On arrival, the patient demonstrated refractory shock and worsening acute kidney injury, severe anaemia and thrombocytopaenia. The peripheral smear revealed absence of microangiopathic haemolytic anaemia. A closer review of the smear displayed red blood cell inclusion bodies consistent with babesiosis. The patient was started on clindamycin and loaded with intravenous quinidine, and subsequently transitioned to oral quinine. A red cell exchange transfusion was pursued with improvement of the parasite load. The patient was discharged home on clindamycin/quinine and scheduled for outpatient intermittent haemodialysis.

Early Corticosteroids for Pneumocystis Pneumonia in Adults Without HIV Are Not Associated With Better Outcome.

BACKGROUND: Evidence supporting adjunctive corticosteroids during the treatment of Pneumocystis jirovecii pneumonia (PcP) in adults without HIV is minimal and controversial. METHODS: This retrospective cohort study included P jirovecii pneumonia-positive, hospitalized patients without HIV admitted to the Mayo Clinic from 2006 to 2016. Change from baseline in the respiratory component of the Sequential Organ Failure Assessment score (SOFAresp) at day 5 was compared between early (within 48 h) steroid recipients and nonrecipients by using multivariable logistic regression and in a propensity-matched analysis. RESULTS: Among the 323 included patients (early steroids, n = 258; no steroids, n = 65), the median (interquartile range) age was 65 (53, 73) years, 63% were male, and 92% were white. Severity-adjusted regression and propensity-matched analyses found that early administration of steroids was associated with less improvement in SOFAresp at day 5 compared with no steroids (P = .001 and P = .017, respectively). No differences were observed in the odds of having at least a one-point improvement in SOFAresp at day 5 compared with baseline between groups (adjusted OR, 0.76 [95% CI, 0.24-2.28]; P = .61). Overall 30-day mortality was 22.9% (95% CI, 18.2-27.4). No differences in mortality, length of stay, admission to the ICU, or need for mechanical ventilation were found between early steroid recipients and nonrecipients. CONCLUSIONS: The addition of early corticosteroids to anti-Pneumocystis therapy in patients without HIV was not associated with improved respiratory outcomes.