Association between CFTR modulators and changes in iron deficiency markers in cystic fibrosis.

BACKGROUND: Iron deficiency (ID) is a common extrapulmonary manifestation in cystic fibrosis (CF). CF transmembrane conductance regulator (CFTR) modulator therapies, particularly highly-effective modulator therapy (HEMT), have drastically improved health status in a majority of people with CF. We hypothesize that CFTR modulator use is associated with improved markers of ID. METHODS: In a multicenter retrospective cohort study across 4 United States CF centers 2012-2022, the association between modulator therapies and ID laboratory outcomes was estimated using multivariable linear mixed effects models overall and by key subgroups. Summary statistics describe the prevalence and trends of ID, defined a priori as transferrin saturation (TSAT) <20 % or serum iron <60 µg/dL (<10.7 µmol/L). RESULTS: A total of 568 patients with 2571 person-years of follow-up were included in analyses. Compared to off modulator therapy, HEMT was associated with +8.4 % TSAT (95 % confidence interval [CI], +6.3-10.6 %; p < 0.0001) and +34.4 µg/dL serum iron (95 % CI, +26.7-42.1 µg/dL; p < 0.0001) overall; +5.4 % TSAT (95 % CI, +2.8-8.0 %; p = 0.0001) and +22.1 µg/dL serum iron (95 % CI, +13.5-30.8 µg/dL; p < 0.0001) in females; and +11.4 % TSAT (95 % CI, +7.9-14.8 %; p < 0.0001) and +46.0 µg/dL serum iron (95 % CI, +33.3-58.8 µg/dL; p < 0.0001) in males. Ferritin was not different in those taking modulator therapy relative to off modulator therapy. Hemoglobin was overall higher with use of modulator therapy. The prevalence of ID was high throughout the study period (32.8 % in those treated with HEMT). CONCLUSIONS: ID remains a prevalent comorbidity in CF, despite availability of HEMT. Modulator use, particularly of HEMT, is associated with improved markers for ID (TSAT, serum iron) and anemia (hemoglobin).

TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.

Tandem detergent-extraction and immunoprecipitation of proteinopathy: Scalable enrichment of ALS-associated TDP-43 aggregates.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved, ubiquitously expressed nucleic acid-binding protein that regulates DNA/RNA metabolism. Genetics and neuropathology studies have linked TDP-43 to several neuromuscular and neurological disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under pathological conditions, TDP-43 mislocalizes to the cytoplasm where it forms insoluble, hyper-phosphorylated aggregates during disease progression. Here, we optimized a scalable in vitro immuno-purification strategy referred to as tandem detergent-extraction and immunoprecipitation of proteinopathy (TDiP) to isolate TDP-43 aggregates that recapitulate those identified in postmortem ALS tissue. Moreover, we demonstrate that these purified aggregates can be utilized in biochemical, proteomics, and live-cell assays. This platform offers a rapid, accessible, and streamlined approach to study ALS disease mechanisms, while overcoming many limitations that have hampered TDP-43 disease modeling and therapeutic drug discovery efforts.

Effects of procalcitonin on antimicrobial treatment decisions in patients with coronavirus disease 2019 (COVID-19).

OBJECTIVE: To describe the natural course of procalcitonin (PCT) in patients with coronavirus disease 2019 (COVID-19) and the correlation between PCT and antimicrobial prescribing to provide insight into best practices for PCT data utilization in antimicrobial stewardship in this population. DESIGN: Single-center, retrospective, observational study. SETTING: Michigan Medicine. PATIENTS: Inpatients aged ≥18 years hospitalized March 1, 2020, through October 31, 2021, who were positive for severe acute respiratory coronavirus virus 2 (SARS-CoV-2), with ≥1 PCT measurement. Exclusion criteria included antibiotics for nonpulmonary bacterial infection on admission, treatment with azithromycin only for chronic obstructive pulmonary disease (COPD) exacerbation, and pre-existing diagnosis of cystic fibrosis with positive respiratory cultures. METHODS: A structured query was used to extract data. For patients started on antibiotics, bacterial pneumonia (bPNA) was determined through chart review. Multivariable models were used to assess associations of PCT level and bPNA with antimicrobial use. RESULTS: Of 793 patients, 224 (28.2%) were initiated on antibiotics: 33 (14.7%) had proven or probable bPNA, 125 (55.8%) had possible bPNA, and 66 (29.5%) had no bPNA. Patients had a mean of 4.1 (SD, ±5.2) PCT measurements if receiving antibiotics versus a mean of 2.0 (SD, ±2.6) if not. Initial PCT level was highest for those with proven/probable bPNA and was associated with antibiotic initiation (odds ratio 95% confidence interval [CI], 1.17-1.30). Initial PCT (rate ratio [RR] 95% CI, 1.01-1.08), change in PCT over time (RR 95% CI, 1.01-1.05), and bPNA group (RR 95% CI, 1.23-1.84) were associated with antibiotic duration. CONCLUSIONS: PCT trends are associated with the decision to initiate antibiotics and duration of treatment, independent of bPNA status and comorbidities. Prospective studies are needed to determine whether PCT level can be used to safely make decisions regarding antibiotic treatment for COVID-19.

Neural differences in social and figurative language processing on the autism spectrum.

Individuals on the autism spectrum often have trouble with social and figurative language. As social language is often figurative, it can be challenging to disentangle the cognitive and neural sources of these difficulties. Neural systems for social cognition and language comprehension overlap in areas involved in retrieving linguistic meaning (semantics), such as the anterior temporal lobe (ATL), ventro-medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), and posterior middle temporal gyrus (pMTG). Using adjective-noun phrases, we manipulated social/nonsocial and figurative/literal dimensions, which we expected to activate distinct but overlapping regions. We hypothesized that activation differences in the group with autism (AUT) would be greater for more social and figurative stimuli. During fMRI, participants in the AUT group (N = 19) and those in the non-autistic comparison (NAC) group (N = 22) made familiarity judgments to 192 phrases in a balanced 2 × 2 (social/nonsocial x figurative/literal) design. Social phrases activated the PCC in all participants, but only the NAC group activated the vmPFC. Figurative phrases were rated as more literal by the AUT group, with the figurative-literal phrase contrast showing no activation in the AUT group, but activating the PCC and right pMTG in the NAC group. The one significant group-level neural difference was for the social-figurative condition predicted to be most different between groups: greater activation for the AUT group in the right ATL. Differences in the right ATL and pMTG in the AUT group suggest altered engagement of right homologues of the canonical semantic network being recruited for processing combined social and figurative language.

Outcomes of cystic fibrosis pulmonary exacerbations treated with antibiotics with activity against anaerobic bacteria.

BACKGROUND: Obligate and facultative anaerobic bacteria are prevalent in cystic fibrosis (CF) airways. Increases in anaerobe relative abundance have been associated with CF pulmonary exacerbations (PEx); however, the impact of antibiotic treatment of anaerobes during PEx is unknown. We hypothesized that PEx treated with antibiotics with activity against anaerobes would improve outcomes compared to antibiotics without anaerobic activity. METHODS: This was a single-center, retrospective study of people with CF, ages 6 years and older, treated with intravenous (IV) antibiotics for PEx. IV antibiotics were classified as either broad or minimal anaerobic activity. PEx treated with broad anaerobe coverage were propensity-score matched to PEx treated with minimal anaerobic coverage. The primary outcome, % of baseline % predicted forced expiratory volume in one second (ppFEV1) recovered, was compared between antibiotic categories with a linear mixed model. The secondary outcome, time to next PEx, was assessed using a Prentice Williams Petersen model. RESULTS: 514 PEx from 182 patients were included. Broad anaerobe coverage was used in 27% of PEx, and was used more often for older patients (p < 0.001) with worse baseline ppFEV1 (p < 0.001), and with Achromobacter (p < 0.001) or Burkholderia infections (p = 0.002). In the matched PEx, broad anaerobe coverage was not a significant predictor of % of baseline ppFEV1 recovered (∆ppFEV1 = -2.4, p = 0.09). Broad anaerobe coverage was also not a significant predictor of time to next PEx (HR 0.89, 95% CI 0.7-1.13, p = 0.35). CONCLUSIONS: In this single center, retrospective study, antibiotics with broad activity against anaerobes were not associated with improved outcomes of CF PEx.

Shared and Unique Features of Human Interferon-Beta and Interferon-Alpha Subtypes.

Type I interferons (IFN-I) were first discovered as an antiviral factor by Isaacs and Lindenmann in 1957, but they are now known to also modulate innate and adaptive immunity and suppress proliferation of cancer cells. While much has been revealed about IFN-I, it remains a mystery as to why there are 16 different IFN-I gene products, including IFNß, IFNω, and 12 subtypes of IFNα. Here, we discuss shared and unique aspects of these IFN-I in the context of their evolution, expression patterns, and signaling through their shared heterodimeric receptor. We propose that rather than investigating responses to individual IFN-I, these contexts can serve as an alternative approach toward investigating roles for IFNα subtypes. Finally, we review uses of IFNα and IFNß as therapeutic agents to suppress chronic viral infections or to treat multiple sclerosis.

Measures of Cystic Fibrosis Airway Microbiota during Periods of Clinical Stability.

Rationale: Differences in cystic fibrosis (CF) airway microbiota between periods of clinical stability and exacerbation of respiratory symptoms have been investigated in efforts to better understand microbial triggers of CF exacerbations. Prior studies have often relied on a single sample or a limited number of samples to represent airway microbiota. However, the variability in airway microbiota during periods of clinical stability is not well known.Objectives: To determine the temporal variability of measures of airway microbiota during periods of clinical stability, and to identify factors associated with this variability.Methods: Sputum samples (N = 527), obtained daily from six adults with CF during 10 periods of clinical stability, underwent sequencing of the V4 region of the bacterial 16S ribosomal RNA gene. The variability in airway microbiota among samples within each period of clinical stability was calculated as the average of the Bray-Curtis similarity measures of each sample to every other sample within the same period. Outlier samples were defined as samples outside 1.5 times the interquartile range within a baseline period with respect to the average Bray-Curtis similarity. Total bacterial load was measured with droplet digital polymerase chain reaction.Results: The variation in Bray-Curtis similarity and total bacterial load among samples within the same baseline period was greater than the variation observed in technical replicate control samples. Overall, 6% of samples were identified as outliers. Within baseline periods, changes in bacterial community structure occurred coincident with changes in maintenance antibiotics (P < 0.05, analysis of molecular variance). Within subjects, bacterial community structure changed between baseline periods (P < 0.01, analysis of molecular variance). Sample-to-sample similarity within baseline periods was greater with fewer interval days between sampling.Conclusions: During periods of clinical stability, airway bacterial community structure and bacterial load vary among daily sputum samples from adults with CF. This day-to-day variation has bearing on study design and interpretation of results, particularly in analyses that rely on single samples to represent periods of interest (e.g., clinical stability vs. pulmonary exacerbation). These data also emphasize the importance of accounting for maintenance antibiotic use and granularity of sample collection in studies designed to assess the dynamics of CF airway microbiota relative to changes in clinical state.

Optimizing Electronic Release of Imaging Results through an Online Patient Portal.

Purpose To determine an optimal embargo period preceding release of radiologic test results to an online patient portal. Materials and Methods This prospective discrete choice conjoint survey with modified orthogonal design was administered to patients by trained interviewers at four outpatient sites and two institutions from December 2016 to February 2018. Three preferences for receiving imaging results associated with a possible or known cancer diagnosis were evaluated: delay in receipt of results (1, 3, or 14 days), method of receipt (online portal, physician's office, or phone), and condition of receipt (before, at the same time as, or after health care provider). Preferences (hereafter, referred to as utilities) were derived from parameter estimates (ß) of multinomial regression stratified according to study participant and choice set. Results Among 464 screened participants, the response and completion rates were 90.5% (420 of 464) and 99.5% (418 of 420), respectively. Participants preferred faster receipt of results (P < .001) from their physician (P < .001) over the telephone (P < .001). Each day of delay decreased preference by 13 percentage points. Participants preferred immediate receipt of results through an online portal (utility, -.57) if made to wait more than 6 days to get results in the office and more than 11 days to get results by telephone. Compared with receiving results in their physician's office on day 7 (utility, -.60), participants preferred immediate release through the online portal without physician involvement if followed by a telephone call within 6 days (utility, -0.49) or an office visit within 2 days (utility, -.53). Older participants preferred physician-directed communication (P < .001). Conclusion The optimal embargo period preceding release of results through an online portal depends on the timing of traditional telephone- and office-based styles of communication. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Arenson et al in this issue.

Waiting for Radiology Test Results: Patient Expectations and Emotional Disutility.

PURPOSE: To measure patient willingness to wait and emotional disutility of waiting for outpatient imaging test results. METHODS: A prospective HIPAA-compliant multicenter outpatient quality improvement survey was administered by a trained interviewer to 218 outpatients from November 1, 2016, to February 1, 2017. The survey was vetted by patient- and family-centered care advocates with experience in survey design and underwent precognitive testing for readability. Six clinical scenarios were tested. Descriptive statistics were calculated. RESULTS: The response (93% [202 of 218]) and completion (93% [188 of 202]) rates were excellent. Anxiety (28% [57 of 202]), depression (26% [53 of 202]), and cancer (23% [46 of 202]) histories were common. Median stated expectations for imaging test results receipt were 3 days after a screening examination (interquartile range [IQR] 5 days); 2 days after chest x-ray for chest pain (IQR 3) or MRI or CT for back pain (IQR 2); and 1 day after chest x-ray for pneumonia (IQR 2), MRI or CT for brain tumor (IQR 2), or CT for cancer treatment (IQR 3). If imaging results are not received, the median time patients stated they would wait to call their provider was 1 to 5 days (varied by indication). Waiting for imaging results exerts an emotional change in 45% (91 of 202) of individuals, with the majority (85% [77 of 91]) experiencing anxiety (minimal 28%, mild 45%, moderate 22%, severe 4%, extreme 1%). CONCLUSIONS: Patients expect outpatient imaging results within 1 to 3 days and will call providers by 1 to 5 days. Waiting for test results commonly induces anxiety.

Patient-Centered Assessment of the Value of Oral Contrast Material.

PURPOSE: The aim of this study was to measure the value of oral contrast material from the patient's point of view. METHODS: A prospective HIPAA-compliant survey was administered from August 30, 2016, to March 9, 2017, at two outpatient centers to consecutive outpatients immediately after oral contrast material consumption for abdominopelvic CT. The survey included validated measures of temporary health disutility and oral contrast-specific questions vetted by patient advocates with experience in survey design. Descriptive statistics were calculated. RESULTS: The response rate (93% [218 of 234]) and completion rate (100% [218 of 218]) were excellent. When given a hypothetical choice to not drink oral contrast, most subjects (89% [193 of 218]) stated that they would always drink it for fear of missing an important finding, and only 5 (2%) stated that they would never drink it regardless of risk. Twenty (9%) said that the decision to drink oral contrast would depend on the level of risk, with 18 (8%) indicating that they would accept a 0.01% to 1.00% risk for missing an important finding if they did not have to drink oral contrast. Most patients rated the oral contrast taste as tolerable (55% [120 of 218]); a minority rated it bad or terrible (10% [21 or 218]). Thirty-six subjects (17%) experienced concern or unease (8 minimal, 15 mild, 10 moderate, 3 extreme) when they learned that they had to drink oral contrast, and 36 (17%) experienced oral contrast-induced nausea or abdominal discomfort (10 minimal, 15 mild, 10 moderate, 1 extreme). CONCLUSIONS: If oral contrast material has any diagnostic benefit, most outpatients (89%) would rather drink it than accept any risk for missing an important finding.