The role of ACT score in mepolizumab discontinuation.

BACKGROUND: Mepolizumab is a therapy for severe asthma. We have little knowledge of the characteristics of people in the US that discontinue mepolizumab in clinical care. OBJECTIVE: To investigate the real-world efficacy and time to clinical discontinuation of mepolizumab, we evaluated individuals with asthma started on mepolizumab at the Cleveland Clinic. We hypothesized that individuals that discontinue mepolizumab have more severe and uncontrolled asthma at baseline. METHODS: Between 2016 and 2022, patients who started on mepolizumab consented to be assessed over 18 months. At baseline, a questionnaire including demographic and medical history was collected. Laboratory findings such as ACT score, FENO (Fractional Excretion of Nitric Oxide), and spirometry were recorded. At the conclusion of the observation period, the participants were divided into two categories: Group A and Group B. RESULTS: Group B [N = 28] discontinued mepolizumab (p < 0.05) at an average of 5.8 months (SD 4.2 months). Group A [N = 129] stayed on the therapy for at least 1 year. A participant with an ACT score less than 13 has an odds ratio of 6.64 (95% CI, 2.1 - 26.0) of discontinuing mepolizumab therapy. For a male, the odds of discontinuing mepolizumab therapy is 3.39 (95% CI, 1.1-11.2). CONCLUSION: In this real-world study, we find that high eosinophil count may not be adequate in screening which individuals will benefit from mepolizumab. Up to 17% of patients fail therapy within 6 months, with male sex and low ACT score increasing risk of mepolizumab discontinuation at Cleveland Clinic.

Outcomes and Resource Use Among Overweight and Obese Children With Sepsis in the Pediatric Intensive Care Unit.

OBJECTIVE: To evaluate the effect of overweight and obesity on outcomes and resource use among patients with sepsis in the pediatric intensive care unit (PICU). DESIGN: Retrospective analysis of clinical characteristics, resource use, and mortality among children 0 to 20 years of age admitted to the C.S. MottChildren's Hospital PICU (University of Michigan) between January 2009 and December 2015, with a diagnostic code for sepsis at admission (based on International Classification of Diseases, Ninth Revision-Clinical Modification codes) and with weight and height measurements at PICU admission. MEASUREMENTS AND MAIN RESULTS: A total of 454 participants met the inclusion criteria. Seventy-six were categorized as underweight (body mass index [BMI] percentile <5th) and were excluded, which left a final sample size of 378 participants. Children with a BMI >5th and <85th percentiles for age were categorized as normal weight and those with a BMI >85th percentile as overweight/obese. After descriptive and bivariate analyses, multivariate regression methods were used to assess the independent effect of obesity status on mortality and the use of PICU technology after adjustment for patient age and illness severity at admission. Of the 378 patients studied, 41.3% were overweight/obese. There was no difference in microbiologic etiology of sepsis (P = .36), median PICU length of stay in days (5.4 vs 5.6; P = .61), or PICU mortality (6.4% vs 7.2%; P = .76) by weight status. The use of specialized PICU technology including extracorporeal membrane oxygenation (odds ratio [OR]: 2.77, 95% confidence interval [CI]:1.13-6.79) and continuous renal replacement therapy (OR: 4.58, 95% CI: 1.16-18.0) was higher among overweight/obese patients, compared with normal weight patients. CONCLUSIONS: Although PICU mortality and length of stay were similar for obese-overweight patients and normal weight critically ill children with sepsis, there was significantly higher use of specialized organ-supportive technology among obese patients, likely indicating higher occurrence of multiple organ dysfunction.

Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1). METHODS: Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later. RESULTS: GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor ß (TGF-ß) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF ß and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice. CONCLUSION: These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.

A multidomain enzyme, with glycerol-3-phosphate dehydrogenase and phosphatase activities, is involved in a chloroplastic pathway for glycerol synthesis in Chlamydomonas reinhardtii.

Understanding the unique features of algal metabolism may be necessary to realize the full potential of algae as feedstock for the production of biofuels and biomaterials. Under nitrogen deprivation, the green alga C. reinhardtii showed substantial triacylglycerol (TAG) accumulation and up-regulation of a gene, GPD2, encoding a multidomain enzyme with a putative phosphoserine phosphatase (PSP) motif fused to glycerol-3-phosphate dehydrogenase (GPD) domains. Canonical GPD enzymes catalyze the synthesis of glycerol-3-phosphate (G3P) by reduction of dihydroxyacetone phosphate (DHAP). G3P forms the backbone of TAGs and membrane glycerolipids and it can be dephosphorylated to yield glycerol, an osmotic stabilizer and compatible solute under hypertonic stress. Recombinant Chlamydomonas GPD2 showed both reductase and phosphatase activities in vitro and it can work as a bifunctional enzyme capable of synthesizing glycerol directly from DHAP. In addition, GPD2 and a gene encoding glycerol kinase were up-regulated in Chlamydomonas cells exposed to high salinity. RNA-mediated silencing of GPD2 revealed that the multidomain enzyme was required for TAG accumulation under nitrogen deprivation and for glycerol synthesis under high salinity. Moreover, a GPD2-mCherry fusion protein was found to localize to the chloroplast, supporting the existence of a GPD2-dependent plastid pathway for the rapid synthesis of glycerol in response to hyperosmotic stress. We hypothesize that the reductase and phosphatase activities of PSP-GPD multidomain enzymes may be modulated by post-translational modifications/mechanisms, allowing them to synthesize primarily G3P or glycerol depending on environmental conditions and/or metabolic demands in algal species of the core Chlorophytes.

Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension.

BACKGROUND: Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. METHODS: We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. RESULTS: Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. CONCLUSIONS: Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans.

Perceptions of Integrated Vascular Surgery Fellowship Graduates among Community Vascular Surgeons.

BACKGROUND: Vascular training includes both integrated residency ("0+5") and postresidency fellowship ("5+2") programs. The impact of training models on attitudes toward graduates as prospective hires is incompletely understood, and existing studies have primarily surveyed surgeons from academic centers. We surveyed surgeons who were in active clinical practice but not affiliated with a medical school or training program to compare perceptions of integrated versus postgraduate programs. METHODS: Vascular surgeons not affiliated with a university-based practice were identified from membership rosters of one regional and one national specialty society and e-mailed an anonymous survey. The survey evaluated respondents' training, practice distribution, general surgery responsibilities, hiring practices, and perception of the integrated and postgraduate trained vascular surgeons. Agreement among specific responses was evaluated using McNemar's test. RESULTS: The survey was sent to 406 surgeons with 71 (17.5%) responding. A total of 42% of respondents indicated that half or more of their cases consisted of open procedures and 10% reported general surgery coverage as part of their practice. More respondents indicated that they consider postgraduate trained surgeons very mature (41% vs. 7%, P < 0.0001) and better prepared for open cases (89% vs. 28%, P < 0.0001), as well as endovascular cases (96% vs. 87%, P = 0.0339). Overall 84% stated that they would interview an integrated program graduate, although only 72% indicated that they would hire one. Overall 16.9% identified ability to cover general surgery as either very important or somewhat important characteristic for a potential hire. CONCLUSIONS: Perceptions of 5+2 graduates as more mature and better prepared for opens surgical cases may influence hiring practices. This suggests that attitudes toward integrated versus 5+2 trained surgeons may differ between academic and community vascular surgeons. Further research is needed to assess whether these differences are related to actual differences in graduate skills, familiarity with integrated graduates, or other factors.

Biomarker-based asthma phenotypes of corticosteroid response.

BACKGROUND: Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable. OBJECTIVE: We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level) might predict steroid responsiveness. METHODS: The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which Feno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1, a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5'-monophosphate causing a 20% decrease in FEV1 (PC20AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients. RESULTS: Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy. CONCLUSION: A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.

Exploring patient involvement in decision making for vascular procedures.

BACKGROUND: Developing patient-centered approaches to health care requires increased engagement of patients in their own care, including treatment decisions. Current levels of patient involvement in treatment choices have not been quantified, however, and whether patients desire greater decision-making responsibility is unknown. We conducted a prospective study to explore patients' desired vs experienced roles in treatment decisions, characterize perceptions of treatment outcomes, and identify important sources of information. METHODS: Patients undergoing elective vascular procedures completed a survey consisting of multiple choice, Likert scale, and open-ended questions. Statistics are displayed as mean ± standard deviation or count (%). Differences among procedure categories were evaluated using χ(2) or the Fisher exact test at P < .05 based on responses scored 1 to 2, indicating importance, agreement, or satisfaction based on a 1 to 5 Likert scale where 1 = "very important," "strongly agree" or "very satisfied". RESULTS: Of 101 patients who were contacted, 81 participated. Procedure categories included abdominal aortic aneurysm (AAA) repair in 20, arteriovenous (AV) hemodialysis access in 21, carotid endarterectomy (CEA) in 20, and intervention for lower extremity peripheral arterial disease (PAD) in 20. Participants preferred discussion of all treatments being considered vs only the provider's recommended treatment (90% vs 56%) and choosing together with the provider vs having the provider choose for them (93% vs 62%). Although participants indicated adequate information to ask questions without feeling overwhelmed, only 77% agreed that they had the opportunity to ask questions and only 54% indicated that they were offered a choice. Thirty-seven participants (46%) considered their first treatment was successful, 38% considered a subsequent treatment was successful, and 16% considered none of their treatments were successful. Participants undergoing PAD and AV access procedures most often felt confused or overwhelmed (25% and 24%, respectively, vs 0% for AAA and CEA; P < .01). Patients with PAD had adequate information least often (70% vs 85% for AAA, 100% for AV access, and 95% for CEA; P = .01), had the lowest satisfaction with understanding of their diagnosis (65% vs 95% for AAA, 100% for AV access, and 95% for CEA; P < .01), and most often considered none of their treatments successful (35% vs 0% for AAA, 15% for AV access, and 15% for CEA; P = .02). Providers were identified as the most important information source. CONCLUSIONS: Patients have variable levels of participation in decision making related to vascular procedures and often consider their treatments unsuccessful. Although providers are important sources of information, patients still prefer to discuss all options being considered and contribute to shared decision making.

Surgeon and nonsurgeon personalities at different career points.

BACKGROUND: Previous studies have demonstrated correlations between personality traits and job performance and satisfaction. Evidence suggests that personality differences exist between surgeons and nonsurgeons, some of which may develop during medical training. Understanding these personality differences may help optimize job performance and satisfaction among surgical trainees and be used to identify individuals at risk of burnout. This study aims to identify personality traits of surgeons and nonsurgeons at different career points. MATERIALS AND METHODS: We used The Big Five Inventory, a 44-item measure of the five factor model. Personality data and demographics were collected from responses to an electronic survey sent to all faculty and house staff in the Departments of Surgery, Medicine, and Family Medicine at The Ohio State University College of Medicine. Data were analyzed to identify differences in personality traits between surgical and nonsurgical specialties according to level of training and to compare surgeons to the general population. RESULTS: One hundred ninety-two house staff and faculty in surgery and medicine completed the survey. Surgeons scored significantly higher on conscientiousness and extraversion but lower on agreeableness compared to nonsurgeons (all P < 0.05). Surgery faculty scored lower in agreeableness compared with that of surgery house staff (P = 0.001), whereas nonsurgeon faculty scored higher on extraversion compared with that of nonsurgeon house staff (P = 0.04). CONCLUSIONS: There appears to be inherent personality differences between surgical and nonsurgical specialties. The use of personality testing may be a useful adjunct in the residency selection process for applicants deciding between surgical and nonsurgical specialties. It may also facilitate early intervention for individuals at high risk for burnout and job dissatisfaction.

Selective mitogen activated protein kinase activity sensors through the application of directionally programmable D domain motifs.

Accurate and quantitative methods for measuring the dynamic fluctuations of protein kinase activities are critically needed as diagnostic tools and for the evaluation of kinase-targeted inhibitors, which represent a major therapeutic development area in the treatment of cancer and other diseases. In particular, rapid and economical methods that utilize simple instrumentation and provide quantitative data in a high throughput format will have the most impact on basic research in systems biology and medicine. There are over 500 protein kinases in the human kinome. Among these, the mitogen activated protein (MAP) kinases are recognized to be central players in key cellular signaling events and are associated with essential processes including growth, proliferation, differentiation, migration, and apoptosis. The major challenge with MAP kinase sensor development is achieving high selectivity since these kinases rely acutely on secondary interactions distal to the phosphorylation site to impart substrate specificity. Herein we describe the development and application of selective sensors for three MAP kinase subfamilies, ERK1/2, p38α/ß, and JNK1/2/3. The new sensors are based on a modular design, which includes a sensing element that exploits a sulfonamido-oxine (Sox) fluorophore for reporting phosphorylation, a recognition and specificity element based on reported docking domain motifs and a variable linker, which can be engineered to optimize the intermodule distance and relative orientation. Following rigorous validation, the capabilities of the new sensors are exemplified through the quantitative analysis of the target MAP kinases in breast cancer progression in a cell culture model, which reveals a strong correlation between p38α/ß activity and increased tumorgenicity.

Gedunin inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis.

Pharmacological inhibition of Hsp90 is an exciting option for cancer therapy. The clinical efficacy of Hsp90 inhibitors is, however, less than expected. Binding of the co-chaperone p23 to Hsp90 and induced overexpression of anti-apoptotic proteins Hsp70 and Hsp27 are thought to contribute to this outcome. Herein, we report that the natural product gedunin may provide a new alternative to inactivate the Hsp90 machine. We show that gedunin directly binds to p23 and inactivates it, without overexpression of Hsp27 and relatively modest induction of Hsp70. Using molecular docking and mutational analysis, we mapped the gedunin-binding site on p23. Functional analysis shows that gedunin inhibits the p23 chaperoning activity, blocks its cellular interaction with Hsp90, and interferes with p23-mediated gene regulation. Cell treatment with gedunin leads to cancer cell death by apoptosis through inactivation of p23 and activation of caspase 7, which cleaves p23 at the C terminus. These results provide important insight into the molecular mechanism of action of this promising lead compound.

SDHB gene mutation in a carotid body paraganglioma: case report and review of the paraganglioma syndromes.

Carotid body tumors represent the most common of head and neck tumors. They account for <0.03% of all human tumors. The underlying physiology and pathogenesis of this tumor type are not well understood. Several different genetic abnormalities have been associated with the development of carotid body paragangliomas. We present a case report with an unusual genetic mutation in the SDHB gene and a review of the paraganglioma syndromes.

Blood Cholesterol and Triglycerides Associate with Right Ventricular Function in Pulmonary Hypertension.

Background: Blood lipids are dysregulated in pulmonary hypertension (PH). Lower high-density lipoproteins cholesterol (HDL-C) and low-density lipoproteins cholesterol (LDL-C) are associated with disease severity and death in PH. Right ventricle (RV) dysfunction and failure are the major determinants of morbidity and mortality in PH. This study aims to test the hypothesis that dyslipidemia is associated with RV dysfunction in PH. Methods: We enrolled healthy control subjects (n=12) and individuals with PH (n=30) (age: 18-65 years old). Clinical characteristics, echocardiogram, 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan, blood lipids, including total cholesterol (TC), triglycerides (TG), lipoproteins (LDL-C and HDL-C), and N-terminal pro-B type Natriuretic Peptide (NT-proBNP) were determined. Results: Individuals with PH had lower HDL-C [PH, 41±12; control, 56±16 mg/dL, p<0.01] and higher TG to HDL-C ratio [PH, 3.6±3.1; control, 2.2±2.2, p<0.01] as compared to controls. TC, TG, and LDL-C were similar between PH and controls. Lower TC and TG were associated with worse RV function measured by RV strain (R=-0.43, p=0.02 and R=-0.37, p=0.05 respectively), RV fractional area change (R=0.51, p<0.01 and R=0.48, p<0.01 respectively), RV end-systolic area (R=-0.63, p<0.001 and R=-0.48, p<0.01 respectively), RV end-diastolic area: R=-0.58, p<0.001 and R=-0.41, p=0.03 respectively), and RV glucose uptake by PET (R=-0.46, p=0.01 and R=-0.30, p=0.10 respectively). NT-proBNP was negatively correlated with TC (R=-0.61, p=0.01) and TG (R=-0.62, p<0.02) in PH. Conclusion: These findings confirm dyslipidemia is associated with worse right ventricular function in PH.

Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.

The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8+ T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression of memory differentiation of CD8+ T cells in dysbiotic mice involving epigenetic regulation of T cell factor 1 (TCF 1) expression. Pulmonary CD8+ T cells from dysbiotic human infants share these transcriptional signatures and functional phenotypes. Mechanistically, intestinal inosine was reduced in dysbiotic human infants and newborn mice, and inosine replacement reversed epigenetic dysregulation of Tcf7 and increased memory differentiation and responsiveness of pulmonary CD8+ T cells. Our data unveils new developmental layers controlling immune cell activation and identifies microbial metabolites that may be used therapeutically in the future to protect at-risk newborns.

Development of a Grp94 inhibitor.

Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/ß (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/ß client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.

The hERG channel is dependent upon the Hsp90α isoform for maturation and trafficking.

Heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of cancer. Several Hsp90 inhibitors have entered clinical trials. However, some toxicological detriments have arisen, such as cardiotoxicity resulting from hERG inhibition following the administration of Hsp90 inhibitors. We sought to investigate this toxicity as hERG has been previously reported as a client protein that depends upon Hsp90 for its maturation and functional trafficking. In this study we show that hERG depends upon a single Hsp90 isoform. hERG preferentially co-immunoprecipitated with Hsp90α, and genetic knockdown of Hsp90α, but not Hsp90ß, resulted in a trafficking-defective hERG channel. This study demonstrates the importance of delineating the isoform dependence of Hsp90 client proteins and provides rationale for the design of isoform-selective Hsp90 inhibitors that avoid detrimental effects.

Telepractice Treatment of Residual Rhotic Errors Using App-Based Biofeedback: A Pilot Study.

PURPOSE: Although mobile apps are used extensively by speech-language pathologists, evidence for app-based treatments remains limited in quantity and quality. This study investigated the efficacy of app-based visual-acoustic biofeedback relative to nonbiofeedback treatment using a single-case randomization design. Because of COVID-19, all intervention was delivered via telepractice. METHOD: Participants were four children aged 9-10 years with residual errors affecting American English /ɹ/. Using a randomization design, individual sessions were randomly assigned to feature practice with or without biofeedback, all delivered using the speech app Speech Therapist's App for /r/ Treatment. Progress was assessed using blinded listener ratings of word probes administered at baseline, posttreatment, and immediately before and after each treatment session. RESULTS: All participants showed a clinically significant response to the overall treatment package, with effect sizes ranging from moderate to very large. One participant showed a significant advantage for biofeedback over nonbiofeedback treatment, although the order of treatment delivery poses a potential confound for interpretation in this case. CONCLUSIONS: While larger scale studies are needed, these results suggest that app-based treatment for residual errors can be effective when delivered via telepractice. These results are compatible with previous findings in the motor learning literature regarding the importance of treatment dose and the timing of feedback conditions. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.18461576.

The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.

Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.

Perinatal infection, inflammation, preterm birth, and brain injury: A review with proposals for future investigations.

Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.