Escalating Oral Treprostinil Dose With Intravenous Treprostinil Bridging Therapy.

Oral treprostinil, approved for the treatment of pulmonary arterial hypertension, remains an attractive option in combination with other medications to delay disease progression and improve exercise capacity. However, patients are often challenged with the ability to overcome adverse effects as outpatients and reach effective doses in a timely manner. We describe a case of a 47-year-old female on oral treprostinil who presented to the clinic with worsening symptoms of disease, necessitating higher dosing. This patient was previously uptitrated outpatient with oral treprostinil, which had allowed her to remain stable for years. Once uptitrated with additional intravenous therapy, the oral treprostinil dose was gradually further increased to the new goal dosage, resulting in improvements in symptoms and right ventricular function. This case highlights the versatility of dose optimization of oral treprostinil with rapid bridging through intravenous therapy.

Lung Underdevelopment: Case Reports and a Literature Review.

Lung underdevelopment is a rare congenital anomaly with variable clinical significance and presenting symptoms. It usually manifests during childhood. We present two cases of developmental lung anomaly subtypes and discuss clinical presentation and outcomes in such patient populations. LEARNING POINTS: Pulmonary underdevelopment is a challenging diagnosis and should be considered in patients with unilateral opacification on chest radiograph.Childhood developmental history is critical for diagnosis as delayed, or misdiagnoses are common. Definitive diagnosis can be made by computed tomography scan.Management is watchful waiting with close monitoring, with long term prognosis remaining unclear.

Amyloid-ß and caspase-1 are indicators of sepsis and organ injury.

Background: Sepsis is a life-threatening condition that results from a dysregulated host response to infection, leading to organ dysfunction. Despite the prevalence and associated socioeconomic costs, treatment of sepsis remains limited to antibiotics and supportive care, and a majority of intensive care unit (ICU) survivors develop long-term cognitive complications post-discharge. The present study identifies a novel regulatory relationship between amyloid-ß (Aß) and the inflammasome-caspase-1 axis as key innate immune mediators that define sepsis outcomes. Methods: Medical ICU patients and healthy individuals were consented for blood and clinical data collection. Plasma cytokine, caspase-1 and Aß levels were measured. Data were compared against indices of multiorgan injury and other clinical parameters. Additionally, recombinant proteins were tested in vitro to examine the effect of caspase-1 on a functional hallmark of Aß, namely aggregation. Results: Plasma caspase-1 levels displayed the best predictive value in discriminating ICU patients with sepsis from non-infected ICU patients (area under the receiver operating characteristic curve=0.7080). Plasma caspase-1 and the Aß isoform Aßx-40 showed a significant positive correlation and Aßx-40 associated with organ injury. Additionally, Aß plasma levels continued to rise from time of ICU admission to 7 days post-admission. In silico, Aß harbours a predicted caspase-1 cleavage site, and in vitro studies demonstrated that caspase-1 cleaved Aß to inhibit its auto-aggregation, suggesting a novel regulatory relationship. Conclusions: Aßx-40 and caspase-1 are potentially useful early indicators of sepsis and its attendant organ injury. Additionally, Aßx-40 has emerged as a potential culprit in the ensuing development of post-ICU syndrome.

Impact of Duodenal Pathology on Oral Drug Bioavailability and Disease Outcomes in Pediatric Crohn's Disease.

BACKGROUND: Crohn's disease with upper gastrointestinal tract involvement occurs more often in children than adults and has the potential to interfere with oral drug absorption. We aimed to compare disease outcomes in children receiving oral azathioprine for the treatment of Crohn's disease with (DP) and without (NDP) duodenal pathology at diagnosis. METHODS: Duodenal villous length, body mass index (BMI), and laboratory studies were compared in DP vs. NDP during the first year post-diagnosis, using parametric/nonparametric tests and regression analysis (SAS v9.4); the data are reported as the median (interquartile range) or the mean ± standard deviation. Thiopurine metabolite concentration (pmol/8 × 108 erythrocytes) 230-400 was considered therapeutic for 6-thioguanine nucleotides (6-TGN), and >5700 was considered hepatotoxic for 6-methylmercaptopurine (6-MMPN). RESULTS: Twenty-six of the fifty-eight children enrolled (29 DP, 29 NDP) started azathioprine for standard medical care, including nine DP and ten NDP who had normal thiopurine methyltransferase activity. Duodenal villous length was significantly shorter in DP vs. NDP (342 ± 153 vs. 460 ± 85 µm; p < 0.001) at diagnosis; age, sex, hemoglobin, and BMI were comparable between groups. A trend toward lower 6-TGN was observed in the DP vs. NDP subset receiving azathioprine (164 (117, 271) vs. 272 (187, 331); p = 0.15). Compared to NDP, DP received significantly higher azathioprine doses (2.5 (2.3, 2.6) vs. 2.2 (2.0, 2.2) mg/kg/day; p = 0.01) and had an increased relative risk of sub-therapeutic 6-TGN. At 9 months post-diagnosis, children with DP had significantly lower hemoglobin (12.5 (11.7, 12.6) vs. 13.1 (12.7, 13.3) g/dL; p = 0.01) and BMI z-scores (-0.29 (-0.93, -0.11) vs. 0.88 (0.53, 0.99); p = 0.02) than children with NDP. CONCLUSION: For children with Crohn's disease, duodenal pathology, marked by villous blunting, increased the risk of sub-therapeutic 6-TGN levels, despite higher azathioprine dosing during the first year post-diagnosis. Lower hemoglobin and BMI z-scores at 9 months post-diagnosis suggest the impaired absorption/bioavailability of nutrients, as well as oral drugs, in children with duodenal disease.

Characterization of the Mucosally-Adherent Duodenal Microbiome in Children with and without Crohn's Disease.

Manipulation of the microbiome is a rational treatment strategy for inflammatory bowel disease (IBD). Compared to the colon and terminal ileum (TI), understanding of the microbial composition in the duodenum is sparse. This gap in knowledge is especially significant for children with Crohn's disease (CD) because the prevalence of duodenal CD is higher in children than in adults. Our aim was to characterize the bacterial composition of the mucosally-adherent duodenal microbiome in children with and without CD as a first step toward development of targeted IBD treatment strategies at this disease location. Fresh-frozen mucosal biopsies were obtained from the duodenum and TI of children with treatment-naïve CD and age- and sex-matched controls. Extracted DNA was analyzed for sequence variation in the 16S ribosomal RNA bacterial gene region V4 (Novogene; Beijing, China). Bacterial relative abundance, alpha and beta composition, and diversity, were compared across duodenal and TI samples from the controls and CD groups with and without chronic active inflammation (118 samples from 73 children total; approx. 50% CD), using UniFrac dissimilarity coefficients (α < 0.05), Linear Discriminant Analysis Effect Size (LEfSe) analysis (LDA score ≥ 2), and Unweighted Pair Group Method with Arithmetic Mean (UPGMA) analysis. The relationships between bacterial abundance, sex, age, concomitant medication use, and villous length were assessed. The microbial composition in the duodenum was significantly different from the TI in the control population(R-value = 0.558, p = 0.001) and in children with active CD (R-value = 0.301, p = 0.001). Significant differences in bacterial abundance were noted between the control and CD duodena (LDA > 4). The duodenum of children without CD was characterized by increased abundance in Pseudomonodales, whereas the actively inflamed duodenum in CD was characterized by increased abundance of Bacteroidales, specifically the family Prevotellaceae. This trend is opposite of previously published observations of microbial composition in the TI, where active inflammation was associated with a relative decrease in the abundance of Bacteroidetes and an increase in Proteobacteria, including Pseudomonadales. No statistically significant correlations were noted between abundance and age, sex, concomitant medication use or villous length, except for Bacteroidetes, which significantly decreased in abundance in the TI with age (p = 0.048). The pediatric duodenal microbiome is distinct from the TI and characterized by an increased abundance of Pseudomonodales and Spirochetes in healthy children, and an increased abundance of Bacteroidales in active CD patients.

Screening for diabetes in an African American community: identifying characteristics associated with abnormal blood glucose readings.

OBJECTIVE: To identify characteristics associated with abnormal blood glucose readings among African Americans and to determine the potential value of a more targeted approach to community-based screenings for type 2 diabetes. METHODS: Data were collected from 7113 participants with no previous diagnosis of diabetes at mobile screening events in Detroit, Michigan. Data collected included gender, race, age, self-reported height and weight, total diabetes risk score, blood pressure, and random capillary blood glucose. RESULTS: Nearly 9% of participants had abnormal random plasma glucose readings (RPG>or=160 mg/dL). Results indicated that higher age, elevated blood pressure, and body mass index (BMI) were significantly associated with abnormal glucose readings. CONCLUSION: These findings suggest that community-based screenings for diabetes that are targeted to adults aged more than 50 years who have high blood pressure or a BMI of at least 25 may enhance detection of abnormal glucose levels among African Americans.

Sustaining effective research/operational collaborations: Lessons learned from a National Partnered Evaluation Initiative.

INTRODUCTION: Effective research-operational partnerships require that researchers ask questions targeting top clinical operational priorities. However, disconnects exist between healthcare researchers and operational leadership that result in significant delays between discovery and implementation of breakthroughs in healthcare. OBJECTIVE: Using the Veterans Health Administration Quality Enhancement Research Initiative (QUERI) Partnered Evaluation Initiative (PEI) as a case study, we identified relationship characteristics of collaborative research projects designed to address the research/operations gap. METHODS: An interview guide was developed focusing on areas identified as essential for effective research/operational partnerships from previous research. Investigators (N = 14) and their operational leadership partners (N = 14) representing 16 PEIs were interviewed by phone related to the characteristics of their partnerships. All investigators had had advanced degrees in fields related to healthcare delivery and administration and were affiliated with VHA research institutes. All operational partners served in national leadership roles within VHA operational offices. Detailed interview notes collected from interviews were coded and themes identified using thematic analysis. RESULTS: Eight relationship themes were identified: leadership support, shared understanding, investment, trust, agreement on products, mutual benefit, adaptability, and collaboration. Most operational and investigator partners discussed the importance of leadership support, shared understanding, investment, trust and product agreement, suggesting that these may be more essential than other areas in supporting effective operations/research collaborations. One theme (mutual benefit) was mentioned by most investigators but only some operations partners, pointing to potential differences related to this area between the two groups. Facilitators of effective collaboration included obtaining formal leadership support, developing a shared understanding of partner priorities and needs, ongoing discussions about resource needs, expanding collaborations beyond the initial project, having a clearly defined plan, planning for flexibility, plans for regular communication, and active participation in project meetings. CONCLUSIONS: Partnership characteristics that facilitate effective collaboration include leadership support, shared understanding of planned work, investment, trust, and product agreement. Future research should assess the overall impact of partnered approaches to healthcare improvement within other large healthcare systems.

Are body surface area based estimates of liver volume applicable to children with overweight or obesity? An in vivo validation study.

The liver is the primary organ responsible for clearing most drugs from the body and thus determines systemic drug concentrations over time. Drug clearance by the liver appears to be directly related to organ size. In children, organ size changes as children age and grow. Liver volume has been correlated with body surface area (BSA) in healthy children and adults and has been estimated by functions of BSA. However, these relationships were derived from "typical" populations and it is unknown whether they extend to estimations of liver volumes for population "outliers," such as children with overweight or obesity, who today represent one-third of the pediatric population. Using computerized tomography or magnetic resonance imaging, this study measured liver volumes in 99 children (2-21 years) with normal weight, overweight, or obesity and compared organ measurements with estimates calculated using an established liver volume equation. A previously developed equation relating BSA to liver volume adequately estimates liver volumes in children, regardless of weight status.

Handheld Indirect Calorimetry as a Clinical Tool for Measuring Resting Energy Expenditure in Children with and without Obesity.

Background: Resting energy expenditure (REE) is a valuable measure in clinical management of obesity and other chronic illnesses. Gold standard methods for measuring REE (e.g., Douglas bags and metabolic cart) are too expensive and cumbersome for an outpatient clinical setting. The purpose of this study was to determine the accuracy of a handheld indirect calorimeter (HHIC) and prediction equations (PEs) for measurement of REE in youth with and without obesity. Methods: Fifty-three children and adolescents (12.8 ± 4.3 years, 50.9% female) had REE measured first with a MedGem™ HHIC for 10 minutes, followed by a reference indirect calorimeter system (ParvoMedics TrueOne 2400™) with hood canopy and dilution pump for 30 minutes. REE was also estimated using nine PEs as follows: Henry-1, Henry-2, Schofield, World Health Organization, Molnar, Muller, Herrmann, Schmelzle, and Harris-Benedict. Concordance correlation coefficients and Bland-Altman analyses were used for comparisons among PEs, MedGem HHIC, and metabolic cart. Results: The observed correlation between the HHIC and the reference system was rc = 0.89 with a mean bias of 2.27 ± 3.41 kcal/(kg·d) (9.1% ± 14.7%). Regarding PE, Molnar had the highest agreement with the reference system [rc = 0.93, bias of 2.17 ± 2.04 kcal/(kg·d); 9.8% ± 8.1%], followed by Harris-Benedict (rc = 0.89; 13.8% ± 8.9%), Henry-2 (rc = 0.89; 15% ± 7.6%), and Henry-1 (rc = 0.86; 16.7% ± 7.3%). All PEs were less accurate for children with overweight/obesity. Conclusions: Compared to PE, the HHIC provided more accurate REE estimates for children across the age and BMI spectrum, although positive bias was present throughout. Difference in positive bias between the HHIC and the Molnar equation may be clinically significant for youth with overweight/obesity.

Recruitment of African Americans with type 2 diabetes to a randomized controlled trial using three sources.

OBJECTIVES: To assess the usefulness of three sources (faith-based organizations (FBOs), health system, and community) for recruitment of African Americans with type 2 diabetes to a randomized controlled trial (RCT). DESIGN: African Americans with type 2 diabetes were recruited to a diabetes self-management program at four FBO sites. An observational study of a multifaceted recruitment strategy to enroll subjects in the RCT that evaluated the effectiveness of a diabetes self-management program and the effect of recruitment source on retention after enrollment. Self-administered demographic surveys and weekly class attendance records were collected. RESULTS: Of 184 interested individuals, 109 (59.2%) were enrolled. Of those enrolled, 60.6% recruited through the health system, 13.8% FBOs, and 19.2% the community. The highest yield was achieved through the health system. However, for both the intervention (I) and control (C) groups, respectively, participants recruited from FBOs (85.7% I; 62.5% C) were more likely to attend four or more sessions than those from the health system (75.0% I; 43.3% C) and community (55.6% I; 25.0% C). Despite similar class size, participants in the intervention group (74.5%; n = 41) were more likely to attend four or more of the seven classes than those in the delayed intervention (control group) (40.7%; n = 22). CONCLUSIONS: The findings suggest that African American adults with diabetes can be successfully recruited and retained in a racially targeted RCT conducted in FBOs. Key elements to consider are the use of a multifaceted approach for participant recruitment, particularly the benefit of health system physician involvement in recruitment since the highest yield was achieved through health system providers, and importance of site location for retention.