Citations

ABSTRACT Intestinal barrier function and microbiota are integrally related and play critical roles in maintenance of host physiology. Sex is a key biologic variable for several disorders. Our aim was to determine sex‐based differences in response to perturbation and subsequent recovery of intestinal barrier function and microbiota in healthy humans. Twenty‐three volunteers underwent duodenal biopsies, mucosal impedance, and in vivo permeability measurement. Permeability testing was repeated after administration of indomethacin, then 4 to 6 wk after its discontinuation. Duodenal and fecal microbiota composition was determined using 16S rRNA amplicon sequencing. Healthy women had lower intestinal permeability and higher duodenal and fecal microbial diversity than healthy men. Intestinal permeability increases after indomethacin administration in both sexes. However, only women demonstrated decreased fecal microbial diversity, including an increase in Prevotella abundance, after indomethacin administration. Duodenal microbiota composition did not show sex‐specific changes. The increase in permeability and microbiota changes normalized after discontinuation of indomethacin. In summary, women have lower intestinal permeability and higher microbial diversity. Intestinal permeability is sensitive to perturbation but recovers to baseline. Gut microbiota in women is sensitive to perturbation but appears to be more stable in men. Sex‐based differences in intestinal barrier function and microbiome should be considered in future studies.—Edogawa, S., Peters, S. A., Jenkins, G. D., Gurunathan, S. V., Sundt, W. J., Johnson, S., Lennon, R. J., Dyer, R. B., Camilleri, M., Kashyap, P. C., Farrugia, G., Chen, J., Singh, R. J., Grover, M. Sex differences in NSAID‐induced perturbation of human intestinal barrier function and microbiota. FASEB J. 32, 6615–6625 (2018). www.fasebj.org

Background: Two-stage subpectoral implant-based breast reconstruction is the most common method for breast reconstruction. Recent advances in surgical techniques and technology have made prepectoral implant-based breast reconstruction feasible. There are limited data on outcomes after prepectoral implant-based breast reconstruction and postmastectomy radiation therapy. Methods: A retrospective review of consecutive patients undergoing immediate two-stage prepectoral implant-based breast reconstruction with postmastectomy radiation therapy was performed. Outcomes of irradiated breasts were compared with nonirradiated breasts in bilateral cases. Results: Ninety-three cases of prepectoral implant-based breast reconstruction in 54 women who underwent immediate two-stage reconstruction (39 bilateral and 15 unilateral) and unilateral postmastectomy radiation therapy were identified. Mean follow-up was 19 months from mastectomy and tissue expander reconstruction and 9 months from implant placement. Crude complication rates in irradiated versus nonirradiated sides were as follows: surgical-site infection, 18.5 percent versus 7.7 percent; seroma, 5.6 percent versus 5.1 percent; mastectomy skin flap necrosis, 1.9 percent versus 2.6 percent; wound dehiscence, 1.9 percent versus 7.7 percent; capsular contracture, 1.9 percent versus 0 percent; hematoma, 1.9 percent versus 2.6 percent; and extrusion, 1.9 percent versus 0 percent. On univariate analysis, there were no risk factors associated with any complication, including radiation therapy, surgical-site infection, unplanned readmissions, and unplanned return to the operating room. To date, reconstruction has been completed in 96 percent of patients, with successful implant-based breast reconstruction in 81 breasts (45 irradiated breasts and 36 nonirradiated breasts). Conclusions: Early data of prepectoral implant-based breast reconstruction in patients with postmastectomy radiation therapy show promising results. Postmastectomy radiation therapy should not be an absolute contraindication to prepectoral implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Background: The dynamin 1-like gene ( DNM1L) encodes a GTPase that mediates mitochondrial and peroxisomal fission and fusion. We report a new clinical presentation associated with a DNM1L pathogenic variant and review the literature. Results: A 13-year-old boy with mild developmental delays and paroxysmal dystonia presented acutely with multifocal myoclonic super-refractory status epilepticus. Despite sustained and aggressive treatment, seizures persisted and care was ultimately withdrawn in the context of extensive global cortical atrophy. Rapid trio-whole exome sequencing revealed a de novo heterozygous c.1207C>T (p.R403C) pathogenic variant in DNM1L. Immunofluorescence staining of fibroblast mitochondria revealed abnormally elongated and tubular morphology. Conclusions: This case highlights the diagnostic importance of rapid whole exome sequencing within a critical care setting and reveals the expanding phenotypic spectrum associated with DNM1L variants. This now includes progressive paroxysmal dystonia and adolescent-onset super-refractory myoclonic status epilepticus contributing to strikingly rapid and progressive cortical atrophy and death.

Purpose: Optimal strategies to detect early interstitial lung disease (ILD) are unknown. ILD is frequently subpleural in distribution and affects lung elasticity. Lung ultrasound surface wave elastography (LUSWE) is a noninvasive method of quantifying superficial lung tissue elastic properties. In LUWSE a handheld device applied at the intercostal space vibrates the chest at a set frequency, and the lung surface wave velocity is measured by an ultrasound probe 5 mm away in the same intercostal space. We explored LUWSE’s ability to detect ILD and correlated LUSWE velocity with physiological, quantitative, and visual radiologic features of subjects with known ILD and of healthy controls. Materials and Methods: Seventy-seven subjects with ILD, mostly caused by connective tissue disease, and 19 healthy controls were recruited. LUSWE was performed on all subjects in 3 intercostal lung regions bilaterally. Comparison of LUSWE velocities pulmonary function testing, visual assessment, and quantitative analysis of recent computed tomographic imaging with Computer-Aided Lung Informatics for Pathology Evaluation and Rating (CALIPER) software. Results: Sonographic velocities were higher in all lung regions for cases, with the greatest difference in the lateral lower lung. Median velocity in m/s was 5.84 versus 4.11 and 5.96 versus 4.27 (P<0.00001) for cases versus controls, left and right lateral lower lung zones, respectively. LUSWE velocity correlated negatively with vital capacity and positively with radiologist and CALIPER-detected interstitial abnormalities. Conclusions: LUSWE is a safe and noninvasive technique that shows high sensitivity to detect ILD and correlated with clinical, physiological, radiologic, and quantitative assessments of ILD. Prospective study in detecting ILD is indicated.

Background: There is a significant need for rapid and cost-effective biomarkers of Alzheimer’s disease (AD) for advancement of clinical practice and therapeutic trials. Objective: The aim of the current study was to cross-validate our previously published serum-based algorithm on an independent assay platform as well as validate across tissues and species. Preliminary analyses were conducted to examine the utility in distinguishing AD from non-AD neurological disease (Parkinson’s disease, PD). Methods: Serum proteins from our previously published algorithm were quantified from 150 AD cases and 150 controls on the Meso Scale Discovery (MSD) platform. Serum samples were analyzed from 49 PD cases and compared to a random sample of 51 AD cases and 62 controls. Support vector machines (SVM) were used to discriminate PD versus AD versus controls. Human and AD mouse model microvessel images were quantified with HAMAMATSU imaging software. Mouse serum biomarkers were assayed via MSD. Results: Analysis of 21 serum proteins from 150 AD cases and 150 controls yielded an algorithm with sensitivity and specificity of 0.90 for correctly classifying AD. This multi-marker approach was then validated across species and tissue. Assay of the top proteins in human and AD mouse model brain microvessels correctly classified 90–100% of the samples. SVM analyses were highly accurate at distinguishing PD versus AD versus controls. Conclusions: This serum-based biomarker panel should be tested in a community-based setting to determine its utility as a first-line screen for AD and non-AD neurological diseases for primary care providers.

AbstractBackground: Since initial report in 1972, misconnections continue to be an issue, especially in hospitalized patients with multiple access devices. A new small‐bore connector standard (ENFit) has been proposed in order to minimize misconnections. Methods: Commercially available finalized ENFit tubes of a variety of sizes (14 French [Fr] size, 18Fr, 20Fr, 24Fr, and low‐profile) were obtained for current testing. Variety of commercially available formulas including blenderized tube feeding (BTF) products (Jevity 1 Cal, Abbott Nutrition, Abbott Park, IL; Nourish, Functional Formularies, Centerville, OH; Real Food Blends, Chesterton, IN) were tested. Results: Data from individual measurements were aggregated for ENFit and legacy tubes and revealed higher syringe compression force in legacy tubes compared with ENFit tubes for 20Fr size with Jevity formula. Our institution's BTF formula revealed that legacy tubes had lower syringe compression force than ENFit tubes for 14Fr tube size. Remaining measurements revealed no significant difference. Model 1 of regression analysis revealed that only formula and tube size were significant with R2 of 0.63. Model 2 evaluating the impact of tube size, blender, time of blending, and legacy vs ENFit revealed that tube size, blender used, and blending time were significant with legacy vs ENFit being nonsignificant (R2 of 0.72). Conclusions: Overall, only a small number of tube sizes (14Fr and 20Fr) with selected formulas revealed a significant difference between ENFit and Legacy tubes, with remaining studies finding no significant difference. Regression analysis revealed that variables such as formula, size of tube, blender used, and time of blending may have more impact on compression force.

Background: Palliative care has been increasingly recognized as an important part of cancer care but remains underutilized in patients with solid cancers. There is a current gap in knowledge regarding why palliative care is underutilized nationwide. Objective: To identify the factors associated with palliative care use among deceased patients with solid cancer tumors. Methods: Using the 2016 National Cancer Data Base, we identified deceased patients (2004-2013) with breast, colon, lung, melanoma, and prostate cancer. Data were described as percentages. Associations between palliative care use and patient, facility, and geographic characteristics were evaluated through multivariate logistic regression. Results: A total of 1 840 111 patients were analyzed; 9.6% received palliative care. Palliative care use was higher in the following patient groups: survival >24 months (17% vs 2%), male (54% vs 46%), higher Charlson-Deyo comorbidity score (16% vs 8%), treatment at designated cancer programs (74% vs 71%), lung cancer (76% vs 28%), higher grade cancer (53% vs 24%), and stage IV cancer (59% vs 13%). Patients who lived in communities with a greater percentage of high school degrees had higher odds of receiving palliative care; Central and Pacific regions of the United States had lower odds of palliative care use than the East Coast. Patients with colon, melanoma, or prostate cancer had lower odds of palliative care than patients with breast cancer, whereas those with lung cancer had higher odds. Conclusions: Palliative care use in solid cancer tumors is variable, with a preference for patients with lung cancer, younger age, known insurance status, and higher educational level.

Abstract Background/aims The rate of recurrent small-bowel bleeding (SBB) remains high despite the advent of balloon assisted enteroscopy (BAE). The study aims were to determine: (1) the diagnostic and therapeutic yields, and adverse event rate of repeat BAE in SBB, and (2) the predictors of a positive repeat BAE. Methods A retrospective review of a BAE database was conducted. Patients who had > 1 BAE for SBB were included. Primary outcomes were diagnostic yield, therapeutic yield, and adverse events of repeat BAE. Secondary outcomes were predictors of a positive repeat BAE. Results A total of 175 patients (55 % men; mean age 64.1 ± 16.3 years) were included. The diagnostic and therapeutic yields of repeat BAE were 55 % and 42 %, respectively. Repeat BAE adverse events occurred in 5 % with self-limited abdominal pain being most common. Patients with a positive repeat BAE were significantly older than the negative group (68.6 ± 13.9 vs. 60.9 ± 17.1; P = 0.001) and were more likely to have cardiac comorbidities (OR 2.4, 95 %CI: 1.3 – 4.6; P = 0.01), chronic kidney disease (OR 2.3, 95 %CI: 1.1 – 4.9; P = 0.04), chronic obstructive pulmonary disease (OR 3.3, 95 %CI: 1.3 – 8.1; P = 0.01), positive initial BAE (OR 3.6, 95 %CI: 1.9 – 6.8; P < 0.001), and antegrade procedure (OR 3.3, 95 %CI: 1.7 – 6.1; P < 0.001). On multivariate analysis, a positive initial BAE and antegrade route were the only significant predictive factors. Conclusions Performing a repeat BAE for SBB appears safe and provided modest yields. A positive initial BAE and antegrade route were predictive of a positive repeat BAE.

We have identified 25 lesions involving alveolar lung parenchyma characterized by nodular proliferation of bland bilayered bronchiolar-type epithelium containing a continuous layer of basal cells. These lesions shared some histologic features with the recently described entity of ciliated muconodular papillary tumor (CMPT); however, the majority did not fit all diagnostic criteria in that they exhibited only focal or absent papillary architecture, and they had variable number of ciliated and mucinous cells, with some lesions entirely lacking 1 or both of these components. The morphologic and immunohistochemical features ranged from those resembling proximal bronchioles (proximal-type: moderate to abundant mucinous and ciliated cells; negative or weak TTF1 in luminal cells; n=8) to those resembling respiratory bronchioles (distal-type: scant or absent mucinous and ciliated cells; positive TTF1 in luminal cells; n=17). The hallmark of all lesions was a continuous layer of basal cells (p40 and CK5/6-positive). We provisionally designated these lesions as bronchiolar adenomas (BAs) and analyzed their clinicopathologic and molecular features. All BAs were discrete, sharply circumscribed lesions with a median size of 0.5 cm (range, 0.2 to 2.0 cm). Most lesions were either entirely flat (n=14) or contained focal papillary architecture (n=7); only 4 lesions, all proximal-type, were predominantly papillary, fitting the classic description of CMPT. Notably, of 9 lesions submitted for frozen section evaluation, 7 were diagnosed as adenocarcinoma. No postsurgical recurrences were observed for any lesions (median follow-up, 11 mo). Twenty-one BAs underwent next-generation sequencing and/or immunohistochemistry for BRAF V600E, revealing mutation profiles similar to those previously described for CMPTs, including BRAF V600E mutations (n=8, 38%), unusual EGFR exon 19 deletions (n=2, 10%), EGFR exon 20 insertions (n=2, 10%), KRAS mutations (n=5, 24%), and HRAS mutations (n=1, 5%). The mutation profiles were similar in proximal-type and distal-type lesions. In conclusion, we describe a family of putatively benign clonal proliferations with a spectrum of morphology recapitulating various levels of the bronchiolar tree, of which only a minor subset fits the classic description of CMPT. Comparable mutation profiles and partially overlapping morphologic features across the spectrum of these lesions support their nosological relationship. We propose designating this entire family of lesions as BAs, and that lesions currently designated CMPTs represent a subgroup of this family.