Primordium of an artificial Bruch’s membrane made of nanofibers for engineering of retinal pigment epithelium cell monolayers

Transplanted retinal pigment epithelium (RPE) cells hold promise for treatment of age-related macular degeneration (AMD) and Stargardt disease (SD), but it is conceivable that the degenerated host Bruch’s membrane (BM) as a natural substrate for RPE might not optimally support transplanted cell survival with correct cellular organization. We fabricated novel ultrathin three-dimensional (3-D) nanofibrous membranes from collagen type I and poly(lactic-co-glycolic acid) (PLGA) by an advanced clinical-grade needle-free electrospinning process. The nanofibrillar 3-D networks closely mimicked the fibrillar architecture of the native inner collagenous layer of human BM. Human RPE cells grown on our nanofibrous membranes bore a striking resemblance to native human RPE. They exhibited a correctly orientated monolayer with a polygonal cell shape and abundant sheet-like microvilli on their apical surfaces. RPE cells built tight junctions and expressed RPE65 protein. Flat 2-D PLGA film and cover glass as controls delivered inferior RPE layers. Our nanofibrous membranes may imitate the natural BM to such extent that they allow for the engineering of an in vivo-like human RPE monolayer that maintains the natural biofunctional characteristics. Such ultrathin membranes may provide a promising vehicle for a functional RPE cell monolayer implantation in the subretinal space in patients with AMD or SD.     

Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age × group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.     

White matter tract signatures of the progressive aphasias

The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.     

Trimethoprim-sulfamethoxazole as de-escalation in ventilator-associated pneumonia: a cohort study subanalysis

European Journal of Clinical Microbiology & Infectious Diseases - This is a subanalysis of a previous study which compared the effectiveness of trimetoprim-sulfametoxazole (TMP-SMX) with all...     

Emergence of racial/ethnic and socioeconomic differences in objectively measured sleep–wake patterns in early infancy: results of the Rise & SHINE study

Study ObjectivesTo characterize objectively assessed sleep–wake patterns in infants at approximately 1 month and 6 months and examine the differences among infants with different racial/ethnic backgrounds and household socioeconomic status (SES).MethodsFull-term healthy singletons wore an ankle-placed actigraph at approximately 1 month and 6 months and parents completed sleep diaries. Associations of racial/ethnic and socioeconomic indices with sleep outcomes were examined using multivariable analyses. Covariates included sex, birth weight for gestational age z-score, age at assessment, maternal education, household income, bed-sharing, and breastfeeding.ResultsThe sample included 306 infants, of whom 51% were female, 42.5% non-Hispanic white, 32.7% Hispanic, 17.3% Asian, and 7.5% black. Between 1 month and 6 months, night sleep duration increased by 65.7 minutes (95% CI: 55.4, 76.0), night awakenings decreased by 2.2 episodes (2.0, 2.4), and daytime sleep duration decreased by 73.3 minutes (66.4, 80.2). Compared to change in night sleep duration over this development period for white infants (82.3 minutes [66.5, 98.0]), night sleep increased less for Hispanic (48.9 minutes [30.8, 66.9]) and black infants (31.6 minutes [−5.9, 69.1]). Night sleep duration also increased less for infants with lower maternal education and household income. Asian infants had more frequent night awakenings. Adjustment for maternal education and household income attenuated all observed day and night sleep duration differences other than in Asians, where persistently reduced nighttime sleep at 6 months was observed.ConclusionsRacial/ethnic differences in sleep emerge in early infancy. Night and 24-hour sleep durations increase less in Hispanic and black infants compared to white infants, with differences largely explained by SES.     

Effect of age and care organization on sources of variation in kidney transplant waiting list registration

Despite national guidelines, medical practices and kidney transplant waiting list registration policies may differ from one dialysis/transplant unit to another. Benefit risk assessment variations, especially for elderly patients, have also been described. The aim of this study was to identify sources of variation in early kidney transplant waiting list registration in France. Among 16 842 incident patients during the period 2016–2017, 4386 were registered on the kidney transplant waiting list at the start of, or during the first year after starting, dialysis (26%). We developed various log-linear mixed effect regression models on three levels: patients, dialysis networks, and transplant centers. Variability was expressed as variance from the random intercepts (± standard error). Although patient characteristics have an important impact on the likelihood of registration, the overall magnitude of variability in registration was low and shared by dialysis networks and transplant centers. Between-transplant center variability (0.23 ± 0.08) was 1.8 higher than between-dialysis network variability (0.13 ± 0.004). Older age was associated with a lower probability of registration and greater variability between networks (0.04, 0.20, & 0.93 in the 18–64, 65–74, and 75–84 age groups). Targeted interventions should focus on elderly patients and/or certain regions with greater variability in waiting list access.     

Transarterial Embolization of Liver Cancer in a Transgenic Pig Model

PurposeTo develop and characterize a porcine model of liver cancer that could be used to test new locoregional therapies.Materials and MethodsLiver tumors were induced in 18 Oncopigs (transgenic pigs with Cre-inducible TP53^R167H and KRAS^G12D mutations) by using an adenoviral vector encoding the Cre-recombinase gene. The resulting 60 tumors were characterized on multiphase contrast-enhanced CT, angiography, perfusion, micro-CT, and necropsy. Transarterial embolization was performed using 40–120 μm (4 pigs) or 100–300 μm (4 pigs) Embosphere microspheres. Response to embolization was evaluated on imaging. Complications were determined based on daily clinical evaluation, laboratory results, imaging, and necropsy.ResultsLiver tumors developed at 60/70 (86%) inoculated sites. Mean tumor size was 2.1 cm (range, 0.3–4 cm) at 1 week. Microscopically, all animals developed poorly differentiated to undifferentiated carcinomas accompanied by a major inflammatory component, which resembled undifferentiated carcinomas of the human pancreatobiliary tract. Cytokeratin and vimentin expression confirmed epithelioid and mesenchymal differentiation, respectively. Lymph node, lung, and peritoneal metastases were seen in some cases. On multiphase CT, all tumors had a hypovascular center, and 17/60 (28%) had a hypervascular rim. After transarterial embolization, noncontrast CT showed retained contrast medium in the tumors. Follow-up contrast-enhanced scan showed reduced size of tumors after embolization using either 40–120 μm or 100–300 μm Embosphere microspheres, while untreated tumors showed continued growth.ConclusionsLiver tumors can be induced in a transgenic pig and can be successfully treated using bland embolization.     

Long-term durability of resection and end-to-end anastomosis for ascending aortic aneurysms

BACKGROUND: Ascending aortic aneurysms with normal sized sinotubular junction are generally treated by resection of the dilated aorta and replacement with tubular graft. Aortic resection and direct end-to-end anastomosis has been applied to repair aortic coarctation, interrupted aortic arch, and traumatic aortic rupture. No data exist regarding the long-term durability of this approach in ascending aortic aneurysms. The aim of this case-control study was to illustrate the durability of this operation by presenting our entire experience and the long-term follow up of a cohort of 34 patients who underwent ascending aortic aneurysm resection and primary end-to-end anastomosis between January 1990 and March 2003 in Caen University Hospital (Caen, France). METHODS: The mean age of patients was 61.5 +/- 12.5 years, and there were 18 male and 16 female patients. The operative technique included extensive mobilization of the arch, supra-aortic trunks, and inferior vena cava to enable approximation of the aortic ends, thus avoiding tension on the suture lines. Associated aortic valve replacement was performed in 27 patients; mechanical valves were used in 19. A bicuspid aortic valve was present in 9 patients; in 3 cases the valve was regurgitant. Aortic valve regurgitation was present in a total of 7 patients. Patients were followed up at regular intervals; total follow-up was 2187 patient-months, with a median follow-up time of 72 months per patient (25th-75th percentile 10.5-102.7 months). RESULTS: One patient died 10 days after the operation of aortic rupture related to suture infection caused by mediastinitis. Late deaths occurred in 3 patients, who died 12, 62, and 71 months after the operation, but none of these deaths were attributable to late aortic repair failure. No patient in this series required reoperation, including patients with aortic regurgitation or bicuspid aortic valve. Follow-up was 91.1% complete at the closing date of April 1, 2003. The Kaplan-Meier estimate of survival for all patients was 120.4 months (95% confidence interval 105.1-135.7 months). The median of preoperative maximal aortic diameter was 55.1 mm (range 50.3 to 67.5 mm, 25th-75th percentile 50.5-56.8 mm). The median immediate postoperative diameter was 40.3 mm (range 33.4-46.4 mm, 25th-75th percentile 37.2-42.0 mm, P <.0001 relative to preoperative diameter), and the median length of the resected aortic segment was 52 mm (range 48-76 mm, 25th-75th percentile 50.1-66.4 mm). The median decrease of aortic diameter was 24.9 mm (range 8.9-32.6 mm, 25th-75th percentile 18.2-26.6 mm).The median aortic diameter at the end of the follow-up was 41.0 mm (range 34.6-46.1 mm, 25th-75th percentile 37.0-43.2 mm, P =.6 relative to immediate postoperative diameter). CONCLUSIONS: Ascending aorta aneurysm resection and primary end-to-end anastomosis provides effective long-term outcome and in selected cases represents a good alternative to aortic interposition grafting. Aortic regurgitation and bicuspid aortic valve do not represent a contraindication for this treatment.