Lymphatic Leakage in Pediatric Heart Transplantation: Early Recognition and Timely Management with Interventional Radiologic and Endoscopic Therapy.

Protein-losing enteropathy (PLE) is a severe complication of the Fontan procedure that leads to systemic complications owing to enteric protein loss. Hepatoduodenal lymphatic leakage resulting from increased lymphatic pressure is one such complication. We present the case of a pediatric heart transplant patient who experienced refractory PLE symptoms requiring serial albumin infusions and exhibited lymphatic leakage into the duodenum. Using diagnostic lymphangiography and endoscopy, we identified the affected area and treated it successfully with endoscopic sclerotherapy using ethanolamine injection. This treatment allowed for the cessation of lymphatic fluid and may serve as a potential intervention for PLE-associated hepatoduodenal lymphatic leakage. The present case highlights the importance of early recognition and timely intervention with radiology and endoscopic therapy to manage PLE and its associated complications.

The Use of Viatorr Stent at the Thoracic Outlet to Maintain Hemodialysis Access Function.

PURPOSE: Venous steno-occlusive disease at the thoracic outlet affects up to 30% of the hemodialysis population [1] causing arm swelling and hemodialysis access dysfunction. Balloon angioplasty in this region can be of limited utility given the rigid compressive effect of surrounding musculoskeletal (MSK) structures. Outcomes of using the Viatorr endoprosthesis (Gore Viatorr TIPS Endoprosthesis, Gore, Flagstaff AR, USA, Viatorr ®) within this region to salvage the HD access in patients who presented with dialysis access dysfunction is presented. METHODS: A retrospective chart review was performed of our tertiary and quaternary care hospital system. Hemodialysis patients were included in the study if they were using an upper extremity arteriovenous fistula or graft for access, had a Viatorr stent placed in the central (subclavian and/or brachiocephalic) veins, and had follow up. RESULTS: A total of nine patients were identified to meet the inclusion criteria. Four interventions were due to refractory lesions of the subclavian or brachiocephalic veins, and the other five interventions were for hemodynamically significant lesions refractory to angioplasty alone, all resulting in access dysfunction. Primary patency ranged from 36-442 days (geometric mean 156.6 days, range 19-442 days). No stent fracture was identified on imaging at any point during follow-up of these patients out to a maximum of 2912 days (Average 837 days). CONCLUSIONS: The Viatorr stent graft used in the HD population for clinically significant lesions at the thoracic outlet (TO) showed no structural failures (fractures) in this cohort.

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders.

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models. While no altered gene expression was observed in cells over-expressing the recessive heritable variant, the gene expression profiles of cells over-expressing de novo variants resulted in similar gene expression changes as observed in CRISPR-Cas9-mediated DEAF1-deleted cells. Altered expression of DEAF1-regulated genes was rescued by exogenous expression of WT-DEAF1 but not by de novo variants in cells lacking endogenous DEAF1. De novo heterozygous variants within the DBD of DEAF1 were identified in 10 individuals with a phenotypic spectrum including autism spectrum disorder, developmental delays, sleep disturbance, high pain tolerance, and mild dysmorphic features. Functional assays demonstrate these variants alter DEAF1 transcriptional activity. Taken together, this study expands the clinical phenotypic spectrum of individuals with DAND, furthers our understanding of potential roles of DEAF1 on neuronal function, and demonstrates dominant negative activity of identified de novo variants.

Comparison of radiofrequency and microwave ablation and identification of risk factors for primary treatment failure and local progression.

PURPOSE: To compare percutaneous radiofrequency ablation (RFA) and microwave ablation (MWA) for treatment of Hepatocellular carcinoma (HCC) and to identify risk factors for treatment failure and local progression. METHODS: 145 unique HCC [87 (60%) RFA, 58 (40%) MWA] were retrospectively reviewed from a single tertiary medical center. Adverse events were classified as severe, moderate, or mild according to the Society of Interventional Radiology Adverse Event Classification system. Primary and secondary efficacy, as well as local progression, were determined using mRECIST. Predictors of treatment failure and time to local progression were analyzed using generalized estimating equations and Cox regression, respectively. RESULTS: Technical success was achieved in 143/145 (99%) HCC. There were 1 (0.7%) severe and 2 (1.4%) moderate adverse events. Of the 143 technically successful initial treatments, 136 (95%) completed at least one follow-up exam. Primary efficacy was achieved in 114/136 (84%). 9/22 (41%) primary failures underwent successful repeat ablation, so secondary efficacy was achieved in 128/136 (90%) HCC. Local progression occurred in 24 (19%) HCC at a median of 25 months (95% CI = 19-32 months). There was no difference in technical success, primary efficacy, or time to local progression between RFA and MWA. In HCC treated with MWA, same-day biopsy was associated with primary failure (RR = 9.0, 95% CI: 1.7-47, P = 0.015), and proximity to the diaphragm or gastrointestinal tract was associated with local progression (HR = 2.40, 95% CI:1.5-80, P = 0.017). CONCLUSION: There was no significant difference in primary efficacy or time to local progression between percutaneous RFA and MWA.

ACR Appropriateness Criteria® Abdominal Aortic Aneurysm Follow-up (Without Repair).

Abdominal aortic aneurysm (AAA) is defined as aneurysmal dilation of the abdominal aorta to 3 cm or greater. A high degree of morbidity and mortality is associated with AAA rupture, and imaging surveillance plays an essential role in mitigating the risk of rupture. Aneurysm size and growth rate are factors associated with the risk of rupture, thus surveillance imaging studies must be accurate and reproducible to characterize aneurysm size. Ultrasound, CT angiography, and MR angiography provide an accurate and reproducible assessment of size, while radiographs and aortography provide limited evaluation. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

DEAF1 binds unmethylated and variably spaced CpG dinucleotide motifs.

DEAF1 is a transcriptional regulator associated with autoimmune and neurological disorders and is known to bind TTCG motifs. To further ascertain preferred DEAF1 DNA ligands, we screened a random oligonucleotide library containing an "anchored" CpG motif. We identified a binding consensus that generally conformed to a repeated TTCGGG motif, with the two invariant CpG dinucleotides separated by 6-11 nucleotides. Alteration of the consensus surrounding the dual CpG dinucleotides, or cytosine methylation of a single CpG half-site, eliminated DEAF1 binding. A sequence within the Htr1a promoter that resembles the binding consensus but contains a single CpG motif was confirmed to have low affinity binding with DEAF1. A DEAF1 binding consensus was identified in the EIF4G3 promoter and ChIP assay showed endogenous DEAF1 was bound to the region. We conclude that DEAF1 preferentially binds variably spaced and unmethylated CpG-containing half-sites when they occur within an appropriate consensus.

Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.

Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.

Improvement in reporting skills of radiology residents with a structured reporting curriculum.

RATIONALE AND OBJECTIVES: Radiology residents must acquire dictation and reporting skills to meet Accreditation Council for Graduate Medical Examination requirements and provide optimal patient care. Historically, these skills have been taught informally and vary between institutions and among radiologists. A structured curriculum improves resident report quality when using a quantitative grading scheme. This study describes the implementation of such a curriculum and evaluates its utility in tracking resident progress. MATERIALS AND METHODS: We implemented a three-stage reporting curriculum in our diagnostic radiology residency program in 2009. Stages 1 and 2 involve instruction and formative feedback composed of suggestions for improvement in a 360° format from faculty, peers, and others within the resident's sphere of influence. The third stage involves individual, biannual, written feedback with scored reports specifically assessing four categories: succinctness, spelling/grammar, clarity, and responsible referral. Biannual scores were collected from 2009 to 2013, sorted by year of residency training (R1 to R4), and average training level scores were statistically compared. RESULTS: Review of 1500 reports over a 4-year period yielded a total of 153 scores: 54, 36, 29, and 34 from R1, R2, R3, and R4 residents, respectively. The mean (standard deviation) scores for R1, R2, R3, and R4 residents were 10.20 (1.06), 10.25 (0.81), 10.5 (0.74), and 10.75 (0.69), respectively. Post hoc analysis identified significant differences between R1 and R4 residents (P = .012) and R2 and R4 residents (P = .009). CONCLUSIONS: Residents' reporting scores showed significant improvement over the course of their residency training. This indicates that there may be a benefit in using an organized reporting curriculum to track resident progress in producing reports that may improve patient care.

A preliminary 6-month prospective study examining self-reported religious preference, religiosity/spirituality, and retention at a Jewish residential treatment center for substance-related disorders.

Although there is a substantial amount of research suggesting that higher levels of religiosity/spirituality (R/S) are associated with better treatment outcomes of substance-related disorders, no studies have explored this relationship at a faith-based residential treatment center. The objective of this prospective study is to explore the relationship between R/S, self-reported religious preference, and retention at a Jewish residential treatment center for substance-related disorders. Using the Daily Spiritual Experience Scale, R/S levels were assessed for 33 subjects at baseline, 1 month, 3 months, and 6 months. Results demonstrated a significant relationship between baseline R/S level and retention at 6 months, while R/S levels were unchanged during the course of treatment. Notably, no relationship was found between self-reported religious affiliation and retention. This study demonstrates that patients' R/S level, rather than religious affiliation, is a possible predictor for better outcome at faith-based residential centers for substance-related disorders.

Deformed epidermal autoregulatory factor-1 (DEAF1) interacts with the Ku70 subunit of the DNA-dependent protein kinase complex.

Deformed Epidermal Autoregulatory Factor 1 (DEAF1) is a transcription factor linked to suicide, cancer, autoimmune disorders and neural tube defects. To better understand the role of DEAF1 in protein interaction networks, a GST-DEAF1 fusion protein was used to isolate interacting proteins in mammalian cell lysates, and the XRCC6 (Ku70) and the XRCC5 (Ku80) subunits of DNA dependent protein kinase (DNA-PK) complex were identified by mass spectrometry, and the DNA-PK catalytic subunit was identified by immunoblotting. Interaction of DEAF1 with Ku70 and Ku80 was confirmed to occur within cells by co-immunoprecipitation of epitope-tagged proteins, and was mediated through interaction with the Ku70 subunit. Using in vitro GST-pulldowns, interaction between DEAF1 and the Ku70 subunit was mapped to the DEAF1 DNA binding domain and the C-terminal Bax-binding region of Ku70. In transfected cells, DEAF1 and Ku70 colocalized to the nucleus, but Ku70 could not relocalize a mutant cytoplasmic form of DEAF1 to the nucleus. Using an in vitro kinase assay, DEAF1 was phosphorylated by DNA-PK in a DNA-independent manner. Electrophoretic mobility shift assays showed that DEAF1 or Ku70/Ku80 did not interfere with the DNA binding of each other, but DNA containing DEAF1 binding sites inhibited the DEAF1-Ku70 interaction. The data demonstrates that DEAF1 can interact with the DNA-PK complex through interactions of its DNA binding domain with the carboxy-terminal region of Ku70 that contains the Bax binding domain, and that DEAF1 is a potential substrate for DNA-PK.

Sleep and gambling severity in a community sample of gamblers.

Although sleep has been extensively studied in substance related disorders, it has yet to be examined as thoroughly in gambling-related disorders. The purpose of this study is to examine the relationship between gambling severity and sleep disturbances in a sample of non-treatment seeking gamblers (N = 96) using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Mean ESS scores for recreational, problem, and pathological gamblers were 4.13, 5.81, and 8.69, respectively, with a significant difference between pathological gamblers and both problem (P = .007) and recreational gamblers (P < .001). Mean PSQI scores for recreational, problem, and pathological gamblers were 3.35, 5.30, and 5.44, respectively, with a significant difference in sleep quality between recreational and problem gamblers (P = .018), as well as recreational and pathological gamblers (P = .008). As the first study to use objective sleep measures, these findings will not only increase awareness of this relationship, but also provide a foundation on which others can investigate the benefits of screening and adjunct treatment for sleep disorders in the gambling population.

Screening for addictive disorders within a workers' compensation clinic: an exploratory study.

We conducted a cross-sectional study investigating the extent of addictive disorders within a workers' compensation (WC) clinic. We also examined the feasibility of substance abuse screening within the same clinic. In 2009 , 100 patients were asked to complete the World Health Organization's Alcohol, Smoking, Substance Involvement Screening Test (WHO-ASSIST) and the Current Opioid Misuse Measure (COMM). According to the WHO-ASSIST, we found that 46% of WC patients required intervention for at least one substance-related disorder (25% tobacco, 23% sedatives, 8% opioids), and according to the COMM, 46% screened positive for prescription opioid misuse. Importantly, the addition of this screening was brief, economical, and well accepted by patients. Further research should analyze the costs and benefits of detection and intervention of substance-related disorders in this setting.

Identification of a nuclear export signal and protein interaction domains in deformed epidermal autoregulatory factor-1 (DEAF-1).

Deformed epidermal autoregulatory factor-1 (DEAF-1) is a DNA-binding protein required for embryonic development and linked to clinical depression and suicidal behavior in humans. Although primarily nuclear, cytoplasmic localization of DEAF-1 has been observed, and this suggests the presence of a nuclear export signal (NES). Using a series of fluorescent fusion proteins, an NES with a novel spacing of leucines (LXLX(6)LLX(5)LX(2)L) was identified near the COOH-terminal MYND domain at amino acids 454-476. The NES was leptomycin B-sensitive and mutation of the leucine residues decreased or eliminated nuclear export activity. In vitro pull downs and an in vivo fluorescent protein interaction assay identified a DEAF-1/DEAF-1 protein interaction domain within the NES region. DNA binding had been previously mapped to a positively charged surface patch in the novel DNA binding fold called the "SAND" domain. A second protein-protein interaction domain was identified at amino acids 243-306 that contains the DNA-binding SAND domain and also an adjacent zinc binding motif and a monopartite nuclear localization signal (NLS). Deletion of these adjacent sequences or mutation of the conserved cysteines or histidine in the zinc binding motif not only inhibits protein interaction but also eliminates DNA binding, demonstrating that DEAF-1 protein-protein interaction is required for DNA recognition. The identification of an NES and NLS provides a basis for the control of DEAF-1 subcellular localization and function, whereas the requirement of protein-protein interaction by the SAND domain appears to be unique among this class of transcription factors.