Percutaneous core needle biopsy of neuroblastoma in the pediatric population: what have we learned in the last decade.

INTRODUCTION: Historically, neuroblastoma has been diagnosed by surgical open biopsy (SB). In recent decades, core needle biopsy (CNB) has replaced surgical biopsy due to its safe and adequate method of obtaining tissue diagnosis. AIM: Our study aimed to assess the effectiveness of CNB in obtaining tissue diagnosis for neuroblastoma and evaluate its safety profile in terms of post-operative complications, in comparison to SB. METHODS: A retrospective cohort study, including all patients younger than 18 years who were diagnosed with neuroblastoma from 2012 until 2022 in a single tertiary medical center. Patients' demographics, tumor size and location, pathological results, and clinical outcomes were collected. RESULTS: 79 patients were included in our study: 35 biopsies were obtained using image-guided CNB and 44 using SB. Patients' and tumor characteristics including age, gender, tumor volume, and stage were similar in both groups. The biopsy adequacy rate in the CNB group was 91% and 3 patients in this group underwent repeated biopsy. The safety profile in the CNB group was similar to the SB group. CONCLUSIONS: CNB is a safe method and should be considered the first choice for obtaining tissue diagnosis when feasible due to its high adequacy in terms of tumor histopathological features.

Inferior vena cava reconstruction to alleviate back pain.

We present the case of a 38-year-old man with end-stage renal disease receiving hemodialysis via a left femoral loop graft who developed debilitating back pain. During a maintenance fistulogram, we found a completely occluded inferior vena cava and engorged lumbar veins. The patient underwent inferior vena cava reconstruction with stenting, which resulted in complete resolution of the engorged lumbar veins on venography and a significant reduction in his back pain. Engorgement of the lumbar veins can cause significant pain, and treatment of the underlying pathology can alleviate these symptoms.

Cutting balloon septotomy for repair of right common iliac artery aneurysm in the setting of type B aortic dissection.

We report a case of using cutting balloon septotomy for a 5-cm right common iliac artery aneurysm repair in a patient with a chronic type B aortic dissection after open repair 10 years before. This technique uses intravenous ultrasound to facilitate deployment of a cutting balloon to shear through the dissection flap, allowing for optimization of the landing zone for endovascular repair of a right common iliac artery aneurysm. Various methods are available for performing septotomy, and the use of a cutting balloon is one that helps with stent placement and position.

Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data.

BACKGROUND: Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment. AIM: To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets. METHODS: We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis. RESULTS: Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms. CONCLUSION: This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.

Transcriptome changes in stages of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and globally. The currently understood model of pathogenesis consists of a 'multiple hit' hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury. AIM: To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis (NASH) tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis. METHODS: We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology. For NAFLD, we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies; for NASH, we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies. RESULTS: Our results from the NAFLD analysis reinforce the role of altered metabolism, inflammation, and cell survival in pathogenesis and support recently described contributors to disease activity, such as altered androgen and long non-coding RNA activity. The top upstream regulator was found to be sterol regulatory element binding transcription factor 1 (SREBF1), a transcription factor involved in lipid homeostasis. Downstream of SREBF1, we observed upregulation in CXCL10, HMGCR, HMGCS1, fatty acid binding protein 5, paternally expressed imprinted gene 10, and downregulation of sex hormone-binding globulin and insulin-like growth factor 1. These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver. Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis. Top canonical pathways, disease networks, and disease functions were related to cholesterol synthesis, lipid metabolism, adipogenesis, and metabolic disease. Top upstream regulators included pro-inflammatory cytokines tumor necrosis factor and IL1B, PDGF BB, and beta-estradiol. Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism, extracellular matrix deposition, and tumor suppression. Lastly, we found riciribine (an AKT inhibitor) and ZSTK-474 (a PI3K inhibitor) as potential drugs that targeted the differential gene expression in our dataset. CONCLUSION: In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy.

Lidocaine Ineffectiveness Suggests New Psychopharmacology Drug Target.

Objectives: The mechanism of many neuropsychiatric disorders remains unknown, but the ineffectiveness of the sodium channel blocker lidocaine has been suggested to be a biomarker for Attention Deficit Hyperactivity Disorder (ADHD) and a severe form of Premenstrual Syndrome (PMS) that is considered psychiatric. We conducted single-arm double-blind clinical trials to test whether lidocaine ineffectiveness can be used as a biomarker to identify people with these conditions and provide a clue as to the molecular mechanism and potential psychopharmacological intervention. Experimental Design: We developed a noninvasive taste test for lidocaine ineffectiveness, validated by comparing lidocaine injections to pain testing in 12 subjects, and assessed it in individuals with ADHD and PMS. Principal Observations: Lidocaine ineffectiveness had a strong association in women with ADHD + PMS in a sample of 53 subjects and controls (p < 0.001). Conclusions: These results suggest the possibility of the biological understanding of the combination of ADHD and PMS that is characteristic of the psychiatric disorder Premenstrual Dysphoric Disorder (PMDD). These results and comparison to family pedigrees of a neuromuscular channelopathy with overlapping symptoms suggest the possibility that the clinical phenotype in PMDD is produced by sensory overstimulation, and amenable to molecular understanding and treatment.

User testing of a diagnostic decision support system with machine-assisted chart review to facilitate clinical genomic diagnosis.

OBJECTIVES: There is a need in clinical genomics for systems that assist in clinical diagnosis, analysis of genomic information and periodic reanalysis of results, and can use information from the electronic health record to do so. Such systems should be built using the concepts of human-centred design, fit within clinical workflows and provide solutions to priority problems. METHODS: We adapted a commercially available diagnostic decision support system (DDSS) to use extracted findings from a patient record and combine them with genomic variant information in the DDSS interface. Three representative patient cases were created in a simulated clinical environment for user testing. A semistructured interview guide was created to illuminate factors relevant to human factors in CDS design and organisational implementation. RESULTS: Six individuals completed the user testing process. Tester responses were positive and noted good fit with real-world clinical genetics workflow. Technical issues related to interface, interaction and design were minor and fixable. Testers suggested solving issues related to terminology and usability through training and infobuttons. Time savings was estimated at 30%-50% and additional uses such as in-house clinical variant analysis were suggested for increase fit with workflow and to further address priority problems. CONCLUSION: This study provides preliminary evidence for usability, workflow fit, acceptability and implementation potential of a modified DDSS that includes machine-assisted chart review. Continued development and testing using principles from human-centred design and implementation science are necessary to improve technical functionality and acceptability for multiple stakeholders and organisational implementation potential to improve the genomic diagnosis process.

The Human Phenotype Ontology in 2021.

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

Clinician-centric diagnosis of rare genetic diseases: performance of a gene pertinence metric in decision support for clinicians.

BACKGROUND: In diagnosis of rare genetic diseases we face a decision as to the degree to which the sequencing lab offers one or more diagnoses based on clinical input provided by the clinician, or the clinician reaches a diagnosis based on the complete set of variants provided by the lab. We tested a software approach to assist the clinician in making the diagnosis based on clinical findings and an annotated genomic variant table, using cases already solved using less automated processes. RESULTS: For the 81 cases studied (involving 216 individuals), 70 had genetic abnormalities with phenotypes previously described in the literature, and 11 were not described in the literature at the time of analysis ("discovery genes"). These included cases beyond a trio, including ones with different variants in the same gene. In 100% of cases the abnormality was recognized. Of the 70, the abnormality was ranked #1 in 94% of cases, with an average rank 1.1 for all cases. Large CNVs could be analyzed in an integrated analysis, performed in 24 of the cases. The process is rapid enough to allow for periodic reanalysis of unsolved cases. CONCLUSIONS: A clinician-friendly environment for clinical correlation can be provided to clinicians who are best positioned to have the clinical information needed for this interpretation.

A rare complication of testicular infarction after femorofemoral bypass highlighting the importance of surgical technique.

We present an interesting case of a 66-year-old male who had acute testicular infarction following a right common femoral artery to left profunda femoris artery bypass with advanced symptoms of claudication. Angiography in the preoperative period demonstrated the extent of peripheral arterial disease present, revealing a calcified aorta, partially occluded left hypogastric artery, occluded left external iliac, common femoral and superficial femoral arteries and an occluded right hypogastric artery. A bypass was performed without any initial complications and subsequent relief of symptoms of claudication and rest pain. Postoperative scrotal pain and follow-up duplex demonstrated lack of perfusion of the testicle necessitating orchiectomy. This case serves to illustrate the importance of preserving collateral vessels as a technical consideration, as well as presenting a rare potential complication.

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

Retrograde embolization of anterior tibial artery for an iatrogenic arterio-venous fistula causing left lower extremity claudication.

Lower extremity angiogram is generally a safe and effective procedure with a low rate of vascular complications. We report here a unique case of a 33-year-old female with anterior tibial artery (ATA) to anterior tibial vein fistula formation after lower extremity endovascular intervention. This was initially treated with open repair of the fistula and ligation of ATA. However, patient continued to complain of claudication like symptoms. Patient subsequently had an endovascular embolization of ATA in a retrograde fashion. Recovery was unremarkable; patient was discharged home same day. Three months postoperatively patient denies leg pain, a follow-up arterial duplex failed to show presence of arterio-venous fistula. This case illustrates the effectiveness of an endovascular approach as a minimally invasive treatment for this uncommon complication that occurs after lower extremity endovascular intervention.

Impact of a Patient-Facing Enhanced Genomic Results Report to Improve Understanding, Engagement, and Communication.

"The objective of this study was to" test the effectiveness of an enhanced genomic report on patient-centered outcome domains including communication, engagement and satisfaction. "Study design utilized" a prospective, randomized, mixed-methods desctiptive study of a whole genome sequencing results report, GenomeCOMPASS™, that was accessed by providers through the electronic health record and by patients through the associated patient portal. "The study was set in" an integrated healthcare delivery system in central Pennsylvania. "Eighty-four" parents of 46 children with undiagnosed Intellectual Disability, Autism Spectrum Disorder and/or multiple congenital anomalies who had participated in a previous study offering whole genome sequencing for their affected child were invited to enroll. Fifty-two parents enrolled. Following a traditional genetics results informing visit, the study coordinator stratified families by diagnostic result and uninformative result and then randomized families within each group to an intervention arm to receive the GenomeCOMPASS™ report or to the usual care arm to receive a summary letter from the medical geneticist. A letter inviting enrollment included a baseline survey, which once returned, constituted enrollment. Surveys were administered at 3 months post-genetics visit. At 6 months, the usual care arm crossed over to receive the intervention and were administered an additional survey at 3 months. Qualitative interviews were conducted following survey completion to augment the survey data regarding the patient centered outcomes of interest. Patient reported outcomes including communication, engagement, empowerment and satisfaction. In the intervention arm, GenomeCOMPASS™ reports were released to 14 families (N = 28 parents) and of those 21 (75%) returned 3 month surveys. In the usual care arm, 12 families (N = 24 parents) received usual care summary letters and of those 20 (83%) returned 3 month surveys. At crossover, GenomeCOMPASS™ reports were released to 20 individuals and 15 (75%) returned 3 month surveys. Qualitative interviews were conducted with 5 individuals. Use of the GenomeCOMPASS™ report was reported by this small group of parents to improve communication with providers and non-health professionals such as educators and therapists and led to increased engagement and high satisfaction. Providers and others involved in the children's care also endorsed the report's effectiveness. Reports that addressed negative findings, i.e. uninformative results, were not found to be useful. Although the number of users was small, this study supports that customizable template reports may provide a useful and durable source of information that can support and enhance the information provided by genetics professionals in traditional face-to-face encounters. TRIAL REGISTRATION: Clinicaltrials.gov (Record 2013-0594).

Case Report: Modified Laparoscopic Subtotal Cholecystectomy: An Alternative Approach to the "Difficult Gallbladder".

BACKGROUND Laparoscopic cholecystectomy is a commonly performed surgical procedure. In certain situations visualization of the Callot triangle can become difficult due to inflammation, adhesions, and sclerosing of the anatomy. Without being able to obtain the "critical view of safety" (CVS), there is increased risk of damage to vital structures. An alternative approach to the conventional conversion to an open cholecystectomy (OC) would be a laparoscopic subtotal cholecystectomy (LSC). CASE REPORT We present a case of a 56-year-old male patient with acute cholecystitis with a "difficult gallbladder" managed with LSC. Due to poor visualization of the Callot triangle due to adhesions, safe dissection was not feasible. In an effort to avoid injury to the common bile duct (CBD), dissection began at the dome of the gallbladder allowing an alternative view while ensuring safety of critical structures. CONCLUSIONS We discuss the potential benefits and risks of LSC versus conversion to OC. Our discussion incorporates the pathophysiology that allows LSC in this particular circumstance to be successful, and the considerations a surgeon faces in making a decision in management.

Experience with Integrating Diagnostic Decision Support Software with Electronic Health Records: Benefits versus Risks of Information Sharing.

INTRODUCTION: Reducing misdiagnosis has long been a goal of medical informatics. Current thinking has focused on achieving this goal by integrating diagnostic decision support into electronic health records. METHODS: A diagnostic decision support system already in clinical use was integrated into electronic health record systems at two large health systems, after clinician input on desired capabilities. The decision support provided three outputs: editable text for use in a clinical note, a summary including the suggested differential diagnosis with a graphical representation of probability, and a list of pertinent positive and pertinent negative findings (with onsets). RESULTS: Structured interviews showed widespread agreement that the tool was useful and that the integration improved workflow. There was disagreement among various specialties over the risks versus benefits of documenting intermediate diagnostic thinking. Benefits were most valued by specialists involved in diagnostic testing, who were able to use the additional clinical context for richer interpretation of test results. Risks were most cited by physicians making clinical diagnoses, who expressed concern that a process that generated diagnostic possibilities exposed them to legal liability. DISCUSSION AND CONCLUSION: Reconciling the preferences of the various groups could include saving only the finding list as a patient-wide resource, saving intermediate diagnostic thinking only temporarily, or adoption of professional guidelines to clarify the role of decision support in diagnosis.

The Human Phenotype Ontology in 2017.

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

Meta-analysis of open and endovascular repair of popliteal artery aneurysms.

OBJECTIVE: Endovascular popliteal artery aneurysm repair (EPAR) is increasingly used over open surgical repair (OPAR). The purpose of this study was to analyze the available literature on their comparative outcomes. METHODS: The PubMed and Embase databases were searched to identify studies comparing OPAR and EPAR. Studies with only one treatment and fewer than five patients were excluded. Demographics and outcomes were collected. Bias risk was assessed using a modified version of the Newcastle-Ottawa Scale. Results were computed from random-effects meta-analyses using the DerSimonian-Laird algorithm. RESULTS: A total of 14 studies were identified encompassing 4880 popliteal artery aneurysm repairs (OPAR, 3915; EPAR, 1210) during the last decade. OPAR patients were younger (standard mean difference, -0.798 [-0.798 to -1.108]; P < .001) and more likely to have worse tibial runoff (odds ratio [OR], 1.949 (1.15-3.31); P = .013) than EPAR patients. OPAR had higher odds of wound complications (OR, 5.182 [2.191-12.256]; P < .001) and lower odds of thrombotic complications (OR, 0.362 [0.155-0.848]; P < .001). OPAR had longer length of stay (standardized mean difference, 2.158 [1.225-3.090]; P < .001) and fewer reinterventions (OR, 0.275 [0.166-0.454]; P < .001). Primary patency was better for OPAR at 1 year and 3 years (relative risk, 0.607 [P = .01] and 0.580 [P = .006], respectively). There was no difference in secondary patency at 1 year and 3 years (0.770 [P = .458] and 0.642 [P = .073], respectively). CONCLUSIONS: EPAR has a lower wound complication rate and shorter length of hospital stay compared with OPAR. This comes at the cost of inferior primary patency but not secondary patency out to 3 years. Studies reporting long-term outcomes are lacking and necessary.