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Ehlers-Danlos syndrome (EDS) refers to a group of genetic disorders involving the connective tissues. Type IV EDS impairs type III collagen that is responsible for vessel integrity. Patients with type IV EDS are susceptible to vascular and visceral complications, including aortic aneurysms, pseudoaneurysms, dissections, and spontaneous rupture of internal organs. Treating aneurysms with open surgery versus endovascular techniques each carry a unique risk-to-benefit ratio that must be applied to each individual carefully. We present a patient with type IV EDS who presented with a rapidly growing inferior mesenteric artery aneurysm. The patient was treated with a percutaneous endovascular technique using coils and n-butyl-cyanoacrylate glue.

Background: The number of total hip arthroplasties (THA) performed across the world is growing rapidly. We performed this meta-analysis to evaluate the incidence of acute kidney injury (AKI) in patients undergoing THA. Methods: A literature search was performed using MEDLINE, EMBASE and Cochrane Database from inception until July 2018 to identify studies assessing the incidence of AKI (using standard AKI definitions of RIFLE, AKIN, and KDIGO classifications) in patients undergoing THA. We applied a random-effects model to estimate the incidence of AKI. The protocol for this meta-analysis is registered with PROSPERO (no. CRD42018101928). Results: Seventeen cohort studies with a total of 24,158 patients undergoing THA were enrolled. Overall, the pooled estimated incidence rates of AKI and severe AKI requiring dialysis following THA were 6.3% (95% CI: 3.8%–10.2%) and 0.5% (95% CI: 0.1%–2.3%). Subgroup analysis based on the countries by continent was performed and demonstrated the pooled estimated incidence of AKI following THA of 9.2% (95% CI: 5.6%–14.8%) in Asia, 8.1% (95% CI: 4.9%–13.2%) in Australia, 7.4% (95% CI: 3.2%–16.3%) in Europe, and 2.8% (95% CI: 1.2%–17.0%) in North America. Meta-regression of all included studies showed significant negative correlation between incidence of AKI following THA and study year (slope = −0.37, p <0.001). There was no publication bias as assessed by the funnel plot and Egger’s regression asymmetry test with p = 0.13 for the incidence of AKI in patients undergoing THA. Conclusion: The overall estimated incidence rates of AKI and severe AKI requiring dialysis in patients undergoing THA are 6.3% and 0.5%, respectively. There has been potential improvement in AKI incidence for patients undergoing THA over time.

Mechanical thrombectomy (MT) is the standard of care for patients who present with an acute ischemic stroke within 6 hours of symptom onset, and up to 24 hours in appropriately selected patients. However, optimal postoperative management of these patients remains uncertain, especially with regard to blood pressure control. To review the existing literature to define potential blood pressure goals in the immediate postoperative period in patients who undergo MT for acute ischemic stroke. The topic was defined through a clinical scenario and the subsequent development of a targeted clinical question. A literature search was performed, with relevant articles selected, one of which, a prospective observational study, was critically appraised. Participants included neurology residents and consultants, a medical librarian, clinical epidemiologists, as well as content experts from vascular neurology and interventional neuroradiology. Permissive hypertension (defined as <220/120 or <180/105 mm Hg as per the American Heart Association/American Stroke Association guidelines) may be harmful in the postoperative period following MT, especially in patients who were successfully recanalized. Moderate blood pressure control (<160/90) was found to be a predictor of improved 3-month mortality on multivariable logistic regression analysis in patients who sustained successful reperfusion [odds ratio (OR), 0.08; 95% confidence interval (CI), 0.01-0.054; P=0.01]. A 10 mm Hg increase in systolic blood pressure was found to result in a lower OR of having a favorable 3-month functional independence (OR, 0.70; 95% CI, 0.56-0.85; P=0.001) as well as higher rates of 3-month mortality (OR, 1.49; 95% CI, 1.18-1.88; P=0.001). Blood pressure goals in the immediate postoperative period in patients who undergo MT should differ than those who do not undergo MT, with data suggesting that lower blood pressure than permissive hypertension may be related to improved outcomes, especially in cases of successful reperfusion. However, current data are derived from observational studies; further studies, preferably in the form of randomized-controlled trials, are needed to further clarify the relationship between postoperative blood pressures and outcomes in this patient population.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety‐three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

Orthotopic liver transplantation remains the only curative therapy for inborn errors of metabolism. Given the tremendous success for primary immunodeficiencies using ex-vivo gene therapy with lentiviral vectors, there is great interest in developing similar curative therapies for metabolic liver diseases. We have previously generated a pig model of hereditary tyrosinemia type 1 (HT1), an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). Using this model, we have demonstrated curative ex-vivo gene and cell therapy using a lentiviral vector to express FAH in autologous hepatocytes. To further evaluate the long-term clinical outcomes of this therapeutic approach, we continued to monitor one of these pigs over the course of three years. The animal continued to thrive off the protective drug NTBC, gaining weight appropriately, and maintaining sexual fecundity for the course of his life. The animal was euthanized 31 months after transplantation to perform a thorough biochemical and histological analysis. Biochemically, liver enzymes and alpha-fetoprotein levels remained normal and abhorrent metabolites specific to HT1 remained corrected. Liver histology showed no evidence of tumorigenicity and Masson’s trichrome staining revealed minimal fibrosis and no evidence of cirrhosis. FAH-immunohistochemistry revealed complete repopulation of the liver by transplanted FAH-positive cells. A complete histopathological report on other organs, including kidney, revealed no abnormalities. This study is the first to demonstrate long-term safety and efficacy of hepatocyte-directed gene therapy in a large animal model. We conclude that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1.

AbstractBackgroundThis study aimed to assess the nationwide trends in optimal diabetic care and complications of elderly type 2 diabetes mellitus (T2DM) patients over a 6‐year period in Thailand.MethodsT2DM patients aged 65 years or older who received medical care at public hospitals in Thailand from 2010 to 2015 were included. The optimal T2DM care in elderly patients was defined as (1) blood pressure (BP) < 140/90, (2) hemoglobin A1C (HbA1c) < 7%, (3) low‐density lipoprotein cholesterol (LDL‐C) < 100 mg/dL, (4) use of antiplatelet medications, and (5) use of angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in hypertensive patients. T2DM treatment‐related complications included hospital admissions due to dysglycemia.ResultsA total of 54 295 elderly T2DM patients were enrolled in this study. From 2010 to 2015, there was an increasing trend in the achievement of BP control and use of antiplatelet medications (P for trend < 0.01), whereas there was a decreasing trend in the achievement of HbA1c and LDL‐C control among elderly T2DM patients (P for trend < 0.001). There was an increasing trend in the use of ACEI/ARB among elderly T2DM patients with hypertension (P for trend < 0.001). Hospital admissions due to dysglycemia decreased over the study period (P for trend < 0.001).ConclusionThere has been a trend change for diabetic care among elderly T2DM patients in Thailand. Further studies are needed to assess the impact on patient outcomes.

Abstract When unrepaired, alkylated DNA can induce cell death or trigger mutagenesis. Cellular capacity for repair of these lesions by O6-methylguanine methyltransferase (MGMT) dictates the equilibrium between cell viability and genetic diversity. Treatment of glioblastoma cells with temozolomide (TMZ) induced ATM- and Rad3-related (ATR) kinase dependent polyribonucleotide nucleotidyltransferase 1 (PNPT1) degradation of miR-181d. miR-181d suppresses MGMT expression; its degradation increases the mean MGMT expression of the cell population. miR-181d degradation also magnifies the cell-to-cell variability in MGMT expression, expanding the genetic heterogeneity of the population. This expanded heterogeneity enhances the “fitness” of the population and constitutes a novel form of chemotherapeutic resistance. These effects can be suppressed by overexpression of miR-181d, suggesting miRNA delivery as a strategy for glioblastoma therapy. To characterize the mechanism of acquired resistance, we profiled the expression of 2400 miRNAs before and after TMZ treatment. In independent patient-derived neurosphere lines, the majority of miRNAs remained unchanged after treatment. However, miR-181d was consistently suppressed after TMZ treatment. Our previous work demonstrated miR-181d as the master regulator of MGMT. We confirmed TMZ-induced suppression of miR-181d using independent in vitro and in vivo models as well as matched pre- and post-TMZ treated clinical specimens. TMZ-induced miR-181d suppression persisted after transcriptional inhibition, suggesting degradation as the primary mechanism. We performed an siRNA screen and identified polyribonucleotide nucleotidyltransferase 1 (PNPT1) as the gene responsible for miR-181d degradation. CRISPR inactivation of PNPT1 eliminated TMZ-induced suppression of miR-181d; this was rescued by wild-type PNPT1 but not by PNPT1 harboring RNAse-inactivating mutations. TMZ-induced degradation of miR-181d requires ATR kinase. Silencing or inhibition of ATR eliminated binding of PNPT1 to miR-181d and prevented degradation of miR-181d. TMZ-sensitizing effects of ATR inhibition were reversed by anti-miR-181d, suggesting miR-181d is essential in this process. In addition to elevating the mean MGMT expression of the population, single-cell analysis revealed that miR-181d degradation broadened the cell-to-cell variability in MGMT expression in vitro. In matched clinical pre- and post-TMZ treated specimens, variability in MGMT expression was significantly elevated in post-TMZ samples. This was recapitulated using The Cancer Genome Atlas (TCGA) database. We propose that miR-181d degradation-mediated expansion of genetic heterogeneity enhances the “fitness” of the population, constituting a novel form of chemotherapeutic resistance. These effects are suppressed by miR-181d overexpression, suggesting miRNA delivery as a strategy for glioblastoma therapy. Citation Format: Valya Ramakrishnan, Johnny Akers, Thien Nguyen, Aaron Wang, Bandita Adhikari, Brian Hirshman, Jie Li, Jann Sarkaria, Wei Hua, Mao Ying, Masayuki Nitta, Tao Jiang, Bob Carter, Clark C. Chen. miR-181d degradation mediated genetic heterogeneity and acquired resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1956.