Publications by authors named "Robert Brown"

1,663 Publications

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Medicaid Expansion Association with End-Stage Liver Disease Mortality Depends on Leniency of Medicaid Hepatitis C Virus Coverage.

Liver Transpl 2021 Jun 12. Epub 2021 Jun 12.

Department of Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York.

Background And Aims: The Affordable Care Act (ACA) expanded Medicaid around the same time that direct-acting antivirals (DAAs) became widely available for the treatment of hepatitis C virus (HCV). However, there is significant variation in Medicaid HCV treatment eligibility criteria between states. We explored the combined effects of Medicaid expansion and leniency of HCV coverage under Medicaid on liver outcomes.

Methods: We assessed state-level end-stage liver disease (ESLD) mortality, listings for liver transplant (LT), and listing-to-death ratio (LDR) for adults 25-64 years old using data from UNOS and CDC WONDER. States were divided into four nonoverlapping groups based on expansion status on January 1, 2014 (expansion versus non-expansion) and leniency of Medicaid HCV coverage (lenient versus restrictive coverage). Joinpoint regression analysis evaluated for significant changes in slope over time (joinpoints) during the pre-expansion (2009-2013) and post-expansion (2014-2018) time periods.

Results: We found significant changes in annual percent change (APC) for population-adjusted ESLD deaths between 2014-2015 in all cohorts except for the non-expansion/restrictive cohort, in which deaths increased at the same APC from 2009-2018 (APC +2.5% [95% CI 1.8, 3.3]). In the expansion/lenient coverage cohort, deaths increased at an APC of +2.6% (95% CI 1.8, 3.5) until 2014 and then tended to decrease at an APC of -0.4% (95% CI -1.5, 0.8). LT listings tended to decrease over time for all cohorts. For LDR, only the expansion/lenient and expansion/restrictive cohorts had statistically significant joinpoints.

Conclusion: Improvements in ESLD mortality and LDR were associated with both Medicaid expansion and leniency of HCV coverage under Medicaid. These findings argue for the implementation of more lenient and widespread public health insurance to improve liver disease outcomes, including mortality.
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http://dx.doi.org/10.1002/lt.26209DOI Listing
June 2021

The level of alcohol consumption in the prior year does not impact clinical outcomes in patients with alcohol-associated hepatitis (AH).

Liver Transpl 2021 Jun 10. Epub 2021 Jun 10.

University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.

Background And Aims: AUDIT-10 and its shorter form, AUDIT-C, are questionnaires used to characterize severity of drinking. We hypothesized that liver injury and short-term outcomes of alcohol-associated hepatitis (AH) would correlate with a patient's recent alcohol consumption as determined by AUDIT-10 and -C.

Methods: We analyzed a prospective international database of patients with AH diagnosed based on the NIAAA standard definitions. All subjects were interviewed using AUDIT-10. Primary outcomes included the discriminatory ability of the AUDIT-10 and AUDIT-C scores for predicting survival status at 28 and 90 days and severity of liver injury, as measured by MELD-Na. The relationship between AUDIT scores and survival status was quantified by calculating the area under the curve (AUC) of the receiver operating characteristics (ROC) analysis. The relationship between AUDIT scores and MELD-Na was examined using correlation coefficients.

Results: In 245 subjects (age range: 25-75 years) (35% female), we found no correlation between AUDIT-10 or AUDIT-C scores and either 28-day or 90-day mortality. Similarly, there was no correlation between AUDIT-10 and AUDIT-C and MELD-Na scores. There was a strong positive correlation between MELD-Na and 28-day and 90-day mortality. Additional measures of severity of alcohol use (average grams of alcohol consumed per day, years of drinking, convictions for driving under the influence and rehab attempts) and psychosocial factors (marriage, paid employment and level of social support) had no influence on MELD-Na.

Conclusions: In patients presenting with AH, AUDIT-10 and AUDIT-C were not predictors of clinical severity of liver disease nor of short-term mortality, suggesting that level of alcohol consumption in the prior year is not key to the presenting features or outcome of AH.
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http://dx.doi.org/10.1002/lt.26203DOI Listing
June 2021

Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance.

Clin Epigenetics 2021 Jun 5;13(1):122. Epub 2021 Jun 5.

Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London, W12 8EE, UK.

Background: Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.

Results: Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions.

Conclusions: Chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.
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http://dx.doi.org/10.1186/s13148-021-01105-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180030PMC
June 2021

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.

Nat Med 2021 May 31. Epub 2021 May 31.

Department of Neurology, Hereditary Neuropathy Foundation Center of Excellence, Neuroscience Institute, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, USA.

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease.
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http://dx.doi.org/10.1038/s41591-021-01346-1DOI Listing
May 2021

Urban heat island (UHI) intensity and magnitude estimations: A systematic literature review.

Sci Total Environ 2021 Jul 17;779:146389. Epub 2021 Mar 17.

Department of Landscape Architecture and Urban Planning, Texas A&M University, College Station, TX 77843, USA. Electronic address:

The severity of urban heat islands (UHIs) is increasing due to global and urban climate change. The damage caused by UHIs is also increasing. To establish a plan to improve the deteriorating thermal environment in cities due to UHIs and to minimize the damage, further research is needed to accurately estimate and analyze the intensity and magnitude of UHIs. This systematic literature review (SLR) is an in-depth review of 51 studies obtained through a five-step filtering process focusing on their analysis of the spatial extent of UHIs, the UHI concept that was used for UHI estimation, and the UHI estimation and analysis methods. This SLR confirmed the need for accurate UHI intensity and magnitude estimation and analysis to reset the existing UHI classification based on the variety of vertical and horizontal ranges where UHIs occur. The results also indicated that the existing UHI energy concepts for estimating UHIs need to be modified and developed to reflect the three-dimensional physical form of the city. Finally, this SLR clarifies the need to develop an optimized analysis method for UHI research. The review results of this SLR will inform future studies and be the cornerstone for establishing policies and plans that can accurately predict and respond to the damage caused by UHIs.
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http://dx.doi.org/10.1016/j.scitotenv.2021.146389DOI Listing
July 2021

Factors Associated with Readmission in the US Following Hospitalization with COVID-19.

Clin Infect Dis 2021 May 20. Epub 2021 May 20.

University of Pennsylvania, Philadelphia, PA, USA.

Background: Patients hospitalized for COVID-19 may experience complications following hospitalization and require readmission. This analysis estimates the rate and risk factors associated with COVID-19-related readmission and inpatient mortality.

Methods: This is a retrospective cohort study utilizing deidentified chargemaster data from 297 hospitals across 40 US states on patients hospitalized with COVID-19 February 15-June 09, 2020. Demographics, comorbidities, acute conditions, and clinical characteristics of first hospitalization are summarized. Mulitvariable logistic regression was used to measure risk factor associations with 30-day readmission and in-hospital mortality.

Results: Among 29,659 patients, 1,070 (3.6%) were readmitted. Readmitted patients were more likely to have diabetes, hypertension, cardiovascular disease (CVD), chronic kidney disease (CKD) vs those not readmitted (p<0.0001) and to present on first admission with acute kidney injury (15.6% vs. 9.2%), congestive heart failure (6.4% vs. 2.4%), and cardiomyopathy (2.1% vs. 0.8%) (p<0.0001). Higher odds of readmission were observed in patients age >60 vs. 1840 (odds ratio [OR]=1.92, 95% confidence interval [CI]=1.48, 2.50), and admitted in the Northeast vs. West (OR=1.43, 95% CI=1.14, 1.79) or South (OR=1.28, 95% CI=1.11, 1.49). Comorbidities including diabetes (OR=1.34, 95% CI=1.12, 1.60), CVD (OR=1.46, 95% CI=1.23, 1.72), CKD stage 1-5 (OR=1.51, 95% CI=1.25,1.81) and stage 5 (OR=2.27, 95% CI=1.81, 2.86) were associated with higher odds of readmission. 12.3% of readmitted patients died during second hospitalization.

Conclusions: Among this large US population of patients hospitalized with COVID-19, readmission was associated with certain comorbidities and acute conditions during first hospitalization. These findings may inform strategies to mitigate risks of readmission due to COVID-19 complications.
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http://dx.doi.org/10.1093/cid/ciab464DOI Listing
May 2021

How Comparable are Microbial Electrochemical Systems around the Globe? An Electrochemical and Microbiological Cross-Laboratory Study.

ChemSusChem 2021 Jun 18;14(11):2267. Epub 2021 May 18.

Institute of Environmental and Sustainable Chemistry, Technische Universität Braunschweig, Hagenring 30, 38106, Braunschweig, Germany.

Invited for this month's cover is the collaborative work among Univ. of Milano-Bicocca, Ricerca sul Sistema Energetico S.p.A., Univ. degli Studi di Milano, Univ. of California Irvine, Univ. of New Mexico, CNRS Toulouse. Technische Univ. Braunschweig, Aquacycl LLC, J. Craig Venter Institute, Helmholtz-Centre for Environmental Research. The image shows a sketch of a microbial fuel cell and a target indicating the need of developing common standards for the field of microbial electrochemical technologies. The Full Paper itself is available at 10.1002/cssc.202100294.
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http://dx.doi.org/10.1002/cssc.202100824DOI Listing
June 2021

In memoriam of Professor Terry Gillespie.

Int J Biometeorol 2021 Jun 10;65(6):985-987. Epub 2021 May 10.

Department of Landscape Architecture and Urban Planning, Texas A&M University, College Station, TX, USA.

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http://dx.doi.org/10.1007/s00484-021-02144-7DOI Listing
June 2021

Dynamic α-Fetoprotein Response and Outcomes After Liver Transplant for Hepatocellular Carcinoma.

JAMA Surg 2021 Jun;156(6):559-567

Multi-Organ Transplant and HPB Surgical Oncology, Division of General Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

Importance: Accurate preoperative prediction of hepatocellular carcinoma (HCC) recurrence after liver transplant is the mainstay of selection tools used by transplant-governing bodies to discern candidacy for patients with HCC. Although progress has been made, few tools incorporate objective measures of tumor biological characteristics, resulting in inclusion of patients with high recurrence rates and exclusion of others who could otherwise be cured.

Objective: To externally validate the New York/California (NYCA) score, a recently published multi-institutional US HCC selection tool that was the first model incorporating a dynamic α-fetoprotein response (AFP-R) and compare the validated score with currently accepted HCC selection tools, namely, the Milan Criteria (MC), the French-AFP (F-AFP), and Metroticket 2.0 models.

Design, Setting, And Participants: A retrospective, multicenter prognostic analysis of prospectively collected databases of 2236 adults undergoing liver transplant for HCC was conducted at 3 US, 1 Canadian, and 4 European centers from January 1, 2001, to December 31, 2013. The AFP-R was measured as the difference between maximum and final pre-liver transplant AFP level. Cox proportional hazards regression and competing risk regression analyses examined recurrence-free and overall survival. Receiver operating characteristic analyses and net reclassification index were used to compare NYCA with MC, F-AFP, and Metroticket 2.0. Data analysis was performed from June 2019 to April 2020.

Main Outcomes And Measures: The primary study outcome was 5-year recurrence-free survival; overall survival was the secondary outcome.

Results: Of 2236 patients, 1808 (80.9%) were men; mean (SD) age was 58.3 (7.96) years. A total of 545 patients (24.4%) did not meet the MC. The NYCA score proved valid on competing risk regression analysis, accurately predicting recurrence-free and overall survival (5-year cumulative incidence of recurrence risk in NYCA risk categories was 9.5% for low-, 20.5%, for acceptable-, and 40.5% for high-risk categories; P < .001 for all). The NYCA also predicted recurrence-free survival on a center-specific level: 453 of 545 patients (83.1%) who did not meet MC, 213 of 308 (69.2%) who did not meet the French-AFP, 292 of 384 (76.1%) who did not meet Metroticket 2.0 would be recategorized into NYCA low- and acceptable-risk groups (>75% 5-year recurrence-free survival). The Harrell C statistic for the validated NYCA score was 0.66 compared with 0.59 for the MC and 0.57 for the F-AFP models (P < .001). The net reclassification index for NYCA was 8.1 vs MC, 12.9 vs F-AFP, and 10.1 vs Metroticket 2.0.

Conclusions And Relevance: This study appears to externally validate the importance of AFP-R in the selection of patients with HCC for liver transplant. The AFP-R represents one of the truly objective measures of biological characteristics available before transplantation. Incorporation of AFP-R into selection criteria allows safe expansion of MC and other models, offering liver transplant to patients with acceptable tumor biological characteristics who would otherwise be denied potential cure.
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http://dx.doi.org/10.1001/jamasurg.2021.0954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100910PMC
June 2021

Improved methods for estimating mean radiant temperature in hot and sunny outdoor settings.

Int J Biometeorol 2021 Jun 28;65(6):967-983. Epub 2021 Apr 28.

School of Environmental Sciences, University of Guelph, Guelph, Ontario, Canada.

Thermal comfort research has utilized various sensors and models to estimate the mean radiant temperature (MRT) experienced by a human, including the standard black globe thermometer (SGT), acrylic globe thermometers (AGT), and cylindrical radiation thermometers (CRT). Rather than directly measuring radiation, a temperature is measured in the center of these low-cost sensors that can be related to MRT after theoretically accounting for convection. However, these sensors have not been systematically tested under long-term hot and clear conditions. Further, under variable weather conditions, many issues can arise due to slow response times, shape, inaccuracies in material properties and assumptions, and color (albedo, emissivity) inconsistencies. Here, we assess the performance of MRT produced by various heat transfer models, with and without new average surface temperature ([Formula: see text]) correction factors, using five instruments-the SGT (15 cm, black), tan and black CRTs, gray and black 38 mm AGTs-compared to 3D integral radiation measurements. Measurements were taken on an unobscured roof throughout summer-to-early-fall months in Tempe, Arizona, examining 58 full-sun days. Deviations without correcting for asymmetrical surface heating-found to be the main cause of errors-reached ± 15-20 °C MRT. By accounting for asymmetric heating through [Formula: see text] calculations, new corrective algorithms were derived for the low-cost sensor models. Results show significant improvements in the estimated MRT error for each sensor (i.e., ∆MRT) when applying the [Formula: see text] corrections. The tan MRT improved from 1.9 ± 6.2 to -0.1 ± 4.4 °C, while the gray AGT and SGT showed improvements from -1.6 ± 7.2 to -0.4 ± 6.3 °C and - 6.6 ± 6.4 to - 0.03 ± 5.7 °C, respectively. The new corrections also eliminated dependence on other meteorological factors (zenith, wind speed). From these results, we provide three simple equations for CRT, AGT, and SGT correction for future research use under warm-hot and clear conditions. This study is the most comprehensive empirical assessment of various low-cost instruments with broad applicability in urban climate and biometeorological research.
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http://dx.doi.org/10.1007/s00484-021-02131-yDOI Listing
June 2021

Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease.

Neurobiol Dis 2021 Jul 20;155:105368. Epub 2021 Apr 20.

Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.

Parkinson's disease (PD) is the most common form of neurodegenerative movement disorder, associated with profound loss of dopaminergic neurons from the basal ganglia. Though loss of dopaminergic neuron cell bodies from the substantia nigra pars compacta is a well-studied feature, atrophy and loss of their axons within the nigrostriatal tract is also emerging as an early event in disease progression. Genes that drive the Wallerian degeneration, like Sterile alpha and toll/interleukin-1 receptor motif containing (Sarm1), are excellent candidates for driving this axon degeneration, given similarities in the morphology of axon degeneration after axotomy and in PD. In the present study we assessed whether Sarm1 contributes to loss of dopaminergic projections in mouse models of PD. In Sarm1 deficient mice, we observed a significant delay in the degeneration of severed dopaminergic axons distal to a 6-OHDA lesion of the medial forebrain bundle (MFB) in the nigrostriatal tract, and an accompanying rescue of morphological, biochemical and behavioural phenotypes. However, we observed no difference compared to controls when striatal terminals were lesioned with 6-OHDA to induce a dying back form of neurodegeneration. Likewise, when PD phenotypes were induced using AAV-induced alpha-synuclein overexpression, we observed similar modest loss of dopaminergic terminals in Sarm1 knockouts and controls. Our data argues that axon degeneration after MFB lesion is Sarm1-dependent, but that other models for PD do not require Sarm1, or that Sarm1 acts with other redundant genetic pathways. This work adds to a growing body of evidence indicating Sarm1 contributes to some, but not all types of neurodegeneration, and supports the notion that while axon degeneration in many context appears morphologically similar, a diversity of axon degeneration programs exist.
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http://dx.doi.org/10.1016/j.nbd.2021.105368DOI Listing
July 2021

Resuscitation of the Critically Ill Older Adult.

Emerg Med Clin North Am 2021 May 11;39(2):273-286. Epub 2021 Mar 11.

Department of Emergency Medicine, Virginia Tech Carilion School of Medicine, Carilion Roanoke Memorial Hospital, 1906 Belleview Ave SE, Roanoke, VA 24014, USA.

In 30 years, adults 65 and older will represent 20% of the US population, with increased medical comorbidities leading to higher rates of critical illness and mortality. Despite significant acute illness, presenting symptoms and vital sign abnormalities may be subtle. Resuscitative guidelines are a helpful starting point but appropriate diagnostics, bedside ultrasound, and frequent reassessments are needed to avoid procrustean care that may worsen outcomes. Baseline functional status is as important as underlying comorbid conditions when prognosticating, and the patient's personal wishes should be sought early and throughout care with clear communication regarding prospects for immediate survival and overall recovery.
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http://dx.doi.org/10.1016/j.emc.2020.12.001DOI Listing
May 2021

The Current Management of Hepatorenal Syndrome-Acute Kidney Injury in the United States and the Potential of Terlipressin.

Liver Transpl 2021 Apr 13. Epub 2021 Apr 13.

Department of Internal Medicine and Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

Acute kidney injury in the setting of cirrhosis (hepatorenal syndrome-acute kidney injury [HRS-AKI]) is a severe and often fatal complication of end-stage liver disease. The goals of treatment are to reverse renal failure and prolong survival in critically ill patients. However, interventions have limited efficacy, and mortality rates remain high. In the US, the mainstay of pharmacologic therapy consists of the off-label use of vasoconstrictive agents in combination with plasma expanders, a strategy that produces modest effects. Liver transplantation is the ultimate solution but is only an option in a minority of patients since contraindications to transplantation are common and organ availability is limited. Renal replacement therapy is a temporary option but is known to confer an extremely poor, short-term prognosis in patients with HRS-AKI and, at best, serves as a bridge to liver transplantation for the minority of patients who are transplantation candidates. The high mortality rate associated with HRS-AKI in the US is a reflection of the suboptimal standard of care. Improved therapeutic options to treat HRS-AKI are sought. Terlipressin is a drug approved in Europe for treatment of HRS-AKI and supported by recommendations for first-line therapy by some liver societies and experts around the world. This review article will discuss the substantial unmet medical need associated with HRS-AKI and the potential benefits if terlipressin was approved in the US.
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http://dx.doi.org/10.1002/lt.26072DOI Listing
April 2021

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Haematol 2021 May 7;8(5):e323-e333. Epub 2021 Apr 7.

UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Background: For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial.

Methods: HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813.

Findings: Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment.

Interpretation: Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease.

Funding: Global Blood Therapeutics.
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http://dx.doi.org/10.1016/S2352-3026(21)00059-4DOI Listing
May 2021

Black Patients Have Unequal Access to Listing for Liver Transplantation in the United States.

Hepatology 2021 Mar 29. Epub 2021 Mar 29.

Weill Cornell Medicin, New York, USA.

The Model for End-Stage Liver Disease score may have eliminated racial disparities on the waitlist for liver transplantation (LT), but disparities prior to waitlist placement have not been adequately quantified. We aimed to analyze differences in patients who are listed for LT, undergo transplantation, and die from end-stage liver disease (ESLD), stratified by state and race/ethnicity. We analyzed two databases retrospectively - the Center for Disease Control Wide-ranging OnLine Data for Epidemiologic Research (CDC WONDER) and the United Network for Organ Sharing (UNOS) databases from 2014-2018. We included patients aged 25-64 years who had a primary cause of death of ESLD and listed for transplant in the CDC WONDER and UNOS databases, respectively. Our primary outcome was the ratio of listing for LT to death from ESLD - listing to death ratio (LDR). Our secondary outcome was the transplant to listing and transplant to death ratios. Chi-squared and multivariable linear regression evaluated for differences between race/ethnicity. 135,367 patients died of ESLD, 54,734 patients were listed for transplant, and 26,571 underwent transplant. Patients were mostly male and White. The national LDR was 0.40, significantly lowest in Black patients (0.30), p<0.001. The national transplant to listing ratio was 0.48, highest in Black patients (0.53), p<0.01. The national transplant to death ratio was 0.20, lowest in Black patients (0.16), p<0.001. States that had an above-mean LDR had a lower transplant to listing ratio, but higher transplant to death ratio. Multivariable analysis confirmed Black race is significantly associated with a lower LDR and transplant to death ratio. Conclusion: Black patients face a disparity in access to LT due to low listing rates for transplant relative to deaths from ESLD.
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http://dx.doi.org/10.1002/hep.31837DOI Listing
March 2021

How Comparable are Microbial Electrochemical Systems around the Globe? An Electrochemical and Microbiological Cross-Laboratory Study.

ChemSusChem 2021 Jun 5;14(11):2313-2330. Epub 2021 May 5.

Institute of Environmental and Sustainable Chemistry, Technische Universität Braunschweig, Hagenring 30, 38106, Braunschweig, Germany.

A cross-laboratory study on microbial fuel cells (MFC) which involved different institutions around the world is presented. The study aims to assess the development of autochthone microbial pools enriched from domestic wastewater, cultivated in identical single-chamber MFCs, operated in the same way, thereby approaching the idea of developing common standards for MFCs. The MFCs are inoculated with domestic wastewater in different geographic locations. The acclimation stage and, consequently, the startup time are longer or shorter depending on the inoculum, but all MFCs reach similar maximum power outputs (55±22 μW cm ) and COD removal efficiencies (87±9 %), despite the diversity of the bacterial communities. It is inferred that the MFC performance starts when the syntrophic interaction of fermentative and electrogenic bacteria stabilizes under anaerobic conditions at the anode. The generated power is mostly limited by electrolytic conductivity, electrode overpotentials, and an unbalanced external resistance. The enriched microbial consortia, although composed of different bacterial groups, share similar functions both on the anode and the cathode of the different MFCs, resulting in similar electrochemical output.
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http://dx.doi.org/10.1002/cssc.202100294DOI Listing
June 2021

BET bromodomain inhibitors PFI-1 and JQ1 are identified in an epigenetic compound screen to enhance C9ORF72 gene expression and shown to ameliorate C9ORF72-associated pathological and behavioral abnormalities in a C9ALS/FTD model.

Clin Epigenetics 2021 Mar 16;13(1):56. Epub 2021 Mar 16.

Institute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile.

Background: An intronic GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), referred to as C9ALS/FTD. No cure or effective treatment exist for C9ALS/FTD. Three major molecular mechanisms have emerged to explain C9ALS/FTD disease mechanisms: (1) C9ORF72 loss-of-function through haploinsufficiency, (2) dipeptide repeat (DPR) proteins mediated toxicity by the translation of the repeat RNAs, and more controversial, (3) RNA-mediated toxicity by bidirectional transcription of the repeats that form intranuclear RNA foci. Recent studies indicate a double-hit pathogenic mechanism in C9ALS/FTD, where reduced C9ORF72 protein levels lead to impaired clearance of toxic DPRs. Here we explored whether pharmacological compounds can revert these pathological hallmarks in vitro and cognitive impairment in a C9ALS/FTD mouse model (C9BAC). We specifically focused our study on small molecule inhibitors targeting chromatin-regulating proteins (epidrugs) with the goal of increasing C9ORF72 gene expression and reduce toxic DPRs.

Results: We generated luciferase reporter cell lines containing 10 (control) or ≥ 90 (mutant) G4C2 HRE located between exon 1a and 1b of the human C9ORF72 gene. In a screen of 14 different epidrugs targeting bromodomains, chromodomains and histone-modifying enzymes, we found that several bromodomain and extra-terminal domain (BET) inhibitors (BETi), including PFI-1 and JQ1, increased luciferase reporter activity. Using primary cortical cultures from C9BAC mice, we further found that PFI-1 treatment increased the expression of V1-V3 transcripts of the human mutant C9ORF72 gene, reduced poly(GP)-DPR inclusions but enhanced intranuclear RNA foci. We also tested whether JQ1, an BETi previously shown to reach the mouse brain by intraperitoneal (i.p.) injection, can revert behavioral abnormalities in C9BAC mice. Interestingly, it was found that JQ1 administration (daily i.p. administration for 7 days) rescued hippocampal-dependent cognitive deficits in C9BAC mice.

Conclusions: Our findings place BET bromodomain inhibitors as a potential therapy for C9ALS/FTD by ameliorating C9ORF72-associated pathological and behavioral abnormalities. Our finding that PFI-1 increases accumulation of intranuclear RNA foci is in agreement with recent data in flies suggesting that nuclear RNA foci can be neuroprotective by sequestering repeat transcripts that result in toxic DPRs.
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http://dx.doi.org/10.1186/s13148-021-01039-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962347PMC
March 2021

AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies.

Trends Mol Med 2021 Jun 10;27(6):520-523. Epub 2021 Mar 10.

Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA; Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address:

De novo glycosphingolipid (GSL) biosynthesis defects cause severe neurological diseases, including hereditary sensory and autonomic neuropathy type 1A (HSAN1A), GM3 synthase deficiency, and hereditary spastic paraplegia type 26 (HSPG26), each lacking effective treatment. Recombinant adeno-associated virus (AAV)-mediated gene therapy has emerged as a powerful treatment for monogenic diseases and might be particularly suitable for these neurological conditions.
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http://dx.doi.org/10.1016/j.molmed.2021.02.004DOI Listing
June 2021

Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer.

EMBO Mol Med 2021 May 11;13(5):e13366. Epub 2021 Mar 11.

Cancer Science Institute of Singapore, National University of Singapore, Singapore.

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.
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http://dx.doi.org/10.15252/emmm.202013366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103098PMC
May 2021

Complex redo cervical and vertebral artery reconstruction for Takayasu arteritis.

J Vasc Surg Cases Innov Tech 2021 Mar 27;7(1):78-83. Epub 2020 Oct 27.

Division of Vascular and Endovascular Surgery, Mayo Clinic, Rochester, Minn.

A 54-year-old woman presented with an enlarging, pulsatile left neck mass and a history of Takayasu arteritis. She had seven prior cervical vascular reconstructions, including a prosthetic right-to-left carotid crossover, and left vertebral and subclavian bypasses done with saphenous vein. The skin of her neck was scarred and thin. The anastomotic pseudoaneurysms were resected, the left carotid bifurcation was reconstructed with the cryopreserved femoral artery because of the concern about wound healing, and the subclavian and vertebral vein grafts were reimplanted. Intraoperative management, clamp sites and sequence, manner of shunting, choice of conduit, and wound healing were important considerations.
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http://dx.doi.org/10.1016/j.jvscit.2020.10.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903197PMC
March 2021

Morphoproteomics Points to the IL-6 Cytokine Storm as One Factor and a Therapeutic Target in the Pathogenesis of Thrombosis in COVID-19 Patients.

Ann Clin Lab Sci 2021 Jan;51(1):145-146

Department of Pathology and Laboratory Medicine, the University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.

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January 2021

Assessing the periprocedural magnitude of platelet count change in response to lusutrombopag.

JHEP Rep 2021 Apr 13;3(2):100228. Epub 2021 Jan 13.

Abteilung Innere Medizin & Gastroenterologie (IMuG), mit Zentrale Aufnahme & Erstversorgung (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria.

Background & Aims: Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials.

Methods: Adults with chronic liver disease-induced thrombocytopaenia and platelet count <50 (× 10/L) received lusutrombopag 3 mg or placebo ≤7 days before invasive procedure scheduled 9-14 days after randomisation. Platelet transfusion was required per protocol if the platelet count remained <50 no more than 2 days before the planned invasive procedure. analysis included: proportion of patients with platelet count ≥50, ≥1.5-fold increase, and a doubling of platelet count; maximum and maximum change in platelet count; and platelet count time course.

Results: Platelet count ≥50, a platelet count increase ≥1.5-fold, and at least a doubling in platelet count were achieved in 88.3%, 86.9%, and 52.6% of patients in the lusutrombopag group (n = 137) 58.6%, 32.3%, and 6.0% of patients in the placebo group (n = 133), respectively. In the lusutrombopag group, median maximum platelet count across baseline platelet counts of <30, ≥30 to <40, and ≥40 was 46, 76, and 87, respectively. Median maximum change in platelet count by baseline platelet count was +24, +42, and +40, respectively. Patients who received lusutrombopag without platelet transfusion achieved a median platelet count ≥50 for 3 weeks.

Conclusions: Patients treated with lusutrombopag experienced a clinically relevant response in platelet count for a substantial duration of time.

Lay Summary: Patients with low platelet counts caused by chronic liver disease may not receive planned invasive procedures or surgeries because of an increased risk of bleeding. Lusutrombopag has previously demonstrated efficacy in raising platelet counts and is approved to treat chronic liver disease patients with low platelet counts in advance of a planned surgery. Physicians need to understand more clearly what to expect in terms of platelet count change when using lusutrombopag; this integrated analysis provides data to help guide its clinical application.
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http://dx.doi.org/10.1016/j.jhepr.2021.100228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887643PMC
April 2021

Transcranial Doppler Screening in a Current Cohort of Children With Sickle Cell Anemia: Results From the DISPLACE Study.

J Pediatr Hematol Oncol 2021 Mar 31. Epub 2021 Mar 31.

Division of Hematology and Oncology, University of Alabama Birmingham, Birmingham, AL College of Nursing Departments of Public Health Sciences Neurology and Neurosurgery, Medical University of South Carolina, Charleston, SC Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Divison of Hematology-Oncology, Children's National Medical Center, Washington, DC Aflac Cancer and Blood Disorder Center, Emory University, Atlanta, GA.

Stroke prevention guidelines for sickle cell anemia (SCA) recommend transcranial Doppler (TCD) screening to identify children at stroke risk; however, TCD screening implementation remains poor. This report describes results from Part 1 of the 28-site DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study, a baseline assessment of TCD implementation rates. This report describes TCD implementation by consortium site characteristics; characteristics of TCDs completed; and TCD results based on age. The cohort included 5247 children with SCA, of whom 5116 were eligible for TCD implementation assessment for at least 1 study year. The majority of children were African American or Black, non-Hispanic and received Medicaid. Mean age at first recorded TCD was 5.9 and 10.5 years at study end. Observed TCD screening rates were unsatisfactory across geographic regions (mean 49.9%; range: 30.9% to 74.7%) independent of size, institution type, or previous stroke prevention trial participation. The abnormal TCD rate was 2.9%, with a median age of 6.3 years for first abnormal TCD result. Findings highlight real-world TCD screening practices and results from the largest SCA cohort to date. Data informed the part 3 implementation study for improving stroke screening and findings may inform clinical practice improvements.
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http://dx.doi.org/10.1097/MPH.0000000000002103DOI Listing
March 2021

A Review of the Current State of Liver Transplantation Disparities.

Liver Transpl 2021 02;27(3):434-443

Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY.

Equity in access is one of the core goals of the Organ Procurement and Transplant Network (OPTN). However, disparities in liver transplantation have been described since the passage of the National Organ Transplant Act, which established OPTN in the 1980s. During the past few decades, several efforts have been made by the United Network for Organ Sharing (UNOS) to address disparities in liver transplantation with notable improvements in many areas. Nonetheless, disparities have persisted across insurance type, sex, race/ethnicity, geographic area, and age. African Americans have lower rates of referral to transplant centers, females have lower rates of transplantation from the liver waiting list than males, and public insurance is associated with worse posttransplant outcomes than private insurance. In addition, pediatric candidates and older adults have a disadvantage on the liver transplant waiting list, and there are widespread regional disparities in transplantation. Given the large degree of inequity in liver transplantation, there is a tremendous need for studies to propose and model policy changes that may make the liver transplant system more just and equitable.
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http://dx.doi.org/10.1002/lt.25964DOI Listing
February 2021

Effect of Statin Use on Cancer-related Mortality in Nonalcoholic Fatty Liver Disease: A Prospective United States Cohort Study.

J Clin Gastroenterol 2021 Feb 17. Epub 2021 Feb 17.

Divisions of Gastroenterology and Hepatology Cardiology, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, NY.

Background: Indications for use of statins are common among patients with nonalcoholic fatty liver disease (NAFLD). Epidemiologic studies have suggested a possible association between statins and decreased risk of malignancies. We hypothesized that statin use has a protective effect on cancer mortality in patients with NAFLD.

Methods: Participants with NAFLD in 8 rounds of National Health and Nutrition Examination Survey (NHANES) were included in this study. Mortality data were obtained by linking the NHANES data to National Death Index. NAFLD was defined using the previously validated Hepatic Steatosis Index model.

Results: A total of 10,821 participants with NAFLD were included and 23% were statin users (n=2523). Statin use was associated with a 43% lower risk of cancer mortality [hazard ratio (HR)=0.57, 95% confidence interval (CI): 0.43-0.75, P<0.001] in multivariable analysis. Statin use under 1 year did not show a significant effect on cancer mortality (HR=0.72, 95% CI: 0.46-1.12), while statin use for 1 to 5 years decreased cancer mortality by 35% (HR=0.65, 95% CI: 0.42-0.99, P=0.46), and statin use >5 years decreased cancer mortality by 56% (HR=0.44, 95% CI: 0.29-0.66, P<0.001). Statin use was associated with a significant decrease in the risk of cancer mortality in NAFLD patients with both low and high risk of liver fibrosis (HR=0.55, 95% CI: 0.38-0.81; and HR=0.53, 95% CI: 0.31-0.89, respectively).

Conclusion: Using a large US prospective cohort, we showed statin use is associated with a considerable decrease in cancer-related mortality among patients with NAFLD. These results are important for clinical decision making, as statin indications are prevalent among NAFLD patients, but many do not receive benefit in the event that the statin is discontinued due to liver test abnormalities.
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http://dx.doi.org/10.1097/MCG.0000000000001503DOI Listing
February 2021