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Background & Aims: Patients require a clear understanding of their prognosis to make informed decisions about their care. The aim of this study was to compare the perceptions of prognosis and transplant candidacy between patients with cirrhosis and their hepatologists., Methods: Patients with cirrhosis and their hepatologists were prospectively recruited at an urban liver transplant center. Patients and hepatologists were asked about transplant candidacy and about how many years patients would live with and without a liver transplant. Agreement between patients and hepatologists was assessed with the weighted kappa statistic. Associations between patient/hepatologists' prognostic estimates and those predicted by patients' Model for End-Stage Liver Disease-Sodium (MELD-Na) score were estimated using the Pearson correlation coefficient., Results: Seventy patients and 6 hepatologists were enrolled in the study. Patients were predominantly male (61.4%) and white (68.6%), with a mean MELD-Na score of 19 ± 9. There was no-slight agreement between patients and hepatologists regarding survival without and with a liver transplant (κ = 0.1 and 0.2, respectively), with patients more optimistic than their hepatologists. There was greater agreement between patients and hepatologists about transplant candidacy (κ = 0.6). There was a negligible association between MELD-Na and patient estimates (r = -0.24, P = .05) but a moderate association between MELD-Na and hepatologist estimates (r = -0.51, P < .001), with higher MELD-Na scores associated with lower predicted survival., Conclusions: Patients with cirrhosis are more optimistic and less accurate in their predictions of survival compared with hepatologists, although they are more realistic about their transplant candidacy. Aligning patient and provider expectations may increase the likelihood that patients receive value-concordant care., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: This report aims to describe changes that centres providing transient ischaemic attack (TIA) pathway services have made to stay operational in response to the SARS-CoV-2 pandemic., Methods: An international cross-sectional description of the adaptions of TIA pathways between 30 th March and 6 th May 2020. Experience was reported from 18 centres with rapid TIA pathways in seven countries (Australia, France, UK, Canada, USA, New Zealand, Italy, Canada) from three continents., Results: All pathways remained active (n = 18). Sixteen (89%) had TIA clinics. Six of these clinics (38%) continued to provide in-person assessment while the majority (63%) used telehealth exclusively. Of these, three reported PPE use and three did not. Five centres with clinics (31%) had adopted a different vascular imaging strategy., Conclusion: The COVID pandemic has led TIA clinics around the world to adapt and move to the use of telemedicine for outpatient clinic review and modified investigation pathways. Despite the pandemic, all have remained operational., Competing Interests: Declarations of Competing Interest None, (Copyright © 2020 Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) function cell-intrinsically to regulate gene expression by base-pairing to complementary mRNA targets while in association with Argonaute, the effector protein of the miRNA-mediated silencing complex (miRISC). A relatively dilute population of miRNAs can be found extracellularly in body fluids such as human blood plasma and cerebrospinal fluid (CSF). The remarkable stability of circulating miRNAs in such harsh extracellular environments can be attributed to their association with protective macromolecular complexes, including extracellular vesicles (EVs), proteins such as Argonaut 2 (AGO2), or high-density lipoproteins. The precise origins and the potential biological significance of various forms of miRNA-containing extracellular complexes are poorly understood. It is also not known whether extracellular miRNAs in their native state may retain the capacity for miRISC-mediated target RNA binding. To explore the potential functionality of circulating extracellular miRNAs, we comprehensively investigated the association between circulating miRNAs and the miRISC Argonaute AGO2. Using AGO2 immunoprecipitation (IP) followed by small-RNA sequencing, we find that miRNAs in circulation are primarily associated with antibody-accessible miRISC/AGO2 complexes. Moreover, we show that circulating miRNAs can base-pair with a target mimic in a seed-based manner, and that the target-bound AGO2 can be recovered from blood plasma in an ∼1:1 ratio with the respective miRNA. Our findings suggest that miRNAs in circulation are largely contained in functional miRISC/AGO2 complexes under normal physiological conditions. However, we find that, in human CSF, the assortment of certain extracellular miRNAs into free miRISC/AGO2 complexes can be affected by pathological conditions such as amyotrophic lateral sclerosis., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Introduction: Although the Hospital Readmissions Reduction Program (HRRP) has decreased readmissions in targeted conditions, outcomes in high-risk subgroups are unknown. This study analyzed the impact of cirrhosis as a comorbidity on readmissions in conditions subjected to the HRRP., Methods: Using a longitudinal analysis of the New York, Florida, and Washington State inpatient databases from 2009 to 2013, adult Medicare beneficiaries with a diagnosis-related group of targeted conditions by the HRRP-pneumonia, congestive heart failure (CHF), and myocardial infarction (MI)-were included. Exclusion criteria included inability to assess for readmission, previous liver transplant, or having a readmission not subject to penalty under the HRRP. A sensitivity analysis used the International Classification of Diseases, 9th Revision, Clinical Modification codes to identify pneumonia, CHF, and MI hospitalizations. The primary outcome was 30-day readmission, with secondary outcomes including 90-day readmission, trends, and cirrhosis-specific risk factors for readmission., Results: Of the 797,432 patients included, 8,964 (1.1%) had cirrhosis. Patients with cirrhosis had significantly higher 30-day readmissions overall (29.3% vs 23.8%, P < 0.001) and specifically for pneumonia and CHF, but not for MI. Thirty-day readmission rates significantly decreased in patients without cirrhosis (annual percent change -1.8%, P < 0.001), but not in patients with cirrhosis (P = 0.39). Similar findings were present for 90-day readmissions. A sensitivity analysis confirmed these findings. On multivariable analysis, cirrhosis was associated with significantly higher 30-day readmissions (odds ratio 1.13, P < 0.001)., Discussion: When cirrhosis is comorbid in patients with conditions subjected to the HRRP, readmissions are higher and have not improved. Focused efforts are needed to improve outcomes in cirrhosis and other high-risk comorbidities within the HRRP cohort.

Background & Aims: Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward., Methods: In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation., Results: Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%)., Conclusions: Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection., Methods: We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment., Results: Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study., Conclusions: Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

Defective RNA metabolism is an emerging mechanism involved in ALS pathogenesis and possibly in other neurodegenerative disorders. Here, we show that microRNA (miRNA) activity is essential for long-term survival of postmitotic spinal motor neurons (SMNs) in vivo. Thus, mice that do not process miRNA in SMNs exhibit hallmarks of spinal muscular atrophy (SMA), including sclerosis of the spinal cord ventral horns, aberrant end plate architecture, and myofiber atrophy with signs of denervation. Furthermore, a neurofilament heavy subunit previously implicated in motor neuron degeneration is specifically up-regulated in miRNA-deficient SMNs. We demonstrate that the heavy neurofilament subunit is a target of miR-9, a miRNA that is specifically down-regulated in a genetic model of SMA. These data provide evidence for miRNA function in SMN diseases and emphasize the potential role of miR-9-based regulatory mechanisms in adult neurons and neurodegenerative states.

Extended-donor criteria liver allografts do not meet traditional criteria for transplantation. Although these organs offer immediate expansion of the donor pool, transplantation of extended-donor criteria liver allografts increases potential short- and long-term risk to the recipient. This risk may manifest as impaired allograft function or donor-transmitted disease. Guidelines defining this category of donor, level of acceptable risk, principles of consent, and post-transplantation surveillance have not been defined. This article reviews the utilization, ethical considerations, and outcomes of extended-donor criteria liver allografts.

Objective: The objective of this study was to evaluate the effect of systematic utilization of extended donor criteria liver allografts (EDC), including living donor allografts (LDLT), on patient access to liver transplantation (LTX)., Summary Background Data: Utilization of liver allografts that do not meet traditional donor criteria (EDC) offer immediate expansion of the donor pool. EDC are typically allocated by transplant center rather than regional wait-list priority (RA). This single-institution series compares outcomes of EDC and RA allocation to determine the impact of EDC utilization on donor use and patient access to LTX., Methods: The authors conducted a retrospective analysis of 99 EDC recipients (49 deceased donor, 50 LDLT) and 116 RA recipients from April 2001 through April 2004. Deceased-donor EDC included: age >65 years, donation after cardiac death, positive viral serology (hepatitis C, hepatitis B core antibody, human T-cell lymphotrophic), split-liver, hypernatremia, prior carcinoma, steatosis, and behavioral high-risk donors. Outcome variables included patient and graft survival, hospitalization, initial graft function, and complication categorized as: biliary, vascular, wound, and other., Results: EDC recipients were more frequently diagnosed with hepatitis C virus or hepatocellular carcinoma and had a lower model for end-stage liver disease (MELD) score at LTX (P < 0.01). Wait-time, technical complications, and hospitalization were comparable. Log-rank analysis of Kaplan-Meier survival estimates demonstrated no difference in patient or graft survival; however, deaths among deceased-donor EDC recipients were frequently the result of patient comorbidities, whereas LDLT and RA deaths resulted from graft failure (P < 0.01). EDC increased patient access to LTX by 77% and reduced pre-LTX mortality by over 50% compared with regional data (P < 0.01)., Conclusion: Systematic EDC utilization maximizes donor use, increases access to LTX, and significantly reduces wait-list mortality by providing satisfactory outcomes to select recipients.

No prior studies have shown that pre-operative loco-regional therapy for hepatocellular carcinoma (HCC) improves survival following orthotopic liver transplantation (OLT). We performed subgroup analyses according to pathologic HCC stage among 168 patients who underwent OLT to test the hypothesis that pre-operative loco-regional therapy confers a survival advantage in a subgroup at intermediate risk for HCC recurrence. Patients with pathologic T3 HCC meeting the proposed UCSF expanded criteria (single lesion not exceeding 6.5 cm or two to three lesions none > 4.5 cm with total tumor diameter within 8 cm) had a similar 5-year recurrence-free survival as patients with pathologic T2 HCC (88.5% vs. 93.8%; p = 0.56). In the subgroup with pathologic T2 or T3 HCC, the 5-year recurrence-free survival was 93.8% for the 85 patients who received pre-operative loco-regional therapy, versus 80.6% for the other 41 patients without treatment (p = 0.049). The treatment benefit, according to 5-year recurrence-free survival, appeared greater for pathologic T3 (85.9% vs. 51.4%; p = 0.05) than T2 HCC (96.4% versus 87.1%; p = 0.12). In conclusion, although the lack of a randomized controlled design precludes drawing firm conclusions, our results suggest that pre-operative loco-regional therapy may confer a survival benefit after OLT in the subgroup with pathologic T2 and T3 HCC.

The progressive shortage of liver donors has mandated investigation of living-donor transplantation (LDT). Concerns about increasing risk to the donor are evident, but the impact of the degree of parenchymal loss has not been quantified. We analyzed clinical and biological variables in 45 LDT performed by our team over 2years to assess risks faced in adult LDT. All donors are alive and well with complete follow-up through to February 2001. When the three operations were compared, right hepatectomy (RH) was significantly longer in terms of anesthesia time and blood loss compared with left hepatectomy (LH) and left lobectomy (LL). Donor remnant liver was significantly reduced after RH compared with LH and LL. There were significant functional differences as a consequence of the remnant size, measured by an increase in peak prothrombin time after RH. RH for adults represents a markedly different insult from pediatric donations in terms of parenchymal loss and early functional impairment. Left hepatectomy donation offers modest advantage over right lobes but seems to confer substantial technical risk for a small gain in graft size. Unless novel strategies are developed to enhance liver function of the LH graft in the adult recipient, right lobe donation will be necessary for adult LDT.

Although the carbonic anhydrase inhibitors have been used in the treatment of the primary periodic paralyses (PPs), their efficacy has not been demonstrated in double-blind, placebo-controlled trials. Therefore, we tested the efficacy of dichlorphenamide (DCP; Daranide), a potent carbonic anhydrase inhibitor, in the treatment of episodic weakness in the primary PPs. We performed two multicenter, randomized, double-blind, placebo-controlled crossover trials, one involving 42 subjects with hypokalemic periodic paralysis (HypoPP) and the other involving 31 subjects with potassium-sensitive periodic paralysis (PSPP). In each trial, two 8-week treatment periods were separated by an active washout period of at least 9 weeks. The primary outcome variable in the HypoPP trial was the occurrence of an intolerable increase in attack severity or frequency (end point). The primary outcome variable in the PSPP trial was the number of attacks per week. In the HypoPP trial, there were 13 subjects who exhibited a preference (in terms of the end point) for either DCP or placebo, and 11 of these preferred DCP. In the PSPP trial, DCP significantly reduced attack rates relative to placebo. DCP also significantly reduced attack rates relative to placebo in the HypoPP subjects. We conclude that DCP is effective in the prevention of episodic weakness in both HypoPP and PSPP.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that is inherited as an autosomal dominant trait in approximately 10% of cases. Recently we and others identified several single-base mutations in the Cu/Zn superoxide dismutase (SOD1) gene in patients with familial ALS (FALS). Using single-strand conformational polymorphism, we studied the C to G mutation in exon 2 of the SOD1 gene (resulting in a leucine to valine substitution in position 38) in affected and unaffected members of a large Belgian family with FALS. We measured the SOD1 activity in red blood cell lysates in 14 members of this family, including the only surviving clinically affected patient. SOD1 activity of the family members carrying the mutation was less than half that of members without the mutation. In addition, in 11 patients with sporadic ALS and 11 age- and sex-matched controls, red blood cell SOD1 activity was normal. These studies indicate that SOD1 activity is reduced in these FALS patients but not in sporadic ALS patients. Moreover, this SOD1 enzyme abnormality is detectable years before onset of clinical ALS in carriers of this FALS mutation.

We have developed a genetic linkage map of chromosome 21 using 17 microsatellite marker polymorphisms. The markers span virtually the entire length of 21q, and define a sex-equal map of 56 cM. Extensive error checking has been used to provide an accurate map. All recombination events have been identified, allowing us to place within a small interval any new markers by genotyping only a few critical individuals. The resulting segregation data has been examined for several meiotic phenomena, including sex differences in recombination, age differences in recombination, interference, and segregation distortion.