Among patients with lumbar spinal stenosis, with or without degenerative spondylolisthesis, decompression surgery plus fusion surgery did not result in better clinical outcomes at 2 years and 5 years than did decompression surgery alone. (Funded by an Uppsala institutional Avtal om Läkarutbildning och Forskning [Agreement concerning Cooperation on Medical Education and Research] and others; Swedish Spinal Stenosis Study ClinicalTrials.gov number, NCT01994512.).

In patients with Parkinson's disease, the therapeutic efficacy of L-DOPA medication is gradually lost over time, and abnormal involuntary movements, dyskinesias, gradually emerge as a prominent side-effect in response to previously beneficial doses of the drug. Here we show that dyskinesia induced by chronic L-DOPA treatment in rats with 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway is critically dependent on the integrity and function of the serotonergic system. Removal of the serotonin afferents, or dampening of serotonin neuron activity by 5-HT1A and 5-HT1B agonist drugs, resulted in a near-complete block of the L-DOPA-induced dyskinesias, suggesting that dysregulated dopamine release from serotonin terminals is the prime trigger of dyskinesia in the rat Parkinson's disease model. In animals with complete dopamine lesions, the spared serotonin innervation was unable to sustain the therapeutic effect of L-DOPA, suggesting that dopamine released as a 'false transmitter' from serotonin terminals is detrimental rather than beneficial. The potent synergistic effect of low doses of 5-HT1A and 5-HT1B agonists to suppress dyskinesia, without affecting the anti-parkinsonian effect of L-DOPA in presence of spared dopamine terminals, suggests an early use of these drugs to counteract the development of dyskinesia in Parkinson's disease patients.

The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT(1A) and 5-HT(1B) agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT(1A) and 5-HT(1B) agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT(1A) and 5-HT(1B) agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT(1) agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT(1A) and 5-HT(1B) agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.

BaCKgRoUND aND aIMS: Hepatitis delta virus (HDV) infection is associated with fast progression to liver cirrhosis and liver complications. Previous studies have, however, been mainly from tertiary care centers, with risk for referral bias toward patients with worse outcomes. Furthermore, the impact of HDV viremia per se on liver-related outcomes is not really known outside the human immunodeficiency virus co-infection setting. We have therefore evaluated the long-term impact of HDV viremia on liver-related outcomes in a nationwide cohort of patients with hepatitis B and D co-infection, cared for at secondary care centers in Sweden. appRoaCH aND ReSUltS: In total, 337 patients with anti-HDV positivity, including 233 patients with HDV RNA viremia and 91 without HDV viremia at baseline, were retrospectively studied, with a mean follow-up of 6.5 years (range, 0.5-33.1). The long-term risks for liver-related events (i.e., hepatocellular carcinoma [HCC], hepatic decompensation, or liver-related death/transplantation) were assessed, using Cox regression analysis. The risk for liver-related events and HCC was 3.8-fold and 2.6-fold higher, respectively, in patients with HDV viremia compared with those without viremia, although the latter was not statistically significant. Among patients with HDV viremia with no baseline cirrhosis, the cumulative risk of being free of liver cirrhosis or liver-related events was 81.9% and 64.0% after 5 and 10 years of follow-up, respectively. This corresponds to an incidence rate of 0.04 cases per person-year. CoNClUSIoNS: HDV RNA viremia is associated with a 3.8-fold higher risk for liver-related outcomes. The prognosis was rather poor for patients with HDV viremia without cirrhosis at baseline, but it was nevertheless more benign than previous estimates from tertiary centers. Our findings may be of importance when making decisions about treatment and evaluating potential outcomes of upcoming antivirals against HDV. (Hepatology 2020;72:1177-1190). H epatitis delta virus (HDV) is considered to cause the most severe form of chronic viral hepatitis, with fast progression to liver cirrhosis and liver complications. (1,2) Previous studies evaluating the natural course of HDV infection have, however, been mainly from tertiary centers, with risk for referral bias toward patients with worse outcomes. (3-7) Published data on the rate of liver disease progression in patients with HDV viremia without cirrhosis are scarce, and knowledge of the outcomes in an unbiased population is lacking.

Clinical trials in patients with

Therapeutic Level I.

Standard therapy for chronic hepatitis C (HCV) is pegylated interferon in combination with ribavirin. There is limited experience with either drug in dialysis [end stage renal disease (ESRD)]. Six haemodialysis patients, four with HCV genotype 1, one with genotype 4 and one genotype 2 were treated with pegylated interferon-alfa-2b (n = 4) and pegylated interferon-alfa-2a (n = 2) for 24-48 weeks according to genotype with a dose of 50 or 135 mug/week respectively. All patients were given reduced ribavirin doses, initially 200-400 mg/day. Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies, aiming at a target concentration of 10-15 micromol/L. Interferon related side-effects were common, in one patient peg-alfa-2b was permanently reduced to 50 mug every 9-10 days with improvement in tolerance. Average ribavirin dose was 170-300 mg/day. Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood-transfusions were not needed. All patients became HCV-RNA-PCR negative during treatment which was completed or nearly completed in four patients. One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infarction probably not related to therapy. Three patients have remained HCV-RNA negative with extended follow-up, two of whom have had a successful kidney transplant. Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However the pharmacokinetics and tolerability of both peg-alfa-2a and 2b need to be studied more closely in prospective studies before definite dosing recommendations can be made.