Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection.

BACKGROUND & AIMS: In the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia. METHODS: We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726, and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101, and followed for treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients, RBV serum levels were additionally measured during treatment. RESULTS: Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ≥3 g/dl during treatment, in genotype (relative risk (RR)=2.1, 95% CI 1.3-3.5) as well as allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as allelic analyses (RR=2.0, 95% CI 1.1-3.4). CONCLUSIONS: The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response, may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.

Overview of sleep management during COVID-19.

The sleep of millions has suffered during the global COVID-19 pandemic. Prevalence rates of 20-45% are reported globally for insomnia symptoms during the pandemic. Affected populations include the public and health care workers. A sleep deprived society faces the increased burden of COVID-related economic disruption, psychosocial problems, substance abuse, and suicide. Disordered sleep is not expected to disappear with control of infection, making interventions acutely necessary. The question becomes how to manage the sleep dysfunction during and after the pandemic. Depression and anxiety are prominent complaints during pandemic restrictions. Insomnia symptoms and fatigue continue even as mood improves in those who are in recovery from COVID-19 infection. Management of disturbed sleep and mental health is particularly needed in frontline health care workers. This overview describes 53 publications, as of February 2021, on disturbed sleep during the pandemic, treatment studies on COVID-related sleep disturbance, and need to rely on current treatment guidelines for common sleep disorders. The available research during the first year of COVID-19 has generally described symptoms of poor sleep rather than addressing treatment strategies. It covers digital cognitive behavioral therapy for insomnia (CBT-i) for the public and frontline workers, recognizing the need of greater acceptance and efficacy of controlled trials of CBT for affected groups. Recommendations based on a tiered public health model are discussed.

Rotigotine improves restless legs syndrome: a 6-month randomized, double-blind, placebo-controlled trial in the United States.

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome.

STUDY OBJECTIVE: To evaluate the efficacy and tolerability of XP13512/ GSK1838262, an investigational nondopaminergic agent for the treatment of moderate-to-severe primary restless legs syndrome (RLS). DESIGN: Randomized, double-blind, placebo-controlled, crossover trial. SETTING: Nine US clinical sites. PATIENTS: Thirty-eight treatment-naive subjects with RLS (mean +/- SD age 50.1 +/- 13.2 years). INTERVENTIONS: XP13512 1800 mg/day followed by placebo or placebo followed by XP13512 1800 mg/day for 14 days, with a 7-day washout between treatment periods. MEASUREMENTS AND RESULTS: The primary endpoint was mean change from baseline International RLS Study Group rating scale (IRLS) total score on Day 14, analyzed using analysis of variance with sequence, period, and treatment as fixed effects and subjects within sequence as a random effect. XP13512 significantly reduced IRLS total score on Day 14 compared with placebo (mean +/- SD: XP13512 -12.1 +/-6.5, placebo -1.9 +/- 6.3; P < 0.0001). Polysomnographic data showed that XP13512 significantly improved sleep architecture on Day 14 compared with placebo (mean +/- SD change from baseline sleep time [minutes]: stage 1: XP13512 -9.8 +/- 23.9, placebo 0.4 +/-23.2; adjusted P<0.0054, nominal P<0.0001; stage 3/4 (slow-wave sleep): XP13512 22.8 +/- 40.8, placebo 1.4 +/- 34.3; adjusted P=0.0092, nominal P=0.0002). The most frequently reported adverse events were somnolence (XP13512 30.6%, placebo 2.8%) and dizziness (XP13512 27.8%, placebo 5.6%). CONCLUSIONS: XP13512 1800 mg/day significantly reduced RLS symptoms, improved sleep, and was generally well tolerated in subjects with moderate-to-severe primary RLS across 14 days of treatment.

Validation of the self-administered version of the international Restless Legs Syndrome study group severity rating scale - The sIRLS.

INTRODUCTION: The International Restless Legs Study Group (IRLSSG) has developed the IRLS (International Restless Legs Syndrome Severity Scale) and validated it as a clinician/researcher administered scale to be used when both patient and examiner are present. The IRLSSG recognized the need for a self-completing scale that can be used economically in clinical practice and in large population-based studies. In this study the validity and the reliability of the IRLS as a self-administered scale (sIRLS) is assessed. METHODS: Established RLS patients were recruited by eight centers in four countries and consented to participate in this study. The validity of the sIRLS was assessed by patients completing the sIRLS before a clinician administered the IRLS. The reliability of the sIRLS was assessed by patients completing the sIRLS again, two weeks after the first one, provided no change had occurred. RESULTS: Overall, 173 patients were recruited and 164 of them were included in the analyses. The sIRLS showed satisfactory scaling assumptions and no relevant floor or ceiling effect. One factor explained 61.3% of the variance. Cronbach's alpha was 0.93 and the item homogeneity index was 0.59. Intraclass correlation coefficient between the sIRLS and the IRLS was 0.94. The sIRLS standard error of measurement was 3.61 (½ SD at baseline = 4.11). The results mostly overlapped those of the IRLS analyzed in parallel. DISCUSSION: The sIRLS is a reliable, valid and precise instrument that showed tight association with the IRLS. These findings support the use of the sIRLS for self-evaluation of RLS severity. The responses obtained on the sIRLS and the IRLS scale varied slightly. Therefore, we recommend that either the sIRLS or the IRLS scale be used as the only scale for serial measures over time.

The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome.

Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.

Identifying clinically important difference on the Epworth Sleepiness Scale: results from a narcolepsy clinical trial of JZP-110.

BACKGROUND: While scores ≤10 on the Epworth Sleepiness Scale (ESS) are within the normal range, the reduction in elevated ESS score that is clinically meaningful in patients with narcolepsy has not been established. METHODS: This post hoc analysis of a clinical trial of patients with narcolepsy evaluated correlations between Patient Global Impression of Change (PGI-C) and ESS. Data of adult patients with narcolepsy from a double-blind, 12-week placebo-controlled study of JZP-110, a wake-promoting agent, were used in this analysis. Descriptive statistics and receiver operating characteristic (ROC) analysis compared PGI-C (anchor measure) to percent change from baseline in ESS to establish the responder criterion from patients taking either placebo or JZP-110 (treatments). RESULTS: At week 12, patients (n = 10) who reported being "very much improved" on the PGI-C had a mean 76.7% reduction in ESS score, and patients (n = 33) who reported being "much improved" on the PGI-C had a mean 49.1% reduction in ESS score. ROC analysis showed that patients who improved were almost exclusively from JZP-110 treatment group, with an area-under-the-curve of 0.9, and revealed that a 25% reduction in ESS (sensitivity, 81.4%; specificity, 80.9%) may be an appropriate threshold for defining a meaningful patient response to JZP-110 and placebo. CONCLUSIONS: A ≥25% reduction in patients' subjective ESS score may be useful as a threshold to identify patients with narcolepsy who respond to JZP-110 treatment.

miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3'UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

Insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation.

When patients report problems sleeping, a psychiatrist must determine their significance based on frequency, duration, and daytime impairment. Because up to 50% of adults report sleep problems in any year, it is necessary to define when insomnia becomes long-standing, severe, and a complication to daytime function. Psychiatrists must determine if a sleep disturbance reduces mood, motor performance, or cognitive function. If insomnia syndrome is present, major depression, dysthymia, and anxiety disorders commonly are comorbid. To assist in evaluating insomnia, psychiatrists are urged to use the 6 Ps + M of insomnia model to conceptualize the characteristics of the insomnia and coordinate therapeutic intervention.

Pharmacologic and nonpharmacologic treatments of insomnia.

Insomnia in its chronic form is present in high numbers of patients presenting to physicians. As older women who have medical problems have the highest rates of chronic insomnia, physicians must have a high index of suspicion and be prepared to explore various etiologic factors that might be operative. Treatment should focus on setting specific goals, with patients using strategies that combine lifestyle changes, behavioral interventions, and appropriate medications. OTC agents, sedating antidepressants at low dosages (trazodone, doxepin, amitriptyline, and others), and nonhypnotic benzodiazepines are insufficiently studied to provide evidence-based support for their use to treat chronic insomnia. Particularly in the elderly, close monitoring is needed to prevent falls, accidents, and cognitive impairment from these agents. FDA-labeled hypnotic agents are efficacious, but long-term studies have not been available until the recent release of eszopiclone in the United States. Recent work encourages the use of CBT even in patients who have used sleeping pills for several years, although the success of CBT has been less encouraging when applied to chronic insomnia sufferers who have concurrent psychiatric disorders and who have taken hypnotics for years.

Hypnosis in the Management of Sleep Disorders.

Hypnosis has been used to manage insomnia and disorders of arousal. The alteration in the state of consciousness produced during hypnotic trance is more similar to relaxed reverie than sleep. Hypnosis typically occurs in a state of repose and the accomplished subject may have no recollection of the experience during a trance, 2 commonalities with sleep. Because hypnosis allows for relaxation, increased suggestibility, posthypnotic suggestion, imagery rehearsal, access to preconscious cognitions and emotions, and cognitive restructuring, disorders of sleep such as the insomnias, parasomnias, and related mood or anxiety disorders can be amenable to this therapeutic intervention.

Diagnosis of Restless Leg Syndrome (Willis-Ekbom Disease).

Restless leg syndrome, or Willis-Ekbom disease, is a neurosensorimotor disorder with significant impact that is diagnosed through 5 clinical criteria. Adherence to 5 criteria and a thorough physical examination are often sufficient for diagnosis. Associated features prove helpful in young children or the cognitively impaired. Polysomnography is not routinely required unless the patient has other sleep-related symptoms. The finding of periodic leg movements in sleep only suggests, instead of confirms, the diagnosis. It is important to arrive at appropriate diagnosis because the prevalence is in the millions and treatment significantly improves sleep quality and daytime function.

Non-Benzodiazepine Receptor Agonists for Insomnia.

Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events.

Performance of Serum microRNAs -122, -192 and -21 as Biomarkers in Patients with Non-Alcoholic Steatohepatitis.

OBJECTIVES: Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers. METHODS: Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH. RESULTS: The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91%) and specificity (83%). CONCLUSIONS: Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.

Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome.

STUDY OBJECTIVES: Polysomnographic study evaluating the efficacy of ropinirole for the treatment of patients with restless legs syndrome (RLS) suffering from periodic leg movements in sleep (PLMS). DESIGN: Double-blinded, placebo-controlled, parallel-group study. SETTING: 15 tertiary referral centers in the USA. PARTICIPANTS: 65 patients with RLS and PLMS. INTERVENTIONS: Ropinirole (0.25-4.0 mg per day) or placebo for 12 weeks. MEASUREMENTS AND RESULTS: Data from 59 patients were included in the primary endpoint analysis. PLMS per hour decreased more with ropinirole (48.5 to 11.8), compared with placebo (35.7 to 34.2; adjusted treatment difference: -27.2; 95% confidence interval [CI]: -39.1, -15.4; P < .0001). Periodic limb movements with arousal per hour decreased from 7.0 to 2.5 with ropinirole but increased from 4.2 to 6.0 with placebo (adjusted treatment difference: -4.3, 95% CI: -7.6, -1.1; P = .0096). Periodic limb movements while awake per hour decreased from 56.5 to 23.6 with ropinirole but increased from 46.6 to 56.1 with placebo (adjusted treatment difference: -39.5; 95% CI: -56.9, -22.1; P < .0001). Ropinirole treatment significantly improved patients' ability to initiate sleep (P < .05) and the amount of Stage 2 sleep compared with placebo (P < .001). There were also non-significant trends toward increases in total sleep time and sleep efficiency. Sleep adequacy (measured on the subjective Medical Outcomes Study sleep scale) was significantly improved with ropinirole treatment (adjusted treatment difference: 12.1; 95% CI: 1.1, 23.1; P = .0316). In contrast, the placebo group showed a greater increase in Stage 3/4 sleep (P < .01). No serious adverse events occurred in either group. CONCLUSIONS: Ropinirole is effective in the treatment of both the sleep and waking symptoms of RLS.

Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy.

INTRODUCTION: In addition to excessive sleepiness, patients with narcolepsy often have significant fatigue, depressed mood, and decreased quality of life. OBJECTIVE: To determine whether treatment with modafinil for excessive sleepiness improves fatigue, mood, and health-related quality of life (HRQOL) in patients with narcolepsy. MATERIALS AND METHODS: Outpatients with narcolepsy underwent a 14-day washout of psychostimulants and then were enrolled in this 6-week, open-label, multicenter study. Patients received modafinil starting at 200 mg once daily for week 1, and then 200 or 400 mg daily for weeks 2 through 6. Efficacy was evaluated using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS). Safety was assessed by monitoring adverse events (AE). RESULTS: At baseline, 151 patients had moderate to severe excessive sleepiness (mean Epworth Sleepiness Scale score=17.8+/-4.4). Most patients (> or =70% of 123 who completed the study) received 400 mg modafinil once daily during weeks 2 through 6. Modafinil significantly improved HRQOL, based on SF-36 measures of mental and physical component summary scores and subdomain scores of role-physical, social functioning, and vitality (each P<0.001). Modafinil treatment was also associated with significantly reduced fatigue and significantly improved vigor and cognition as assessed by the POMS (each P<0.001) from weeks 1 through 6. The most frequent AE with modafinil treatment were headache, nausea, and insomnia; most AE were mild or moderate in nature. Only seven patients (5%) withdrew from the study because of AE. CONCLUSION: In narcolepsy patients who were switched from psychostimulants, modafinil therapy improved HRQOL and subjective feelings of vigor and cognitive functioning and reduced fatigue.