Enhanced tactile identification of musical emotion in the deaf.

Functional neuroimaging studies have demonstrated that following deafness, auditory regions can respond to tactile stimuli. However, research to date has not conclusively demonstrated the behavioral correlates of these functional changes, with most studies showing normal-like tactile capabilities in the deaf. It has recently been suggested that more cognitive and complex tactile processes, such as music perception, could help to uncover superior tactile capabilities in the deaf. Indeed, following deafness music seems to be perceived through vibration, but the extent to which they can perceive musical features though the tactile modality remains undetermined. The goal of this study was to investigate tactile identification of musical emotion in the deaf. Participants had to rate melodies based on their emotional perception. Stimuli were presented through an haptic glove. Data suggest that deaf and control participants were comparable in the identification of three of the four emotions tested (sad, fear/threat, peacefulness). However and most importantly, for the simplest emotion (happiness), significant differences emerged between groups, suggesting an improved tactile identification of musical emotion in the deaf. Results support the hypothesis that brain plasticity following deafness can lead to improved complex tactile ability.

Audiomotor interaction induced by mental imagery.

Mental imagery can induce audiovisual integration, but whether it can induce interactions in other modalities remains uncertain. It has been demonstrated that audiomotor interaction can be generated following training, but whether such audiomotor interaction can be induced by auditory imagery training remains unknown. The present study aims at determining whether auditory mental imagery could induce a multimodal association with postural control. We examined static postural control in the presence of a frequency-modulated sound in three groups of participants, prior to and following a short period of training designed to create an association between auditory mental imagery of sounds and postural swaying. Results suggest that mental imagery impacted performance, as a significant decrease in postural control was observed in the experimental group following mental imagery training. Results of the control groups confirmed that the effect of mental imagery was not due to response bias, but to a significant multimodal interaction following training. These findings are in accordance with previous studies suggesting that mental imagery stimuli can interact with perceptual stimuli of a different sensory modality and lead to multisensory integration. The results also confirm that audiomotor interaction can be generated a mental imagery training. However, the full extent of mental imagery influence on multimodal interaction remains to be determined.

Real-world effectiveness for 12 weeks of ledipasvir-sofosbuvir for genotype 1 hepatitis C: the Trio Health study.

Early data regarding the "real-world" experience with novel therapies for hepatitis C (HCV) are encouraging. Data are still limited, however, regarding real-world rates of sustained virologic response (SVR) for ledipasvir-sofosbuvir (LDV-SOF), particularly for patients with prior treatment failure. We performed a retrospective cohort study of 1597 patients with chronic genotype 1 HCV who were treated using 12 weeks of the following regimens LDV-SOF±ribavirin (RBV) (n=1521 without RBV, n=76 with RBV). The primary outcome was SVR-determined at 12 weeks in an intention-to-treat design. Prescription according to Food and Drug Administration (FDA) approved labelling (adding RBV for patients with cirrhosis and treatment failure) was assessed in multivariate models. The study population was aged 60 years on average (range 19-89), 60% male, 50% Caucasian, 43% cared for at an academic centre and 30% cirrhotic. Overall, LDV-SOF resulted in a 94% SVR rate. Only 44 (2.9%) patients relapsed. LDV-SOF+RBV yielded SVR in 97% with 0 viral relapses. While cirrhosis and thrombocytopenia were associated with lower odds of SVR, in a multivariable regression model, only treatment at an academic centre and prescriptions contrary to FDA labelling were significantly associated with lower SVR-odds ratios, 0.56 95% CI (0.35-0.87) and 0.29 95% CI(0.12-0.68), respectively. The real-world experience with LDV-SOF mirrors the SVR rates observed in clinical trials. Efforts to promote prescription within FDA recommendations are warranted.

Disparate access to treatment regimens in chronic hepatitis C patients: data from the TRIO network.

Despite the clinical success in the real-world of all oral hepatitis C virus (HCV) therapy with response rates approaching that seen in the clinical trials, access has been limited by many payers with discussion of prioritization of treatment based upon AASLD guidelines. We evaluated patients in the TRIO network who were prescribed sofosbuvir (SOF)-based regimens to determine reasons for not starting treatment. Trio Health is a disease management company that works in partnership with academic medical centres, community physicians and specialty pharmacies in the United States to optimize care for HCV. Data for 3841 patients prescribed a sofosbuvir-containing regimen between December 2013 and September 2014 were obtained through this programme. Of the entire group, 315 (8%) patients did not start the prescribed sofosbuvir-containing therapy. A total of 141 (45%) of the nonstart patients had a commercial plan as their primary insurance, 137 (44%) were primarily covered by Medicaid, 17 (5%) were primarily covered by Medicare, and 20 (6%) were either without coverage or coverage was not specified. Reasons for nonstarts were varied and overlapping. Only 15 patients (5% of nonstarts) did not start because they were unreachable or failed to complete required testing. Another 39 patients who did not start (12%) were following their physicians' direction to either wait for new treatment options or to hold treatment for an unspecified reason. Insurance-related processes and financial reasons accounted for 254 (81%) of the 315 nonstarts. The remaining 7 (2%) patients did not have a specified reason for not starting treatment. Nonstart rates were highest in the Medicaid-covered population at 35%. Medicare and Commercial nonstart rates were 2% and 6%, respectively. In a matched comparison, patients with commercial coverage were 6.5 times as likely to start SOF-based therapy compared to patients with Medicaid. Despite high SVR rates of SOF-based regimens in clinical practice, there are still barriers to access to care. In fact, almost half of the nonstart patients had advanced fibrosis scores (F3 or F4) and should have been prioritized to start treatment. As better treatment for HCV with high efficacy and low side effect rates become available, the disparity in access to treatment, as evidenced by the high nonstart rate in the Medicaid-covered group, must be resolved.

Hearing Aid Amplification Improves Postural Control for Older Adults With Hearing Loss When Other Sensory Cues Are Impoverished.

Recent studies suggest that sound amplification via hearing aids can improve postural control in adults with hearing impairments. Unfortunately, only a few studies used well-defined posturography measures to assess balance in adults with hearing loss with and without their hearing aids. Of these, only two examined postural control specifically in the elderly with hearing loss. The present study examined the impact of hearing aid use on postural control during various sensory perturbations in older adults with age-related hearing loss. Thirty individuals with age-related hearing impairments and using hearing aids bilaterally were tested. Participants were asked to perform a modified clinical sensory integration in balance test on a force platform with and without hearing aids. The experiment was conducted in the presence of a broadband noise ranging from 0.1 to 4 kHz presented through a loudspeaker. As expected, hearing aid use had a beneficial impact on postural control, but only when visual and somatosensory inputs were both reduced. Data also suggest that hearing aid use decreases the dependence on somatosensory input for maintaining postural control. This finding can be of particular importance in older adults considering the reduction of tactile and proprioceptive sensitivity and acuity often associated with aging. These results provide an additional argument for encouraging early hearing aid fitting for people with hearing loss.

Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin.

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN α-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.

Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes.

We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 × 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 × 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 × 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC.

Functional reorganization of the auditory pathways following late callosotomy.

Injuries at various levels of the auditory system have been shown to lead to functional reorganization of the auditory pathways. In particular, it has recently been shown that such reorganization can occur in callosal agenesis. The pattern of cortical activity following callosotomy is however still unknown, but behavioral results suggest that it could be significantly different from that observed in callosal agenesis. We aimed to confirm this hypothesis by investigating fMRI responses to complex sounds presented binaurally and monaurally in a callosotomized patient. In the binaural condition, the callosotomized subject showed patterns of auditory cortical activation that were similar to those of neurologically intact individuals. However, in both monaural conditions, the callosotomized individual showed a significant increase of the asymmetries favoring the contralateral pathways. Such patterns of cortical responses are only partially consistent with the results obtained from callosal agenesis subjects using the exact same procedure. Indeed, the latter show differences compared with normals in both binaural and monaural conditions. These findings provide neurological evidence that callosotomy could lead to distinctive functional reorganization of the human auditory pathways.

Vestibular status: A missing factor in our understanding of brain reorganization in deaf individuals.

The brain of deaf people is definitely not just deaf, and we have to reconsider what we know about the impact of hearing loss on brain development in light of comorbid vestibular impairments.

Functional reorganization of the human auditory pathways following hemispherectomy: an fMRI demonstration.

The present study investigated the functional reorganization of ipsilateral and contralateral auditory pathways in hemispherectomized subjects. Functional reorganization was assessed using functional Magnetic Resonance Imaging (fMRI) and stimulation with complex sounds presented binaurally and monaurally. For neurologically intact control subjects, results showed that binaural stimulations evoked balanced activity in both hemispheres while monaural stimulations induced strong contralateral activity and weak ipsilateral activity. The results obtained from hemispherectomized subjects were substantially different from those obtained from control subjects. Specifically, activity in the intact hemisphere showed a significant decrease in response to contralateral stimulation but, concomitantly, an increase in response to ipsilateral stimulation. The present findings suggest that a substantial functional reorganization takes place in the auditory pathways following an early hemispherectomy. The exact nature of this functional reorganization remains to be specified.

Alternative mode of presentation of Kanizsa figures sheds new light on the chronometry of the mechanisms underlying the perception of illusory figures.

The mechanisms responsible for the perception of illusory modal figures are usually studied by presenting entire Kanizsa figures at stimulus onset. However, with this mode of presentation, the brain activity generated by the inducers (the 'pacmen') is difficult to differentiate from the activity underlying the perception of the illusory figure. Therefore, in addition to this usual presentation mode, we used an alternative presentation mode. Inducer disks remained permanently on the screen and the illusory figure was induced by just removing the notches from the disks. The results support the heuristic value of this alternative mode of presentation. The P1 deflection of the visual evoked potentials (VEPs) was found to be greater for the illusory modal figure than for its control and for an amodal figure. This modulation is one of the earliest direct evidences for a low-level processing of illusory forms in the human brain. Meanwhile, larger N1s were obtained for the control figures than for the illusory figures in the notch mode of presentation. While this new type of N1 modulation could shed some light on the stage of processing indexed by this deflection, several propositions are put forward to account for the P1 and N1 variations found.

Receptive field properties and sensitivity to edges defined by motion in the postero-lateral lateral suprasylvian (PLLS) area of the cat.

The present study investigated the spatial properties of cells in the postero-lateral lateral suprasylvian (PLLS) area of the cat and assessed their sensitivity to edges defined by motion. A total of one hundred and seventeen (117) single units were isolated. First, drifting sinusoidal gratings were used to assess the spatial properties of the cells' receptive fields and to determine their spatial frequency tuning functions. Second, random-dot kinematograms were used to create illusory edges by drifting textured stimuli (i.e. a horizontal bar) against a similarly textured but static background. Almost all the cells recorded in PLLS (96.0%) were binocular, and a substantial majority of receptive fields (79.2%) were end-stopped. Most units (81.0%) had band-pass spatial frequency tuning functions and responded optimally to low spatial frequencies (mean spatial frequency: 0.08 c./degree). The remaining units (19.0%) were low-pass. All the recorded cells responded vigorously to edges defined by motion. The vast majority (96.0%) of cells responded optimally to large texture elements; approximately half the cells (57.3%) also responded to finer texture elements. Moreover, 38.5% of the cells were selective to the width of the bar (i.e., the distance between the leading and the trailing edges). Finally, some (9.0%) cells responded in a transient fashion to leading and to trailing edges. In conclusion, cells in the PLLS area are low spatial frequency analyzers that are sensitive to texture and to the distance between edges defined by motion.

Real-world use of elbasvir-grazoprevir in patients with chronic hepatitis C: retrospective analyses from the TRIO network.

BACKGROUND: Elbasvir-grazoprevir is indicated for chronic hepatitis C virus (HCV) genotypes 1 and 4. AIM: To evaluate the utilization and outcomes of chronic HCV patients treated with elbasvir-grazoprevir in the United States. METHODS: We conducted a retrospective cohort study of adults treated with elbasvir-grazoprevir with or without ribavirin for chronic HCV genotypes 1 or 4 infection. Data were collected from healthcare providers and specialty pharmacies through Innervation Platform, a proprietary, cloud-based disease management program from Trio Health. The primary endpoint was per protocol sustained virological response 12 weeks post-treatment (SVR12). RESULTS: Among 470 patients treated in 2016, 95% had HCV genotype 1 infection, 80% (373/468) were HCV treatment naïve and 70% (327/468) had non-cirrhotic disease. Almost 3 quarters (73%) of patients received care in community practices. The majority (89%) of patients received elbasvir-grazoprevir for 12 weeks. Per protocol SVR12 rates were 99% (396/402) for HCV genotype 1 and 95% (21/22) for HCV genotype 4. Among patients with Stage 4 or 5 chronic kidney diseases, 99% (113/114) achieved SVR12. In univariate analyses, variables significantly associated with per protocol SVR12 for the entire sample were therapy duration (P = 0.001), treatment experience (P = 0.016), and cirrhosis status (P = 0.001). However, among HCV genotype 1 patients, no variables were significant. Intent-to-treat SVR12 rates were 89% (396/447) for HCV genotype 1 and 91% (21/23) for HCV genotype 4. CONCLUSION: Elbasvir-grazoprevir is highly effective, and in this 2016 cohort, its use was predominantly in patients with HCV genotype 1 and as a 12-week therapy without ribavirin.

Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes.

Hepatic iron overload causes lipocyte activation with resultant fibrogenesis. This study examines whether rat lipocytes express ferritin receptors, which could be involved in paracellular iron movement and in cellular regulation. Lipocytes from normal rat liver were cultured on plastic and incubated with 125I-labeled rat liver ferritin (RLF) +/- a 100-fold excess of either unlabeled RLF or human heart ferritin, human liver ferritin, human recombinant H-ferritin, a mutant human recombinant L-ferritin, or a variety of nonspecific proteins. Specific binding sites for ferritin were demonstrated by displacement of 125I-RLF by RLF (64.5 +/- 4.3%) and by other ferritins (55-60%), but not by recombinant L-ferritin. Scatchard analysis demonstrated a single class of binding sites with a Kd of 5.1 +/- 2.9 x 10(-10) M, maximum binding capacity of 4.7 +/- 1.3 x 10(-12) M, and 5,000-10,000 receptor sites/cell. Ferritin receptor expression was observed only in activated lipocytes. Internalization of RLF was observed within 15 min using FITC-RLF and confocal microscopy. This study demonstrates that (a) activated lipocytes express a specific high affinity ferritin receptor; (b) the binding appears to be dependent on the H-ferritin subunit; and (c) lipocytes internalize ferritin. Expression of ferritin receptors in activated lipocytes suggests that the receptor may either be involved in the activation cascade or may be a marker of activation.

Hepatic lipid peroxidation in vivo in rats with chronic iron overload.

Peroxidative decomposition of cellular membrane lipids is a postulated mechanism of hepatocellular injury in parenchymal iron overload. In the present study, we looked for direct evidence of lipid peroxidation in vivo (as measured by lipid-conjugated diene formation in hepatic organelle membranes) from rats with experimental chronic iron overload. Both parenteral ferric nitrilotriacetate (FeNTA) administration and dietary supplementation with carbonyl iron were used to produce chronic iron overload. Biochemical and histologic evaluation of liver tissue confirmed moderate increases in hepatic storage iron. FeNTA administration produced excessive iron deposition throughout the hepatic lobule in both hepatocytes and Kupffer cells, whereas dietary carbonyl iron supplementation produced greater hepatic iron overload in a periportal distribution with iron deposition predominantly in hepatocytes. Evidence for mitochondrial lipid peroxidation in vivo was demonstrated at all three mean hepatic iron concentrations studied (1,197, 3,231, and 4,216 micrograms Fe/g) in both models of experimental chronic iron overload. In contrast, increased conjugated diene formation was detected in microsomal lipids only at the higher liver iron concentration (4,161 micrograms Fe/g) achieved by dietary carbonyl iron supplementation. When iron as either FeNTA or ferritin was added in vitro to normal liver homogenates before lipid extraction, no conjugated diene formation was observed. We conclude that the presence of conjugated dienes in the subcellular fractions of rat liver provide direct evidence of iron-induced hepatic mitochondrial and microsomal lipid peroxidation in vivo in two models of experimental chronic iron overload.

Effectiveness of 8- or 12-weeks of ledipasvir and sofosbuvir in real-world treatment-naïve, genotype 1 hepatitis C infected patients.

BACKGROUND: Treatment of genotype 1 hepatitis C virus (HCV) infection with combination direct acting anti-virals is associated with very high rates of sustained virological response (SVR). Daily combination of ledipasvir and sofosbuvir for 12 weeks is approved for the treatment of genotype 1 HCV patients, though noncirrhotic patients who are naïve to treatment with a baseline HCV RNA <6 million IU/mL can be treated for 8 weeks. This guidance stemmed from a post hoc analysis of the ION 3 clinical trial, which demonstrated similar SVR for patients treated with ledipasvir and sofosbuvir with or without ribavirin for 8 or 12 weeks. AIM: To compare the SVR for 8 weeks vs 12 weeks of ledipasvir and sofosbuvir in HCV infected patients in a real-world setting. METHODS: We performed an observational real-world cohort study of treatment success following 8 or 12 weeks of ledipasvir and sofosbuvir for treatment-naïve genotype 1 HCV patients. RESULTS: A total of 826 patients were treated for either 8 (n=252) or 12 weeks (n=574) with ledipasvir and sofosbuvir and achieved SVR rate of 95.3% and there was no statistical difference in SVR rates in the two groups irrespective of any clinical or virological variables. CONCLUSIONS: In treatment-naïve HCV genotype 1 patients, SVR was 95% in those treated for either 8 weeks or 12 weeks with ledipasvir and sofosbuvir. 8 week ledipasvir and sofosbuvir can reduce costs without compromising outcomes for those patients who qualify for such regimen.

Azathioprine-induced pancytopenia. Occurrence in two patients with connective-tissue diseases.

Two patients became severely pancytopenic while receiving azathioprine in low dosages for treatment of connective-tissue diseases. While mild hematologic complications are common with this drug, we believe that the degree of bone marrow suppression exhibited in these two patients is unusual, especially at the dosages (0.75 and 1.25 mg/kg/day) of azathioprine being used.

Renal artery stenosis with erythrocytosis after renal transplantation.

We present here results of studies on four patients (three men, one woman) who had had cadaver renal transplants and in whom renal artery stenosis and hypertension developed. Erythropoietin-dependent erythrocytosis developed in association with these changes in the three men. All patients had stable renal function and the hypertension was well controlled. Absolute erythrocytosis thought to be secondary to local renal hypoxia due to decreased renal blood flow developed in two of the men. Erythrocytosis developed in the other man but his RBC mass was at the upper limit of normal. In these patients, we suspect that the erythropoietin-dependent erythrocytosis is secondary to intrarenal hypoxia due to renal artery stenosis. Erythrocytosis or elevated erythropoietin levels failed to develop in the woman despite severe renal artery stenosis. Possible reasons for this discrepancy are discussed.

Available options for treatment of interferon nonresponders.

In the great majority of patients, hepatitis C virus (HCV) infection is not self-limiting. Approximately 70% to 85% of patients exposed to HCV will go on to develop chronic hepatitis. Among those who undergo treatment with interferon alpha, only 15% to 20% can be expected to respond to a 12- to 18-month course of therapy. With the addition of ribavirin to interferon monotherapy, the likelihood of sustained response (defined as normal alanine aminotransferase levels and negative HCV RNA persisting 6 months after the end of therapy) increases to approximately 40%. The fact remains, however, that there is still a substantial proportion of patients who will fail to respond to treatment. Without viral eradication, cirrhosis and hepatocellular carcinoma persist as long-term risks. Several options are available for the treatment of patients who fail to respond to interferon monotherapy. These include interferon dose escalation, whether by administering higher doses or administering them more frequently; changing to a different form of interferon; retreatment with a combination of interferon and ribavirin; adjunctive therapies, of which the best studied is phlebotomy to decrease hepatic iron stores; use of long-term, low-dose "maintenance"-type therapy; and watchful waiting with frequent follow-up. In the absence of long-term, large-scale clinical trials to support these modalities, physicians must exercise their best clinical judgment and individualize treatment to suit the patient's condition, needs, and preferences.