Combining treatment for chronic hepatitis C with opioid agonist therapy is an effective microelimination strategy for people who inject drugs with high risk of non-adherence to direct-acting antiviral therapy.

Background & aims: Despite effective direct-acting antivirals (DAAs), hepatitis C virus (HCV) prevalence is high among people who inject drugs (PWIDs) and non-adherence to therapy remains a major obstacle towards HCV elimination in this subpopulation. To overcome this issue, we have combined ongoing opioid agonist therapy (OAT) with DAAs in a directly-observed therapy (DOT) setting. Method: From September 2014 until January 2021 PWIDs at high risk of non-adherence to DAA therapy, who were also on OAT, were included into this microelimination project. Individuals received their OAT and DAAs under supervision of healthcare workers as DOT in a pharmacy or low-threshold facility. Results: In total, 504 HCV RNA-positive PWIDs on OAT (387 men, 76.8%; median age: 38 years [IQR 33-45], HIV: 4.6%; hepatitis B: 1.4%) were included into this study. Two thirds reported ongoing intravenous drug use (IDU) and half of them had no permanent housing. Only 41 (8.1%) were lost to follow-up and two (0.4%) died of reasons unrelated to DAA toxicity. Overall, 90.7% of PWIDs achieved sustained virological response 12 weeks after treatment (SVR12) (95% CI: 88.1-93.2%). By excluding those lost to follow-up and hose who had died of causes unrelated to DAAs, the SVR12 rate was 99.1% (95% CI: 98.3-100.0%; modified intention-to-treat analysis). Four PWIDs (0.9%) experienced treatment failure. Over a median follow-up of 24 weeks (IQR 12-39), 27 reinfections (5.9%) were observed in individuals with the highest IDU rates (81.2%). Importantly, even though some were lost to follow-up, all completed their DAA treatment. By using DOT, adherence to DAAs was excellent with only a total of 86 missed doses (0.3% of 25,224 doses). Conclusions: In this difficult-to-treat population of PWIDs with high rates of IDU , coupling DAA treatment to OAT in a DOT setting resulted in high SVR12 rates equivalent to conventional treatment settings in non-PWID populations.

Directly observed therapy of chronic hepatitis C with ledipasvir/sofosbuvir in people who inject drugs at risk of nonadherence to direct-acting antivirals.

An important subgroup of people who inject drugs (PWID) receiving opioid agonist therapy (OAT) cannot be treated in the setting of a hepatology centre and would not regularly ingest their medication when handed to them for self-administration. Our hypothesis was that chronic hepatitis C in these patients could be ideally managed if modern, interferon-free regimens were administered together with OAT under direct observation of a physician or nurse at a low-threshold facility. In this open-label, noninterventional, proof-of-concept study (ClinicalTrials.gov number, NCT02638233), 40 PWID at risk of nonadherence to direct-acting antivirals (DAA) and previously untreated chronic hepatitis C virus genotype 1 infection without cirrhosis were treated with ledipasvir/sofosbuvir for 8 weeks. Patients received antiviral treatment together with OAT under direct observation of a physician or nurse at a low-threshold facility. By following the concept of directly observed therapy, excellent adherence to antiviral therapy was achieved as follows: only 0.16% (95% CI: 0.03-0.47) of scheduled dates for ingestion of the antiviral therapy in combination with OAT were missed by the 40 patients. The rate of sustained virological response 12 weeks after end of therapy was 100% (95% CI: 91.2-100.0). Between week 12 and week 24 of follow-up reinfections were recorded in 2 of 40 patients (5%). Directly observed therapy of chronic hepatitis C is highly effective in PWID at risk of nonadherence to DAA. By this new concept, a group of difficult-to-treat patients can be cured, who could not have been treated in settings of studies published so far.

Electrochemical flowcell for in-situ investigations by soft x-ray absorption and emission spectroscopy.

A new liquid flow-cell designed for electronic structure investigations at the liquid-solid interface by soft X-ray absorption and emission spectroscopy is presented. A thin membrane serves simultaneously as a substrate for the working electrode and solid state samples as well as for separating the liquid from the surrounding vacuum conditions. In combination with counter and reference electrodes this approach allows in-situ studies of electrochemical deposition processes and catalytic reactions at the liquid-solid interface in combination with potentiostatic measurements. As model system in-situ monitoring of the deposition process of Co metal from a 10 mM CoCl2 aqueous solution by X-ray absorption and emission spectroscopy is presented.

The electronic structure of perfluorodecalin studied by soft X-ray spectroscopy and electronic structure calculations.

Fluorine and carbon K absorption and emission spectra of liquid perfluorodecalin are presented and analyzed in terms of density functional calculations-configuration interaction. A comprehensive view of the electronic structure is given, and site-specific intramolecular interactions are investigated in detail. It is found that, while the outer fluorine atoms have excess charge in the ground state, the lowest excitations must be associated with charge transfer towards the inner carbon atoms.

'Deletion rescue' by mitotic 11q uniparental disomy in a family with recurrence of 11q deletion Jacobsen syndrome.

We describe a family with recurrent 11q23-qter deletion Jacobsen syndrome in two affected brothers, with unique mosaic deletion 'rescue' through development of uniparental disomy (UPD) in the mother and one of the brothers. Inheritance studies show that the deleted chromosome is of maternal origin in both boys, and microarray shows a break near the ASAM gene. Parental lymphocyte chromosomes were normal. However, the mother is homozygous in lymphocytes for all loci within the deleted region in her sons, and presumably has UPD for this region. In addition, she is mosaic for the 11q deletion seen in her sons at a level of 20-30% in skin fibroblasts. We hypothesize that one of her #11 chromosomes shows fragility, that breakage at 11q23 occurred with telomeric loss in some cells, but 'rescue' from the deletion occurred in most cells by the development of mitotic UPD. She apparently carries the 11q deletion in her germ line resulting in recurrence of the syndrome. The older son is mosaic for the 11q cell line (70-88%, remainder 46,XY), and segmental UPD11 'rescue' apparently also occurred in his cytogenetically normal cells. This is a novel phenomenon restoring disomy to an individual with a chromosomal deletion.

Genome-wide androgenetic mosaicism.

Individuals with mosaic paternal uniparental disomy (UPD) of apparently all chromosomes have recently been described. They show a 46,XX karyotype, but with a mixture of normal biparental cells and cells entirely of paternal isodisomic origin. We describe an infant who primarily showed signs of Beckwith-Wiedemann syndrome (BWS), but also had other severe and eventually lethal medical problems, notably refractory hypoglycemia. We performed methylation studies for BWS, but incidentally for Angelman syndrome (AS) on leukocytes and in a skin FFPE sample. We also performed chromosome microarray [CNV and single-nucleotide polymorphism (SNP) array] on leukocytes. We found that the patient had hypomethylation consistent with both BWS and AS. Remarkably, this was due to mosaic paternal UPD for chromosomes 11 and 15, respectively. The SNP microarray showed mosaic paternal UPD for all chromosomes. Patients with unusual phenotypes for a typical imprinting disorder should be studied further with assays for imprinted loci on other chromosomes. Chromosomal SNP microarrays are useful in identifying patients with multiple UPDs, sometimes of the whole genome.

Effect of green tea (Camellia sinensis) consumption on the components of metabolic syndrome in elderly.

OBJECTIVE: To evaluate the effect of the consumption of green tea on components of MS in the elderly. DESIGN: Intervention study. SETTING: The sample was selected from the Geriatric Service of Hospital São Lucas of Pontifical Catholic University of Rio Grande do Sul. PARTICIPANTS: 45 elderly with MS were enrolled and allocated into two groups: green tea group (GTG, n= 24), who drank green tea and control group (CG, n= 21) without intervention. INTERVENTION: The GTG received sachets of 1.0 g of green tea, and should drink three cups per day for 60 days and the CG was instructed not to make changes in their lifestyle. MEASUREMENTS: The diagnostic criteria for MS used were the International Diabetes Federation. The lipidic and glycemic profile, and anthropometric measurements were evaluated before and after intervention. RESULTS: There was a statistically significant weight loss only in GTG [71.5±12.6 kg to 70.3±12.6 kg (p<0.001)]. A statistically significant decrease in BMI [-0.5±0.4 kg/m2 in GTG and -0.2±0.6 kg/m2 in CG (P=0.032)] and waist circumference [-2.2±2.0 cm in GTG and - 0.3±1.8 cm in CG (P=0.002)] were observed. The intake of green tea did not change the biochemical parameters. CONCLUSION: The consumption of green tea was effective in inducing weight loss, reducing BMI and waist circumference in the elderly with MS.

Association between interleukin-1 beta polymorphism (+3953) and obesity.

It now appears that obesity is associated with a low-grade inflammation of white adipose tissue resulting from chronic activation of the innate immune system as interleukin-1 beta (IL-1). Previous investigations have described a positive association between IL-1 beta +3953 (C>T) gene polymorphism (rs 1143634) and obesity, suggesting functional effects on fat mass, fat metabolism and body mass. However, it is necessary to determine if these results occur in other populations and if they are influenced by sex and age. Therefore, we performed a case-control study using 880 Caucasian subjects (59.7+/-11.9 years old) from the Brazilian Aging Research Program (non-overweight=283, overweight=334, obese=263) previously investigated in genetic studies, in whom we analyzed the IL-1 beta +3953C/T polymorphism. We observed higher T allele (CT/TT) frequency in non-overweight than overweight and obese groups. The odds ratio showed 1.340 (95% CI: 1.119-1.605) times more chance of the obese group being CC carriers compared to non-overweight group independent of sex and age. This study corroborates the idea that the IL-1 system is linked to the development of obesity.

The polymorphism of the serotonin-2A receptor T102C is associated with age.

Epidemiological investigations suggest that T102C polymorphism of gene 5-HT2A may be associated with mean life span because diseases and behaviors related to this polymorphism, such as schizophrenia, suicide, aggression, and addiction, may potentially shorten mean life span. A sample of 687 individuals without previous neuropsychiatric disease was genotyped and separated into 3 groups according to their gender and age: 14-45 years old, 46-64 years old and 65-100 years old. Molecular genotyping was performed using the technique of polymerase chain reaction followed by restriction fragment length polymorphism using HpaII restriction enzyme. 5-HT2A genotype frequencies were: TT = 21.5% (148), CC = 16.6% (114) and TC = 61.9% (425) and allele frequencies were T = 52.5% and C = 46.5%. Significant differences were found between mean age of the TT genotype carriers (60.27 +/- 12.60 years) and TC genotype carriers (56.80 +/- 13.18 years) of T102C polymorphism of gene 5-HT2A (P = 0.026) as well as the age groups (P = 0.012). Carriers of genotype TT were older than the other two genotypes, whereas carriers of genotype CC had an intermediate age compared with TT and CC subjects. The present results demonstrate an association between T102C polymorphism of gene 5-HT2A and age. Our results suggest that T102C polymorphism of gene 5-HT2A is associated with mean life span, and thus this gene becomes a possible candidate for the group of adaptive genes to meat consumption proposed in the literature. Further studies should be conducted in order to elucidate this association.

The polymorphism of the serotonin-2A receptor T102C is associated with age

Epidemiological investigations suggest that T102C polymorphism of gene 5-HT2A may be associated with mean life span because diseases and behaviors related to this polymorphism, such as schizophrenia, suicide, aggression, and addiction, may potentially shorten mean life span. A sample of 687 individuals without previous neuropsychiatric disease was genotyped and separated into 3 groups according to their gender and age: 14-45 years old, 46-64 years old and 65-100 years old. Molecular genotyping was performed using the technique of polymerase chain reaction followed by restriction fragment length polymorphism using HpaII restriction enzyme. 5-HT2A genotype frequencies were: TT = 21.5 percent (148), CC = 16.6 percent (114) and TC = 61.9 percent (425) and allele frequencies were T = 52.5 percent and C = 46.5 percent. Significant differences were found between mean age of the TT genotype carriers (60.27 ± 12.60 years) and TC genotype carriers (56.80 ± 13.18 years) of T102C polymorphism of gene 5-HT2A (P = 0.026) as well as the age groups (P = 0.012). Carriers of genotype TT were older than the other two genotypes, whereas carriers of genotype CC had an intermediate age compared with TT and CC subjects. The present results demonstrate an association between T102C polymorphism of gene 5-HT2A and age. Our results suggest that T102C polymorphism of gene 5-HT2A is associated with mean life span, and thus this gene becomes a possible candidate for the group of adaptive genes to meat consumption proposed in the literature. Further studies should be conducted in order to elucidate this association.

Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence?

The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A) has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 ± 6.35 years (60-100 years), with 16.9 percent males and 83.1 percent females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78 percent, the CT genotype frequency was 55.24 percent and the TT genotype frequency was 22.98 percent. We found an independent significant association between the TT genotype (35.7 percent) and urinary incontinence (OR = 2.06, 95 percentCI = 1.16-3.65). Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.

Is there an association between T102C polymorphism of the serotonin receptor 2A gene and urinary incontinence?

The regulation of bladder function is influenced by central serotonergic modulation. Several genetic polymorphisms related to serotonin control have been described in the literature. T102C polymorphism of the serotonin receptor 2A gene (5-HT2A) has been shown to be associated with certain diseases such as non-fatal acute myocardial infarction, essential hypertension, and alcoholism. In the present study, we examined the association between 5-HT2A gene polymorphism and urinary incontinence in the elderly. A case-control study was performed in 298 elderly community dwellers enrolled in the Gravataí-GENESIS Project, Brazil, which studies gene-environmental interactions in aging and age-related diseases. Clinical, physical, biochemical, and molecular analyses were performed on volunteers. 5-HT2A genotyping was determined by PCR-RFLP techniques using the HpaII restriction enzyme. The subjects had a mean age of 68.05 +/- 6.35 years (60-100 years), with 16.9% males and 83.1% females. The C allele frequency was 0.494 and the T allele frequency was 0.506. The CC genotype frequency was 21.78%, the CT genotype frequency was 55.24% and the TT genotype frequency was 22.98%. We found an independent significant association between the TT genotype (35.7%) and urinary incontinence (OR = 2.06, 95%CI = 1.16-3.65). Additionally, urinary incontinence was associated with functional dependence and systolic hypertension. The results suggest a possible genetic influence on urinary incontinence involving the serotonergic pathway. Further investigations including urodynamic evaluation will be performed to better explain our findings.

Association among oxidized LDL levels, MnSOD, apolipoprotein E polymorphisms, and cardiovascular risk factors in a south Brazilian region population

Oxidized LDL (ox-LDL) is involved in the initiation and progression of atherosclerosis. Many factors can affect the LDL oxidation such as oxidative stress. The present study tested whether ox-LDL levels would be associated with apolipoprotein E (APOE), manganese superoxide dismutase (MnSOD) Ala16Val polymorphisms, and classic cardiovascular risk factors. ox-LDL levels were measured by thiobarbituric acid-reactive substances and both polymorphisms were determined by polymerase chain reaction/restriction fragment length polymorphism in a sample of 252 subjects (70 men, 182 women, mean age, 54-85 years). Subjects with ox-LDL >or=0.5 nmol/mg apoprotein were considered the high level group (HLG, N = 82) and subjects with ox-LDL <0.5 nmol/mg apoprotein were considered the expected level group (ELG, N = 170). Classic risk factors were also evaluated. The results showed that diabetes mellitus was more prevalent in HLG, whereas other cardiovascular risk factors were similar between groups. The APOE genotype frequencies did not differ between HLG and ELG subjects. However, AA genotype from MnSOD polymorphism was more frequent in ELG (chi(2) = 8.48; P = 0.014). AV and VV subjects from ELG present highest ox-LDL levels (OR = 3.61; CI95% = 1.42-9.17) than AA. Additional analysis did not find gene-gene interactions associated with ox-LDL levels. Multivariate analysis showed that diabetes and the MnSOD polymorphism were independent factors associated with higher ox-LDL levels in HLG. The results suggest that an important framework on modulation of the redox status influenced by genetic polymorphisms could affect the cardiovascular homeostasis.